The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

The Diagnosis: Dermatofibrosarcoma Protuberans

Histopathologic examination showed a dermal tumor composed of spindle cells in a storiform arrangement (Figure 1). Immunohistochemistry demonstrated positive CD34 staining of the tumoral cells (Figure 2). Clinical review, histopathologic examination, and immunohistochemistry confirmed a diagnosis of dermatofibrosarcoma protuberans (DFSP). The patient underwent Mohs micrographic surgery (MMS) with clear margins after 3 stages, followed by repair with a rotation flap. No evidence of recurrence was found at 4-year follow-up.

Dermatofibrosarcoma protuberans is a rare low-grade sarcoma of fibroblast origin with an annual incidence of 0.8 to 5 cases per million individuals.¹ It typically presents in patients aged 30 to 50 years on the trunk, scalp, or proximal extremities as an asymptomatic, flesh-colored, erythematous or brown, indurated plaque or nodule.² Due to its variable presentation, these lesions often may be misdiagnosed as lipomas or epidermoid cysts, preventing proper targeted treatment. Therefore, suspicious enlarging indurated nodules require a lower threshold for biopsy.¹

A definitive diagnosis of DFSP is achieved after a biopsy and histopathologic evaluation. Hematoxylin and eosin staining typically shows diffuse infiltration of the dermis and the subcutaneous fat by densely packed, cytologic, relatively uniform, spindle-shaped tumor cells arranged in a characteristic storiform shape. Tumor cells are spread along the septae of the subcutaneous fatty tissue.³ Immunohistochemistry is characterized by positive CD34 and negative factor XIIIa, with rare exceptions.

The differential diagnosis includes lipoma, epidermoid cyst, plexiform fibrohistiocytic tumor, and malignant peripheral nerve sheath tumor.³ Positive CD34 immunostaining, negative S-100 staining, and a storiform pattern of spindle cells can assist in differentiating DFSP from these possible differential diagnoses; lesions of these other entities are characterized by different pathologic findings. Lipomas are composed of fat tissue, epidermoid cysts have epithelial-lined cysts filled with keratin, plexiform fibrohistiocytic tumors have plexiform rays of fibrous tissue extending into fat with negative CD34 staining, and malignant peripheral nerve sheath tumors have fleshy variegated masses involving the peripheral nerve trunks with partial S-100 staining.^4-7 Additional evaluation to confirm DFSP can be accomplished by analysis of tumor samples by fluorescence in situ hybridization or reverse transcriptase–polymerase chain reaction to detect chromosomal translocations and fusion gene transcripts, as chromosomal translocations may be found in more than 90% of cases.³

Early diagnosis of DFSP is beneficial, as it can help prevent recurrence as well as metastasis. Studies have attempted to document the risk for recurrence as well as metastasis based on characteristic features and treatment strategies of DFSP. In a study of 186 patients, 3 had metastatic disease to the lungs, the most common site of metastasis.⁸ These 3 patients had fibrosarcomatous transformation within DFSP, emphasizing the importance of detailing this finding early in the diagnosis, as it was characterized by a higher degree of cellularity, cytologic atypia, mitotic activity, and negative CD34 immunostaining.⁹ In patients with suspected metastasis, lymph node ultrasonography, chest radiography, and computed tomography may be utilized.³

When treating DFSP, the goal is complete removal of the tumor with clear margins. Mohs micrographic surgery, modified MMS, and wide local excision (WLE) with 2- to 4-cm margins are appropriate treatment options, though MMS is the treatment of choice. A study comparing MMS and WLE demonstrated 3% and 30.8% recurrence rates, respectively.⁸ In MMS, complete margin evaluation on microscopy is performed after each stage to ensure negative surgical margins. The presence of positive surgical margins elicits continued resection until the margins are clear.^10,11

Other treatment modalities may be considered for patients with DFSP. Molecular therapy with imatinib, an oral tyrosine kinase inhibitor targeting platelet-derived growth factor–regulated expression, can be utilized for inoperable tumors; however, additional clinical trials are required to ensure efficacy.³ Surgical removal of the possible remaining tumor is still recommended after molecular therapy. Radiotherapy is an additional method of treatment that may be used for inoperable tumors.³

Dermatofibrosarcoma protuberans is a rare lowgrade sarcoma of fibroblast origin that typically does not metastasize but often has notable subclinical extension and recurrence. Differentiating DFSP from other tumors often may be difficult. A protuberant, flesh-colored, slowgrowing, and asymptomatic lesion often may be confused with lipomas or epidermoid cysts; therefore, biopsies with immunohistostaining for suspicious lesions is required.¹² Mohs micrographic surgery has evolved as the treatment of choice for this tumor, though WLE and new targeted molecular therapies still are considered. Proper diagnosis and treatment of DFSP is paramount in preventing future morbidity.

Field cancerization and subsequent second cancer in squamous cell carcinoma (SCC) patients was significantly associated with cigarette and alcohol use, based on data from more than 300 individuals.

Cigarette and alcohol use are established risk factors for SCCs of the esophagus, head, and neck, Manabu Moto, MD, of Kyoto University and colleagues wrote. “In addition, squamous cell carcinoma and squamous dysplastic epithelium develop multifocally in these organs,” in a phenomenon known as field cancerization, but the interaction of multiple dysplastic epithelium with other factors, notably whether cessation of cigarette and alcohol use would reduce risk of SCC, has not been well studied.

In a study published in Gastro Hep Advances, the researchers identified 331 adults with newly diagnosed superficial esophageal SCC who underwent endoscopic resection, and 1,022 healthy controls. Field cancerization was based on the number of Lugol-voiding lesions (LVLs) per endoscopic view according to three groups: grade A, 0 LVLs; grade B, 1-9; or grade C, at least 10. The primary study outcome was a measure of risk factors for the development of LVLs.

“Multiple LVLs are closely associated with inactive aldehyde dehydrogenase 2 (ALDH2) and field cancerization,” the researchers wrote. Before assessing their human subjects, they used a mouse model to investigate whether alcohol intake and abstinence would affect acetaldehyde-induced DNA damage to the esophageal epithelium among individuals with ALDH2 dysfunction.

The researchers found that DNA damage, measured by acetaldehyde-derived DNA adduct levels (via N²-ethylidene-dG), accumulated with alcohol consumption over time, but decreased with alcohol cessation in the mouse model.

For the human part of the study, participants completed a lifestyle survey at entry, with questions about alcohol consumption history, alcohol flushing response, smoking, consumption of high-temperature foods, and consumption of green and yellow vegetables and fruit. Drinking status was divided into five groups: never/rarely (of less than 1 unit/week), light (1-8.9 units/week), moderate (9-17.9 units/week), heavy (18 or more units/week), and ex-drinker, with 1 unit defined as 22 g of ethanol. Smoking was divided into three groups: never (0 pack-years), light (less than 30 pack-years), and heavy (30 or more pack-years). Patients were given educational materials at study entry about the importance of alcohol and smoking cessation, as well as verbal advice to cease these behaviors.

Participants underwent endoscopic surveillance at 3-month intervals for up to 6 months following endoscopic resection.

Overall, increased alcohol consumption was associated with increased risk in development of LVL across all LVL grades; higher grades of LVLs were positively associated with high-intensity alcohol consumption, smoking, flushing, and high-temperature foods, and negatively associated with eating vegetables and fruit.

The risk of LVL grade progression was most strongly associated with increased alcohol consumption and with reported flushing. “The greatest risk was observed in the patients with flushing reactions who consumed an average of 30 units per week in grade C LVL,” with an odds ratio of 534, compared with healthy controls. “Since flushing reaction is caused by accumulation of acetaldehyde due to ALDH2 deficient, our result also means that acetaldehyde is a strong carcinogen in field cancerization.”

Secondary outcomes included the incidence of second primary esophageal SCC and head/neck SCC; these were significantly more prevalent in patients with grade C LVL (cumulative 5-year incidence of 47.1% for ESCC and 13.3% for head and neck SCC). However, alcohol and smoking cessation significantly reduced the development of second primary esophageal SCC (adjusted hazard ratios, 0.47 for alcohol and 0.49 for smoking).

The study findings were limited by several factors including the lack of randomization to noncessation and cessation groups and the inclusion of cancer patients, but not long-term cancer survivors, the researchers noted.

“We believe that our data will be useful to establish a prevention and surveillance strategy for cancer survivors, because the overall prognosis of esophageal cancer and head and neck cancer is still poor,” with a 5-year survival rate of less than 20%, and the results highlight the need to educate cancer survivors on the value of smoking and alcohol cessation, they added.

The study was supported by the National Cancer Center Research and Development Fund 36 by the Ministry of Health, Labour, and Welfare of Japan. The researchers had no financial conflicts to disclose.

Field cancerization and subsequent second cancer in squamous cell carcinoma (SCC) patients was significantly associated with cigarette and alcohol use, based on data from more than 300 individuals.

Cigarette and alcohol use are established risk factors for SCCs of the esophagus, head, and neck, Manabu Moto, MD, of Kyoto University and colleagues wrote. “In addition, squamous cell carcinoma and squamous dysplastic epithelium develop multifocally in these organs,” in a phenomenon known as field cancerization, but the interaction of multiple dysplastic epithelium with other factors, notably whether cessation of cigarette and alcohol use would reduce risk of SCC, has not been well studied.

In a study published in Gastro Hep Advances, the researchers identified 331 adults with newly diagnosed superficial esophageal SCC who underwent endoscopic resection, and 1,022 healthy controls. Field cancerization was based on the number of Lugol-voiding lesions (LVLs) per endoscopic view according to three groups: grade A, 0 LVLs; grade B, 1-9; or grade C, at least 10. The primary study outcome was a measure of risk factors for the development of LVLs.

“Multiple LVLs are closely associated with inactive aldehyde dehydrogenase 2 (ALDH2) and field cancerization,” the researchers wrote. Before assessing their human subjects, they used a mouse model to investigate whether alcohol intake and abstinence would affect acetaldehyde-induced DNA damage to the esophageal epithelium among individuals with ALDH2 dysfunction.

The researchers found that DNA damage, measured by acetaldehyde-derived DNA adduct levels (via N²-ethylidene-dG), accumulated with alcohol consumption over time, but decreased with alcohol cessation in the mouse model.

For the human part of the study, participants completed a lifestyle survey at entry, with questions about alcohol consumption history, alcohol flushing response, smoking, consumption of high-temperature foods, and consumption of green and yellow vegetables and fruit. Drinking status was divided into five groups: never/rarely (of less than 1 unit/week), light (1-8.9 units/week), moderate (9-17.9 units/week), heavy (18 or more units/week), and ex-drinker, with 1 unit defined as 22 g of ethanol. Smoking was divided into three groups: never (0 pack-years), light (less than 30 pack-years), and heavy (30 or more pack-years). Patients were given educational materials at study entry about the importance of alcohol and smoking cessation, as well as verbal advice to cease these behaviors.

Participants underwent endoscopic surveillance at 3-month intervals for up to 6 months following endoscopic resection.

Overall, increased alcohol consumption was associated with increased risk in development of LVL across all LVL grades; higher grades of LVLs were positively associated with high-intensity alcohol consumption, smoking, flushing, and high-temperature foods, and negatively associated with eating vegetables and fruit.

The risk of LVL grade progression was most strongly associated with increased alcohol consumption and with reported flushing. “The greatest risk was observed in the patients with flushing reactions who consumed an average of 30 units per week in grade C LVL,” with an odds ratio of 534, compared with healthy controls. “Since flushing reaction is caused by accumulation of acetaldehyde due to ALDH2 deficient, our result also means that acetaldehyde is a strong carcinogen in field cancerization.”

Secondary outcomes included the incidence of second primary esophageal SCC and head/neck SCC; these were significantly more prevalent in patients with grade C LVL (cumulative 5-year incidence of 47.1% for ESCC and 13.3% for head and neck SCC). However, alcohol and smoking cessation significantly reduced the development of second primary esophageal SCC (adjusted hazard ratios, 0.47 for alcohol and 0.49 for smoking).

The study findings were limited by several factors including the lack of randomization to noncessation and cessation groups and the inclusion of cancer patients, but not long-term cancer survivors, the researchers noted.

“We believe that our data will be useful to establish a prevention and surveillance strategy for cancer survivors, because the overall prognosis of esophageal cancer and head and neck cancer is still poor,” with a 5-year survival rate of less than 20%, and the results highlight the need to educate cancer survivors on the value of smoking and alcohol cessation, they added.

The study was supported by the National Cancer Center Research and Development Fund 36 by the Ministry of Health, Labour, and Welfare of Japan. The researchers had no financial conflicts to disclose.

Field cancerization and subsequent second cancer in squamous cell carcinoma (SCC) patients was significantly associated with cigarette and alcohol use, based on data from more than 300 individuals.

Cigarette and alcohol use are established risk factors for SCCs of the esophagus, head, and neck, Manabu Moto, MD, of Kyoto University and colleagues wrote. “In addition, squamous cell carcinoma and squamous dysplastic epithelium develop multifocally in these organs,” in a phenomenon known as field cancerization, but the interaction of multiple dysplastic epithelium with other factors, notably whether cessation of cigarette and alcohol use would reduce risk of SCC, has not been well studied.

In a study published in Gastro Hep Advances, the researchers identified 331 adults with newly diagnosed superficial esophageal SCC who underwent endoscopic resection, and 1,022 healthy controls. Field cancerization was based on the number of Lugol-voiding lesions (LVLs) per endoscopic view according to three groups: grade A, 0 LVLs; grade B, 1-9; or grade C, at least 10. The primary study outcome was a measure of risk factors for the development of LVLs.

“Multiple LVLs are closely associated with inactive aldehyde dehydrogenase 2 (ALDH2) and field cancerization,” the researchers wrote. Before assessing their human subjects, they used a mouse model to investigate whether alcohol intake and abstinence would affect acetaldehyde-induced DNA damage to the esophageal epithelium among individuals with ALDH2 dysfunction.

The researchers found that DNA damage, measured by acetaldehyde-derived DNA adduct levels (via N²-ethylidene-dG), accumulated with alcohol consumption over time, but decreased with alcohol cessation in the mouse model.

For the human part of the study, participants completed a lifestyle survey at entry, with questions about alcohol consumption history, alcohol flushing response, smoking, consumption of high-temperature foods, and consumption of green and yellow vegetables and fruit. Drinking status was divided into five groups: never/rarely (of less than 1 unit/week), light (1-8.9 units/week), moderate (9-17.9 units/week), heavy (18 or more units/week), and ex-drinker, with 1 unit defined as 22 g of ethanol. Smoking was divided into three groups: never (0 pack-years), light (less than 30 pack-years), and heavy (30 or more pack-years). Patients were given educational materials at study entry about the importance of alcohol and smoking cessation, as well as verbal advice to cease these behaviors.

Participants underwent endoscopic surveillance at 3-month intervals for up to 6 months following endoscopic resection.

Overall, increased alcohol consumption was associated with increased risk in development of LVL across all LVL grades; higher grades of LVLs were positively associated with high-intensity alcohol consumption, smoking, flushing, and high-temperature foods, and negatively associated with eating vegetables and fruit.

The risk of LVL grade progression was most strongly associated with increased alcohol consumption and with reported flushing. “The greatest risk was observed in the patients with flushing reactions who consumed an average of 30 units per week in grade C LVL,” with an odds ratio of 534, compared with healthy controls. “Since flushing reaction is caused by accumulation of acetaldehyde due to ALDH2 deficient, our result also means that acetaldehyde is a strong carcinogen in field cancerization.”

Secondary outcomes included the incidence of second primary esophageal SCC and head/neck SCC; these were significantly more prevalent in patients with grade C LVL (cumulative 5-year incidence of 47.1% for ESCC and 13.3% for head and neck SCC). However, alcohol and smoking cessation significantly reduced the development of second primary esophageal SCC (adjusted hazard ratios, 0.47 for alcohol and 0.49 for smoking).

The study findings were limited by several factors including the lack of randomization to noncessation and cessation groups and the inclusion of cancer patients, but not long-term cancer survivors, the researchers noted.

“We believe that our data will be useful to establish a prevention and surveillance strategy for cancer survivors, because the overall prognosis of esophageal cancer and head and neck cancer is still poor,” with a 5-year survival rate of less than 20%, and the results highlight the need to educate cancer survivors on the value of smoking and alcohol cessation, they added.

The study was supported by the National Cancer Center Research and Development Fund 36 by the Ministry of Health, Labour, and Welfare of Japan. The researchers had no financial conflicts to disclose.

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Pink, elevated, granulomatous, indurated plaques on the face, including the nasal alae, of a 52-year-old woman with a darker skin tone.

B Orange and pink, elevated, granulomatous, indurated plaques on the face of a 55-year-old woman with a lighter skin tone.

Sarcoidosis is a granulomatous disease that may affect the skin in addition to multiple body organ systems, including the lungs. Bilateral hilar adenopathy on a chest radiograph is the most common finding. Sarcoidosis also has a variety of cutaneous manifestations. Early diagnosis is vital, as patients with with sarcoidosis and pulmonary fibrosis have a shortened life span compared to the overall population.¹ With a growing skin of color population, it is important to recognize sarcoidosis as soon as possible.²

Epidemiology

People of African descent have the highest sarcoidosis prevalence in the United States.³ In the United States, the incidence of sarcoidosis in Black individuals peaks in the fourth decade of life. A 5-year study in a US health maintenance organization found that the age-adjusted annual incidence was 10.9 per 100,000 cases among Whites and 35.5 per 100,000 cases among Blacks.⁴

Key clinical features in people with darker skin tones:

• Papules are seen in sarcoidosis, primarily on the face, and may start as orange hued or yellow-brown and then become brown-red or pink to violaceous before involuting into faint macules.^5-7

• When round or oval sarcoid plaques appear, they often are more erythematous. In skin of color, plaques may become hypopigmented.⁸

• Erythema nodosum, the most common nonspecific cutaneous lesion seen in sarcoidosis, is less commonly seen in those of African and Asian descent.^9-11 This is in contrast to distinctive forms of specific sarcoid skin lesions such as lupus pernio and scar sarcoidosis, as well as papules and plaques and minor forms of specific sarcoid skin lesions including subcutaneous nodules; hypopigmented macules; psoriasiform lesions; and ulcerative, localized erythrodermic, ichthyosiform, scalp, and nail lesions.

• Lupus pernio is a cutaneous manifestation of sarcoidosis that appears on the face. It looks similar to lupus erythematosus and occurs most commonly in women of African descent.^8,12

• Hypopigmented lesions are more common in those with darker skin tones.⁹

• Ulcerative lesions are more common in those of African descent and women.¹³

• Scalp sarcoidosis is more common in patients of African descent.¹⁴

• Sarcoidosis may develop at sites of trauma, such as scars and tattoos.^15-17

Worth noting

The cutaneous lesions seen in sarcoidosis may be emotionally devastating and disfiguring. Due to the variety of clinical manifestations, sarcoidosis may be misdiagnosed, leading to delays in treatment.¹⁸

Health disparity highlight

Patients older than 40 years presenting with sarcoidosis and those of African descent have a worse prognosis.¹⁹ Despite adjusting for race, ethnic group, age, and sex, patients with low income and financial barriers present with more severe sarcoidosis.²⁰

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Pink, elevated, granulomatous, indurated plaques on the face, including the nasal alae, of a 52-year-old woman with a darker skin tone.

B Orange and pink, elevated, granulomatous, indurated plaques on the face of a 55-year-old woman with a lighter skin tone.

Sarcoidosis is a granulomatous disease that may affect the skin in addition to multiple body organ systems, including the lungs. Bilateral hilar adenopathy on a chest radiograph is the most common finding. Sarcoidosis also has a variety of cutaneous manifestations. Early diagnosis is vital, as patients with with sarcoidosis and pulmonary fibrosis have a shortened life span compared to the overall population.¹ With a growing skin of color population, it is important to recognize sarcoidosis as soon as possible.²

Epidemiology

People of African descent have the highest sarcoidosis prevalence in the United States.³ In the United States, the incidence of sarcoidosis in Black individuals peaks in the fourth decade of life. A 5-year study in a US health maintenance organization found that the age-adjusted annual incidence was 10.9 per 100,000 cases among Whites and 35.5 per 100,000 cases among Blacks.⁴

Key clinical features in people with darker skin tones:

• Papules are seen in sarcoidosis, primarily on the face, and may start as orange hued or yellow-brown and then become brown-red or pink to violaceous before involuting into faint macules.^5-7

• When round or oval sarcoid plaques appear, they often are more erythematous. In skin of color, plaques may become hypopigmented.⁸

• Erythema nodosum, the most common nonspecific cutaneous lesion seen in sarcoidosis, is less commonly seen in those of African and Asian descent.^9-11 This is in contrast to distinctive forms of specific sarcoid skin lesions such as lupus pernio and scar sarcoidosis, as well as papules and plaques and minor forms of specific sarcoid skin lesions including subcutaneous nodules; hypopigmented macules; psoriasiform lesions; and ulcerative, localized erythrodermic, ichthyosiform, scalp, and nail lesions.

• Lupus pernio is a cutaneous manifestation of sarcoidosis that appears on the face. It looks similar to lupus erythematosus and occurs most commonly in women of African descent.^8,12

• Hypopigmented lesions are more common in those with darker skin tones.⁹

• Ulcerative lesions are more common in those of African descent and women.¹³

• Scalp sarcoidosis is more common in patients of African descent.¹⁴

• Sarcoidosis may develop at sites of trauma, such as scars and tattoos.^15-17

Worth noting

The cutaneous lesions seen in sarcoidosis may be emotionally devastating and disfiguring. Due to the variety of clinical manifestations, sarcoidosis may be misdiagnosed, leading to delays in treatment.¹⁸

Health disparity highlight

Patients older than 40 years presenting with sarcoidosis and those of African descent have a worse prognosis.¹⁹ Despite adjusting for race, ethnic group, age, and sex, patients with low income and financial barriers present with more severe sarcoidosis.²⁰

Photographs courtesy of Richard P. Usatine, MD.

THE COMPARISON

A Pink, elevated, granulomatous, indurated plaques on the face, including the nasal alae, of a 52-year-old woman with a darker skin tone.

B Orange and pink, elevated, granulomatous, indurated plaques on the face of a 55-year-old woman with a lighter skin tone.

Sarcoidosis is a granulomatous disease that may affect the skin in addition to multiple body organ systems, including the lungs. Bilateral hilar adenopathy on a chest radiograph is the most common finding. Sarcoidosis also has a variety of cutaneous manifestations. Early diagnosis is vital, as patients with with sarcoidosis and pulmonary fibrosis have a shortened life span compared to the overall population.¹ With a growing skin of color population, it is important to recognize sarcoidosis as soon as possible.²

Epidemiology

People of African descent have the highest sarcoidosis prevalence in the United States.³ In the United States, the incidence of sarcoidosis in Black individuals peaks in the fourth decade of life. A 5-year study in a US health maintenance organization found that the age-adjusted annual incidence was 10.9 per 100,000 cases among Whites and 35.5 per 100,000 cases among Blacks.⁴

Key clinical features in people with darker skin tones:

• Papules are seen in sarcoidosis, primarily on the face, and may start as orange hued or yellow-brown and then become brown-red or pink to violaceous before involuting into faint macules.^5-7

• When round or oval sarcoid plaques appear, they often are more erythematous. In skin of color, plaques may become hypopigmented.⁸

• Erythema nodosum, the most common nonspecific cutaneous lesion seen in sarcoidosis, is less commonly seen in those of African and Asian descent.^9-11 This is in contrast to distinctive forms of specific sarcoid skin lesions such as lupus pernio and scar sarcoidosis, as well as papules and plaques and minor forms of specific sarcoid skin lesions including subcutaneous nodules; hypopigmented macules; psoriasiform lesions; and ulcerative, localized erythrodermic, ichthyosiform, scalp, and nail lesions.

• Lupus pernio is a cutaneous manifestation of sarcoidosis that appears on the face. It looks similar to lupus erythematosus and occurs most commonly in women of African descent.^8,12

• Hypopigmented lesions are more common in those with darker skin tones.⁹

• Ulcerative lesions are more common in those of African descent and women.¹³

• Scalp sarcoidosis is more common in patients of African descent.¹⁴

• Sarcoidosis may develop at sites of trauma, such as scars and tattoos.^15-17

Worth noting

The cutaneous lesions seen in sarcoidosis may be emotionally devastating and disfiguring. Due to the variety of clinical manifestations, sarcoidosis may be misdiagnosed, leading to delays in treatment.¹⁸

Health disparity highlight

Patients older than 40 years presenting with sarcoidosis and those of African descent have a worse prognosis.¹⁹ Despite adjusting for race, ethnic group, age, and sex, patients with low income and financial barriers present with more severe sarcoidosis.²⁰

In the first part of this 2-part series (Cutis. 2021;108:271-275), we discussed topical medicament allergic contact dermatitis (ACD) from acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations. In part 2 of this series, we focus on topical corticosteroids, immunomodulators, and anesthetics.

Corticosteroids

Given their anti-inflammatory and immune-modulating effects, topical corticosteroids are utilized for the treatment of contact dermatitis and yet also are frequent culprits of ACD. The North American Contact Dermatitis Group (NACDG) demonstrated a 4% frequency of positive patch tests to at least one corticosteroid from 2007 to 2014; the relevant allergens were tixocortol pivalate (TP)(2.3%), budesonide (0.9%), hydrocortisone-17-butyrate (0.4%), clobetasol-17-propionate (0.3%), and desoximetasone (0.2%).¹ Corticosteroid contact allergy can be difficult to recognize and may present as a flare of the underlying condition being treated. Clinically, these rashes may demonstrate an edge effect, characterized by pronounced dermatitis adjacent to and surrounding the treatment area due to concentrated anti-inflammatory effects in the center.

Traditionally, corticosteroids are divided into 4 basic structural groups—classes A, B, C, and D—based on the Coopman et al² classification (Table). The class D corticosteroids were further subdivided into classes D1, defined by C16-methyl substitution and halogenation of the B ring, and D2, which lacks the aforementioned substitutions.⁴ However, more recently Baeck et al⁵ simplified this classification into 3 main groups of steroids based on molecular modeling in combination with patch test results. Group 1 combines the nonmethylated and (mostly) nonhalogenated class A and D2 molecules plus budesonide; group 2 accounts for some halogenated class B molecules with the C16, C17 cis ketal or diol structure; and group 3 includes halogenated and C16-methylated molecules from classes C and D1.⁴ For the purposes of this review, discussion of classes A through D refers to the Coopman et al² classification, and groups 1 through 3 refers to Baeck et al.⁵

Tixocortol pivalate is used as a surrogate marker for hydrocortisone allergy and other class A corticosteroids and is part of the group 1 steroid classification. Interestingly, patients with TP-positive patch tests may not exhibit signs or symptoms of ACD from the use of hydrocortisone products. Repeat open application testing (ROAT) or provocative use testing may elicit a positive response in these patients, especially with the use of hydrocortisone cream (vs ointment), likely due to greater transepidermal penetration.⁶ There is little consensus on the optimal concentration of TP for patch testing. Although TP 1% often is recommended, studies have shown mixed findings of notable differences between high (1% petrolatum) and low (0.1% petrolatum) concentrations of TP.^7,8

Budesonide also is part of group 1 and is a marker for contact allergy to class B corticosteroids, such as triamcinolone and fluocinonide. Cross-reactions between budesonide and other corticosteroids traditionally classified as group B may be explained by structural similarities, whereas cross-reactions with certain class D corticosteroids, such as hydrocortisone-17-butyrate, may be better explained by the diastereomer composition of budesonide.^9,10 In a European study, budesonide 0.01% and TP 0.1% included in the European Baseline Series detected 85% (23/27) of cases of corticosteroid allergies.¹¹ Use of inhaled budesonide can provoke recall dermatitis and therefore should be avoided in allergic patients.¹²

Testing for ACD to topical steroids is complex, as the potent anti-inflammatory properties of these medications can complicate results. Selecting the appropriate test, vehicle, and concentration can help avoid false negatives. Although intradermal testing previously was thought to be superior to patch testing in detecting topical corticosteroid contact allergy, newer data have demonstrated strong concordance between the two methods.^13,14 The risk for skin atrophy, particularly with the use of suspensions, limits the use of intradermal testing.¹⁴ An ethanol vehicle is recommended for patch testing, except when testing with TP or budesonide when petrolatum provides greater corticosteroid stability.^14-16 An irritant pattern or a rim effect on patch testing often is considered positive when testing corticosteroids, as the effect of the steroid itself can diminish a positive reaction. As a result, 0.1% dilutions sometimes are favored over 1% test concentrations.^14,15,17 Late readings (>7 days) may be necessary to detect positive reactions in both adults and children.^18,19

The authors (M.R., A.R.A.) find these varied classifications of steroids daunting (and somewhat confusing!). In general, when ACD to topical steroids is suspected, in addition to standard patch testing with a corticosteroid series, ROAT of the suspected steroid may be necessary, as the rules of steroid classification may not be reproducible in the real world. For patients with only corticosteroid allergy, calcineurin inhibitors are a safe alternative.

Immunomodulators

Calcipotriol is a vitamin D analogue commonly used to treat psoriasis. Although it is a well-known irritant, ACD to topical calcipotriol rarely has been reported.^20-23 Topical calcipotriol does not seem to cross-react with other vitamin D analogues, including tacalcitol and calcitriol.^21,24 Based on the literature and the nonirritant reactive thresholds described by Fullerton et al,²⁵ recommended patch test concentrations of calcipotriol in isopropanol are 2 to 10 µg/mL. Given its immunomodulating effects, calcipotriol may suppress contact hypersensitization from other allergens, similar to the effects seen with UV radiation.²⁶

Calcineurin inhibitors act on the nuclear factor of activated T cells signaling pathway, resulting in downstream suppression of proinflammatory cytokines. Contact allergy to these topical medications is rare and mainly has involved pimecrolimus.^27-30 In one case, a patient with a previously documented topical tacrolimus contact allergy demonstrated cross-reactivity with pimecrolimus on a double-blinded, right-vs-left ROAT, as well as by patch testing with pimecrolimus cream 1%, which was only weakly positive (+).²⁷ Patch test concentrations of 2.5% or higher may be required to elicit positive reactions to tacrolimus, as shown in one case where this was attributed to high molecular weight and poor extrafacial skin absorption of tacrolimus.³⁰ In an unusual case, a patient reacted positively to patch testing and ROAT using pimecrolimus cream 1% but not pimecrolimus 1% to 5% in petrolatum or alcohol nor the individual excipients, illustrating the importance of testing with both active and inactive ingredients.²⁹

Anesthetics

Local anesthetics can be separated into 2 main groups—amides and esters—based on their chemical structures. From 2001 to 2004, the NACDG patch tested 10,061 patients and found 344 (3.4%) with a positive reaction to at least one topical anesthetic.³¹ We will discuss some of the allergic cutaneous reactions associated with topical benzocaine (an ester) and lidocaine and prilocaine (amides).

According to the NACDG, the estimated prevalence of topical benzocaine allergy from 2001 to 2018 was roughly 3%.³² Allergic contact dermatitis has been reported in patients who used topical benzocaine to treat localized pain disorders, including herpes zoster and dental pain.^33,34 Benzocaine may be used in the anogenital region in the form of antihemorrhoidal creams and in condoms and is a considerably more common allergen in those with anogenital dermatitis compared to those without.^35-38 Although cross-reactions within the same anesthetic group are common, clinicians also should be aware of the potential for concomitant sensitivity between unrelated local anesthetics.^39-41

From 2001 to 2018, the prevalence of ACD to topical lidocaine was estimated to be 7.9%, according to the NACDG.³² A topical anesthetic containing both lidocaine and prilocaine often is used preprocedurally and can be a source of ACD. Interestingly, several cases of ACD to combination lidocaine/prilocaine cream demonstrated positive patch tests to prilocaine but not lidocaine, despite their structural similarities.^42-44 One case report described simultaneous positive reactions to both prilocaine 5% and lidocaine 1%.⁴⁵

There are a few key points to consider when working up contact allergy to local anesthetics. Patients who develop positive patch test reactions to a local anesthetic should undergo further testing to better understand alternatives and future use. As previously mentioned, ACD to one anesthetic does not necessarily preclude the use of other related anesthetics. Intradermal testing may help differentiate immediate and delayed-type allergic reactions to local anesthetics and should therefore follow positive patch tests.⁴⁶ Importantly, a delayed reading (ie, after day 6 or 7) also should be performed as part of intradermal testing. Patients with positive patch tests but negative intradermal test results may be able to tolerate systemic anesthetic use.⁴⁷

Patch Testing for Potential Medicament ACD

In this article, we touched on several topical medications that have nuanced patch testing specifications given their immunomodulating effects. A simplified outline of recommended patch test concentrations is provided in the eTable, and we encourage you to revisit these useful resources as needed. In many cases, referral to a specialized patch test clinic may be necessary. Although they are not reviewed in this article, always consider inactive ingredients such as preservatives, softening agents, and emulsifiers in the setting of medicament dermatitis, as they also may be culprits of ACD.

Final Interpretation

In this 2-part series, we covered ACD to several common topical drugs with a focus on active ingredients as the source of allergy, and yet this is just the tip of the iceberg. Topical medicaments are prevalent in the field of dermatology, and associated cases of ACD have been reported proportionately. Consider ACD when topical medication efficacy plateaus, triggers new-onset dermatitis, or seems to exacerbate an underlying dermatitis.

In the first part of this 2-part series (Cutis. 2021;108:271-275), we discussed topical medicament allergic contact dermatitis (ACD) from acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations. In part 2 of this series, we focus on topical corticosteroids, immunomodulators, and anesthetics.

Corticosteroids

Given their anti-inflammatory and immune-modulating effects, topical corticosteroids are utilized for the treatment of contact dermatitis and yet also are frequent culprits of ACD. The North American Contact Dermatitis Group (NACDG) demonstrated a 4% frequency of positive patch tests to at least one corticosteroid from 2007 to 2014; the relevant allergens were tixocortol pivalate (TP)(2.3%), budesonide (0.9%), hydrocortisone-17-butyrate (0.4%), clobetasol-17-propionate (0.3%), and desoximetasone (0.2%).¹ Corticosteroid contact allergy can be difficult to recognize and may present as a flare of the underlying condition being treated. Clinically, these rashes may demonstrate an edge effect, characterized by pronounced dermatitis adjacent to and surrounding the treatment area due to concentrated anti-inflammatory effects in the center.

Traditionally, corticosteroids are divided into 4 basic structural groups—classes A, B, C, and D—based on the Coopman et al² classification (Table). The class D corticosteroids were further subdivided into classes D1, defined by C16-methyl substitution and halogenation of the B ring, and D2, which lacks the aforementioned substitutions.⁴ However, more recently Baeck et al⁵ simplified this classification into 3 main groups of steroids based on molecular modeling in combination with patch test results. Group 1 combines the nonmethylated and (mostly) nonhalogenated class A and D2 molecules plus budesonide; group 2 accounts for some halogenated class B molecules with the C16, C17 cis ketal or diol structure; and group 3 includes halogenated and C16-methylated molecules from classes C and D1.⁴ For the purposes of this review, discussion of classes A through D refers to the Coopman et al² classification, and groups 1 through 3 refers to Baeck et al.⁵

Tixocortol pivalate is used as a surrogate marker for hydrocortisone allergy and other class A corticosteroids and is part of the group 1 steroid classification. Interestingly, patients with TP-positive patch tests may not exhibit signs or symptoms of ACD from the use of hydrocortisone products. Repeat open application testing (ROAT) or provocative use testing may elicit a positive response in these patients, especially with the use of hydrocortisone cream (vs ointment), likely due to greater transepidermal penetration.⁶ There is little consensus on the optimal concentration of TP for patch testing. Although TP 1% often is recommended, studies have shown mixed findings of notable differences between high (1% petrolatum) and low (0.1% petrolatum) concentrations of TP.^7,8

Budesonide also is part of group 1 and is a marker for contact allergy to class B corticosteroids, such as triamcinolone and fluocinonide. Cross-reactions between budesonide and other corticosteroids traditionally classified as group B may be explained by structural similarities, whereas cross-reactions with certain class D corticosteroids, such as hydrocortisone-17-butyrate, may be better explained by the diastereomer composition of budesonide.^9,10 In a European study, budesonide 0.01% and TP 0.1% included in the European Baseline Series detected 85% (23/27) of cases of corticosteroid allergies.¹¹ Use of inhaled budesonide can provoke recall dermatitis and therefore should be avoided in allergic patients.¹²

Testing for ACD to topical steroids is complex, as the potent anti-inflammatory properties of these medications can complicate results. Selecting the appropriate test, vehicle, and concentration can help avoid false negatives. Although intradermal testing previously was thought to be superior to patch testing in detecting topical corticosteroid contact allergy, newer data have demonstrated strong concordance between the two methods.^13,14 The risk for skin atrophy, particularly with the use of suspensions, limits the use of intradermal testing.¹⁴ An ethanol vehicle is recommended for patch testing, except when testing with TP or budesonide when petrolatum provides greater corticosteroid stability.^14-16 An irritant pattern or a rim effect on patch testing often is considered positive when testing corticosteroids, as the effect of the steroid itself can diminish a positive reaction. As a result, 0.1% dilutions sometimes are favored over 1% test concentrations.^14,15,17 Late readings (>7 days) may be necessary to detect positive reactions in both adults and children.^18,19

The authors (M.R., A.R.A.) find these varied classifications of steroids daunting (and somewhat confusing!). In general, when ACD to topical steroids is suspected, in addition to standard patch testing with a corticosteroid series, ROAT of the suspected steroid may be necessary, as the rules of steroid classification may not be reproducible in the real world. For patients with only corticosteroid allergy, calcineurin inhibitors are a safe alternative.

Immunomodulators

Calcipotriol is a vitamin D analogue commonly used to treat psoriasis. Although it is a well-known irritant, ACD to topical calcipotriol rarely has been reported.^20-23 Topical calcipotriol does not seem to cross-react with other vitamin D analogues, including tacalcitol and calcitriol.^21,24 Based on the literature and the nonirritant reactive thresholds described by Fullerton et al,²⁵ recommended patch test concentrations of calcipotriol in isopropanol are 2 to 10 µg/mL. Given its immunomodulating effects, calcipotriol may suppress contact hypersensitization from other allergens, similar to the effects seen with UV radiation.²⁶

Calcineurin inhibitors act on the nuclear factor of activated T cells signaling pathway, resulting in downstream suppression of proinflammatory cytokines. Contact allergy to these topical medications is rare and mainly has involved pimecrolimus.^27-30 In one case, a patient with a previously documented topical tacrolimus contact allergy demonstrated cross-reactivity with pimecrolimus on a double-blinded, right-vs-left ROAT, as well as by patch testing with pimecrolimus cream 1%, which was only weakly positive (+).²⁷ Patch test concentrations of 2.5% or higher may be required to elicit positive reactions to tacrolimus, as shown in one case where this was attributed to high molecular weight and poor extrafacial skin absorption of tacrolimus.³⁰ In an unusual case, a patient reacted positively to patch testing and ROAT using pimecrolimus cream 1% but not pimecrolimus 1% to 5% in petrolatum or alcohol nor the individual excipients, illustrating the importance of testing with both active and inactive ingredients.²⁹

Anesthetics

Local anesthetics can be separated into 2 main groups—amides and esters—based on their chemical structures. From 2001 to 2004, the NACDG patch tested 10,061 patients and found 344 (3.4%) with a positive reaction to at least one topical anesthetic.³¹ We will discuss some of the allergic cutaneous reactions associated with topical benzocaine (an ester) and lidocaine and prilocaine (amides).

According to the NACDG, the estimated prevalence of topical benzocaine allergy from 2001 to 2018 was roughly 3%.³² Allergic contact dermatitis has been reported in patients who used topical benzocaine to treat localized pain disorders, including herpes zoster and dental pain.^33,34 Benzocaine may be used in the anogenital region in the form of antihemorrhoidal creams and in condoms and is a considerably more common allergen in those with anogenital dermatitis compared to those without.^35-38 Although cross-reactions within the same anesthetic group are common, clinicians also should be aware of the potential for concomitant sensitivity between unrelated local anesthetics.^39-41

From 2001 to 2018, the prevalence of ACD to topical lidocaine was estimated to be 7.9%, according to the NACDG.³² A topical anesthetic containing both lidocaine and prilocaine often is used preprocedurally and can be a source of ACD. Interestingly, several cases of ACD to combination lidocaine/prilocaine cream demonstrated positive patch tests to prilocaine but not lidocaine, despite their structural similarities.^42-44 One case report described simultaneous positive reactions to both prilocaine 5% and lidocaine 1%.⁴⁵

There are a few key points to consider when working up contact allergy to local anesthetics. Patients who develop positive patch test reactions to a local anesthetic should undergo further testing to better understand alternatives and future use. As previously mentioned, ACD to one anesthetic does not necessarily preclude the use of other related anesthetics. Intradermal testing may help differentiate immediate and delayed-type allergic reactions to local anesthetics and should therefore follow positive patch tests.⁴⁶ Importantly, a delayed reading (ie, after day 6 or 7) also should be performed as part of intradermal testing. Patients with positive patch tests but negative intradermal test results may be able to tolerate systemic anesthetic use.⁴⁷

Patch Testing for Potential Medicament ACD

In this article, we touched on several topical medications that have nuanced patch testing specifications given their immunomodulating effects. A simplified outline of recommended patch test concentrations is provided in the eTable, and we encourage you to revisit these useful resources as needed. In many cases, referral to a specialized patch test clinic may be necessary. Although they are not reviewed in this article, always consider inactive ingredients such as preservatives, softening agents, and emulsifiers in the setting of medicament dermatitis, as they also may be culprits of ACD.

Final Interpretation

In this 2-part series, we covered ACD to several common topical drugs with a focus on active ingredients as the source of allergy, and yet this is just the tip of the iceberg. Topical medicaments are prevalent in the field of dermatology, and associated cases of ACD have been reported proportionately. Consider ACD when topical medication efficacy plateaus, triggers new-onset dermatitis, or seems to exacerbate an underlying dermatitis.

In the first part of this 2-part series (Cutis. 2021;108:271-275), we discussed topical medicament allergic contact dermatitis (ACD) from acne and rosacea medications, antimicrobials, antihistamines, and topical pain preparations. In part 2 of this series, we focus on topical corticosteroids, immunomodulators, and anesthetics.

Corticosteroids

Given their anti-inflammatory and immune-modulating effects, topical corticosteroids are utilized for the treatment of contact dermatitis and yet also are frequent culprits of ACD. The North American Contact Dermatitis Group (NACDG) demonstrated a 4% frequency of positive patch tests to at least one corticosteroid from 2007 to 2014; the relevant allergens were tixocortol pivalate (TP)(2.3%), budesonide (0.9%), hydrocortisone-17-butyrate (0.4%), clobetasol-17-propionate (0.3%), and desoximetasone (0.2%).¹ Corticosteroid contact allergy can be difficult to recognize and may present as a flare of the underlying condition being treated. Clinically, these rashes may demonstrate an edge effect, characterized by pronounced dermatitis adjacent to and surrounding the treatment area due to concentrated anti-inflammatory effects in the center.

Traditionally, corticosteroids are divided into 4 basic structural groups—classes A, B, C, and D—based on the Coopman et al² classification (Table). The class D corticosteroids were further subdivided into classes D1, defined by C16-methyl substitution and halogenation of the B ring, and D2, which lacks the aforementioned substitutions.⁴ However, more recently Baeck et al⁵ simplified this classification into 3 main groups of steroids based on molecular modeling in combination with patch test results. Group 1 combines the nonmethylated and (mostly) nonhalogenated class A and D2 molecules plus budesonide; group 2 accounts for some halogenated class B molecules with the C16, C17 cis ketal or diol structure; and group 3 includes halogenated and C16-methylated molecules from classes C and D1.⁴ For the purposes of this review, discussion of classes A through D refers to the Coopman et al² classification, and groups 1 through 3 refers to Baeck et al.⁵

Tixocortol pivalate is used as a surrogate marker for hydrocortisone allergy and other class A corticosteroids and is part of the group 1 steroid classification. Interestingly, patients with TP-positive patch tests may not exhibit signs or symptoms of ACD from the use of hydrocortisone products. Repeat open application testing (ROAT) or provocative use testing may elicit a positive response in these patients, especially with the use of hydrocortisone cream (vs ointment), likely due to greater transepidermal penetration.⁶ There is little consensus on the optimal concentration of TP for patch testing. Although TP 1% often is recommended, studies have shown mixed findings of notable differences between high (1% petrolatum) and low (0.1% petrolatum) concentrations of TP.^7,8

Budesonide also is part of group 1 and is a marker for contact allergy to class B corticosteroids, such as triamcinolone and fluocinonide. Cross-reactions between budesonide and other corticosteroids traditionally classified as group B may be explained by structural similarities, whereas cross-reactions with certain class D corticosteroids, such as hydrocortisone-17-butyrate, may be better explained by the diastereomer composition of budesonide.^9,10 In a European study, budesonide 0.01% and TP 0.1% included in the European Baseline Series detected 85% (23/27) of cases of corticosteroid allergies.¹¹ Use of inhaled budesonide can provoke recall dermatitis and therefore should be avoided in allergic patients.¹²

Testing for ACD to topical steroids is complex, as the potent anti-inflammatory properties of these medications can complicate results. Selecting the appropriate test, vehicle, and concentration can help avoid false negatives. Although intradermal testing previously was thought to be superior to patch testing in detecting topical corticosteroid contact allergy, newer data have demonstrated strong concordance between the two methods.^13,14 The risk for skin atrophy, particularly with the use of suspensions, limits the use of intradermal testing.¹⁴ An ethanol vehicle is recommended for patch testing, except when testing with TP or budesonide when petrolatum provides greater corticosteroid stability.^14-16 An irritant pattern or a rim effect on patch testing often is considered positive when testing corticosteroids, as the effect of the steroid itself can diminish a positive reaction. As a result, 0.1% dilutions sometimes are favored over 1% test concentrations.^14,15,17 Late readings (>7 days) may be necessary to detect positive reactions in both adults and children.^18,19

The authors (M.R., A.R.A.) find these varied classifications of steroids daunting (and somewhat confusing!). In general, when ACD to topical steroids is suspected, in addition to standard patch testing with a corticosteroid series, ROAT of the suspected steroid may be necessary, as the rules of steroid classification may not be reproducible in the real world. For patients with only corticosteroid allergy, calcineurin inhibitors are a safe alternative.

Immunomodulators

Calcipotriol is a vitamin D analogue commonly used to treat psoriasis. Although it is a well-known irritant, ACD to topical calcipotriol rarely has been reported.^20-23 Topical calcipotriol does not seem to cross-react with other vitamin D analogues, including tacalcitol and calcitriol.^21,24 Based on the literature and the nonirritant reactive thresholds described by Fullerton et al,²⁵ recommended patch test concentrations of calcipotriol in isopropanol are 2 to 10 µg/mL. Given its immunomodulating effects, calcipotriol may suppress contact hypersensitization from other allergens, similar to the effects seen with UV radiation.²⁶

Calcineurin inhibitors act on the nuclear factor of activated T cells signaling pathway, resulting in downstream suppression of proinflammatory cytokines. Contact allergy to these topical medications is rare and mainly has involved pimecrolimus.^27-30 In one case, a patient with a previously documented topical tacrolimus contact allergy demonstrated cross-reactivity with pimecrolimus on a double-blinded, right-vs-left ROAT, as well as by patch testing with pimecrolimus cream 1%, which was only weakly positive (+).²⁷ Patch test concentrations of 2.5% or higher may be required to elicit positive reactions to tacrolimus, as shown in one case where this was attributed to high molecular weight and poor extrafacial skin absorption of tacrolimus.³⁰ In an unusual case, a patient reacted positively to patch testing and ROAT using pimecrolimus cream 1% but not pimecrolimus 1% to 5% in petrolatum or alcohol nor the individual excipients, illustrating the importance of testing with both active and inactive ingredients.²⁹

Anesthetics

Local anesthetics can be separated into 2 main groups—amides and esters—based on their chemical structures. From 2001 to 2004, the NACDG patch tested 10,061 patients and found 344 (3.4%) with a positive reaction to at least one topical anesthetic.³¹ We will discuss some of the allergic cutaneous reactions associated with topical benzocaine (an ester) and lidocaine and prilocaine (amides).

According to the NACDG, the estimated prevalence of topical benzocaine allergy from 2001 to 2018 was roughly 3%.³² Allergic contact dermatitis has been reported in patients who used topical benzocaine to treat localized pain disorders, including herpes zoster and dental pain.^33,34 Benzocaine may be used in the anogenital region in the form of antihemorrhoidal creams and in condoms and is a considerably more common allergen in those with anogenital dermatitis compared to those without.^35-38 Although cross-reactions within the same anesthetic group are common, clinicians also should be aware of the potential for concomitant sensitivity between unrelated local anesthetics.^39-41

From 2001 to 2018, the prevalence of ACD to topical lidocaine was estimated to be 7.9%, according to the NACDG.³² A topical anesthetic containing both lidocaine and prilocaine often is used preprocedurally and can be a source of ACD. Interestingly, several cases of ACD to combination lidocaine/prilocaine cream demonstrated positive patch tests to prilocaine but not lidocaine, despite their structural similarities.^42-44 One case report described simultaneous positive reactions to both prilocaine 5% and lidocaine 1%.⁴⁵

There are a few key points to consider when working up contact allergy to local anesthetics. Patients who develop positive patch test reactions to a local anesthetic should undergo further testing to better understand alternatives and future use. As previously mentioned, ACD to one anesthetic does not necessarily preclude the use of other related anesthetics. Intradermal testing may help differentiate immediate and delayed-type allergic reactions to local anesthetics and should therefore follow positive patch tests.⁴⁶ Importantly, a delayed reading (ie, after day 6 or 7) also should be performed as part of intradermal testing. Patients with positive patch tests but negative intradermal test results may be able to tolerate systemic anesthetic use.⁴⁷

Patch Testing for Potential Medicament ACD

In this article, we touched on several topical medications that have nuanced patch testing specifications given their immunomodulating effects. A simplified outline of recommended patch test concentrations is provided in the eTable, and we encourage you to revisit these useful resources as needed. In many cases, referral to a specialized patch test clinic may be necessary. Although they are not reviewed in this article, always consider inactive ingredients such as preservatives, softening agents, and emulsifiers in the setting of medicament dermatitis, as they also may be culprits of ACD.

Final Interpretation

In this 2-part series, we covered ACD to several common topical drugs with a focus on active ingredients as the source of allergy, and yet this is just the tip of the iceberg. Topical medicaments are prevalent in the field of dermatology, and associated cases of ACD have been reported proportionately. Consider ACD when topical medication efficacy plateaus, triggers new-onset dermatitis, or seems to exacerbate an underlying dermatitis.

The buccal fat pad (Bichat fat pad) is a tubular-shaped collection of adipose tissue that occupies a prominent position in the midface. The buccal fat pad has been described as having 3 lobes: an anterior lobe, which is anterior to the masseter muscle; an intermediate lobe between the masseter and buccinator muscles; and a posterior lobe between the temporal masticatory space.¹ There are 4 extensions from the body of the buccal fat pad: the buccal, the sublevator, the melolabial, and the pterygoid. It is the buccal extension and main body that are removed intraorally to achieve midfacial and lower facial contouring, as these support the contours of the cheeks. The deep fat pad within the temporal fossa is a true extension of the buccal fat pad (Figure).² It has a complex relationship to the facial structures, with known variability in the positions of the buccal branch of the facial nerve and the parotid duct.³ The parotid duct travels over, superior to, or through the buccal extension 42%, 32%, and 26% of the time, respectively. The duct travels along the surface of the masseter, then pierces the buccinator to drain into the vestibule of the mouth at the second superior molar tooth. The buccal branch of the facial nerve travels on the surface of the buccal fat pad 73% of the time, whereas 27% of the time it travels deeper through the buccal extension.⁴ A study that used ultrasonography to map the surface anatomy path of the parotid duct in 50 healthy patients showed that the duct was within 1.5 cm of the middle half of a line between the lower border of the tragus and the oral commissure in 93% of individuals.⁵ We describe a technique in which part of the buccal fat pad is removed and the fat is transferred to the temple to achieve aesthetically pleasing facial contouring. We used a vertical line from the lateral canthus as a surface anatomy landmark to determine when the duct emerges from the gland and is most susceptible to injury.

Illustration by Ni-ka Ford, MS. Printed with permission from Mount Sinai Health System (New York, New York).

Operative Technique

Correct instrumentation is important to obtain appropriate anatomic exposure for this procedure. The surgical tray should include 4-0 poliglecaprone 25 suture, bite guards, a needle driver, a hemostat, surgical scissors, toothed forceps, a Beaver surgical handle with #15 blade, a protected diathermy needle, cotton tip applicators, and gauze.

Fat Harvest—With the patient supine, bite blocks are placed, and the buccal fat pad incision line is marked with a surgical marker. A 1-cm line is drawn approximately 4 cm posterior to the oral commissure by the buccal bite marks. The location is verified by balloting externally on the buccal fat pad on the cheek. The incision line is then anesthetized transorally with lidocaine and epinephrine-containing solution. The cheek is retracted laterally with Caldwell-Luc retractors, and a 1-cm incision is made and carried through the mucosa and superficial muscle using the Colorado needle. Scissors are then used to spread the deeper muscle fibers to expose the deeper fascia and fat pads. Metzenbaum scissors are used to gently spread the fat while the surgeon places pressure on the external cheek, manipulating the fat into the wound. Without excess traction, the walnut-sized portion of the fat pad that protrudes is grasped with Debakey forceps, gently teased into the field, clamped at its base with a curved hemostat, and excised. The stump is electrocoagulated with an extendable protected Colorado needle, with care to prevent inadvertent cauterization of the lips. The wound is closed with a single 4-0 poliglecaprone-25 suture.

A 5-cc Luer lock syringe is preloaded with 2 cc of normal saline and attached to another 5-cc Luer lock syringe via a female-female attachment. The excised fat is then placed in a 5-cc Luer lock syringe by removing the plunger. The plunger is then reinstalled, and the fat is injected back and forth approximately 30 times. The fat is centrifuged at 3500 rpm for 3 minutes. The purified fat is then transferred to a 1-cc Luer lock syringe attached to an 18-gauge needle.

Fat Injection—The authors use an 18-gauge needle to perform depot injections into the temporal fossae above the periosteum. This is a relatively safe area of the face to inject, but care must be taken to avoid injury to the superficial temporal artery. Between 1.5 and 3 cc of high-quality fat usually are administered to each temple.

Aftercare Instructions—The patient is instructed to have a soft diet for 24 to 48 hours and can return to work the next day. The patient also is given prophylactic antibiotics with Gram-negative coverage for 7 days (amoxicillin-clavulanate 875 mg/125 mg orally twice daily for 7 days).

Candidates for Buccal Fat Pad Reduction

Buccal fat pad reduction has become an increasingly popular technique for midface and lower face shaping to decrease the appearance of a round face. To achieve an aesthetically pleasing midface, surgeons should consider enhancing zygomatic eminences while emphasizing the border between the zygomatic prominence and cheek hollow.⁶ Selection criteria for buccal fat pad reduction are not well established. One study recommended avoiding the procedure in pregnant or lactating patients, patients with chronic illnesses, patients on blood-thinning agents, and patients younger than 18 years. In addition, this study suggested ensuring the malar fullness is in the anteromedial portion of the face, as posterolateral fullness may be due to masseter hypertrophy.⁶

Complications associated with buccal fat pad reduction include inadvertent damage to surrounding structures, including the buccal branch of the facial nerve and parotid duct. Because the location of the facial nerve in relation to the parotid duct is highly variable, surgeons must be aware of its anatomy to avoid unintentional damage. Hwang et al⁷ reported that the parotid duct and buccal branches of the facial nerves passed through the buccal extension in 26.3% of cadavers. The transbuccal approach is preferred over the sub–superficial muscular aponeurotic system approach largely because it avoids these structures. In addition, blunt dissection may further decrease chances of injury. Although the long-term effects are unknown, there is a potential risk for facial hollowing.³ The use of preprocedure ultrasonography to quantify the buccal fat pad may avoid overresection and enhanced potential for facial hollowing.⁶

Avoidance of Temporal Hollowing

Because the buccal fat pad extends into the temporal space, buccal fat pad reduction may lead to further temporal hollowing, contributing to an aged appearance. The authors’ technique addresses both midface and upper face contouring in one minimally invasive procedure. Temporal hollowing commonly has been corrected with autologous fat grafting from the thigh or abdomen, which leads to an additional scar at the donor site. Our technique relies on autologous adjacent fat transfer from previously removed buccal fat. In addition, compared with the use of hyaluronic acid fillers for temple reflation, fat transfer largely is safe and biocompatible. Major complications of autologous fat transfer to the temples include nodularity or fat clumping, fat necrosis, sensory or motor nerve damage, and edema or ecchymosis.⁴ Also, with time there will be ongoing hollowing of the temples as part of the aging process with soft tissue and bone resorption. Therefore, further volume restoration procedures may be required in the future to address these dynamic changes.

Conclusion

The buccal fat pad has been extensively used to reconstruct oral defects, including oroantral and cranial base defects, owing to its high vascularity.⁶ However, there also is great potential to utilize buccal fat for autologous fat transfer to improve temporal wasting. Further studies are needed to determine optimal technique as well as longer-term safety and efficacy of this procedure.

The buccal fat pad (Bichat fat pad) is a tubular-shaped collection of adipose tissue that occupies a prominent position in the midface. The buccal fat pad has been described as having 3 lobes: an anterior lobe, which is anterior to the masseter muscle; an intermediate lobe between the masseter and buccinator muscles; and a posterior lobe between the temporal masticatory space.¹ There are 4 extensions from the body of the buccal fat pad: the buccal, the sublevator, the melolabial, and the pterygoid. It is the buccal extension and main body that are removed intraorally to achieve midfacial and lower facial contouring, as these support the contours of the cheeks. The deep fat pad within the temporal fossa is a true extension of the buccal fat pad (Figure).² It has a complex relationship to the facial structures, with known variability in the positions of the buccal branch of the facial nerve and the parotid duct.³ The parotid duct travels over, superior to, or through the buccal extension 42%, 32%, and 26% of the time, respectively. The duct travels along the surface of the masseter, then pierces the buccinator to drain into the vestibule of the mouth at the second superior molar tooth. The buccal branch of the facial nerve travels on the surface of the buccal fat pad 73% of the time, whereas 27% of the time it travels deeper through the buccal extension.⁴ A study that used ultrasonography to map the surface anatomy path of the parotid duct in 50 healthy patients showed that the duct was within 1.5 cm of the middle half of a line between the lower border of the tragus and the oral commissure in 93% of individuals.⁵ We describe a technique in which part of the buccal fat pad is removed and the fat is transferred to the temple to achieve aesthetically pleasing facial contouring. We used a vertical line from the lateral canthus as a surface anatomy landmark to determine when the duct emerges from the gland and is most susceptible to injury.

Illustration by Ni-ka Ford, MS. Printed with permission from Mount Sinai Health System (New York, New York).

Operative Technique

Correct instrumentation is important to obtain appropriate anatomic exposure for this procedure. The surgical tray should include 4-0 poliglecaprone 25 suture, bite guards, a needle driver, a hemostat, surgical scissors, toothed forceps, a Beaver surgical handle with #15 blade, a protected diathermy needle, cotton tip applicators, and gauze.

Fat Harvest—With the patient supine, bite blocks are placed, and the buccal fat pad incision line is marked with a surgical marker. A 1-cm line is drawn approximately 4 cm posterior to the oral commissure by the buccal bite marks. The location is verified by balloting externally on the buccal fat pad on the cheek. The incision line is then anesthetized transorally with lidocaine and epinephrine-containing solution. The cheek is retracted laterally with Caldwell-Luc retractors, and a 1-cm incision is made and carried through the mucosa and superficial muscle using the Colorado needle. Scissors are then used to spread the deeper muscle fibers to expose the deeper fascia and fat pads. Metzenbaum scissors are used to gently spread the fat while the surgeon places pressure on the external cheek, manipulating the fat into the wound. Without excess traction, the walnut-sized portion of the fat pad that protrudes is grasped with Debakey forceps, gently teased into the field, clamped at its base with a curved hemostat, and excised. The stump is electrocoagulated with an extendable protected Colorado needle, with care to prevent inadvertent cauterization of the lips. The wound is closed with a single 4-0 poliglecaprone-25 suture.

A 5-cc Luer lock syringe is preloaded with 2 cc of normal saline and attached to another 5-cc Luer lock syringe via a female-female attachment. The excised fat is then placed in a 5-cc Luer lock syringe by removing the plunger. The plunger is then reinstalled, and the fat is injected back and forth approximately 30 times. The fat is centrifuged at 3500 rpm for 3 minutes. The purified fat is then transferred to a 1-cc Luer lock syringe attached to an 18-gauge needle.

Fat Injection—The authors use an 18-gauge needle to perform depot injections into the temporal fossae above the periosteum. This is a relatively safe area of the face to inject, but care must be taken to avoid injury to the superficial temporal artery. Between 1.5 and 3 cc of high-quality fat usually are administered to each temple.

Aftercare Instructions—The patient is instructed to have a soft diet for 24 to 48 hours and can return to work the next day. The patient also is given prophylactic antibiotics with Gram-negative coverage for 7 days (amoxicillin-clavulanate 875 mg/125 mg orally twice daily for 7 days).

Candidates for Buccal Fat Pad Reduction

Buccal fat pad reduction has become an increasingly popular technique for midface and lower face shaping to decrease the appearance of a round face. To achieve an aesthetically pleasing midface, surgeons should consider enhancing zygomatic eminences while emphasizing the border between the zygomatic prominence and cheek hollow.⁶ Selection criteria for buccal fat pad reduction are not well established. One study recommended avoiding the procedure in pregnant or lactating patients, patients with chronic illnesses, patients on blood-thinning agents, and patients younger than 18 years. In addition, this study suggested ensuring the malar fullness is in the anteromedial portion of the face, as posterolateral fullness may be due to masseter hypertrophy.⁶

Complications associated with buccal fat pad reduction include inadvertent damage to surrounding structures, including the buccal branch of the facial nerve and parotid duct. Because the location of the facial nerve in relation to the parotid duct is highly variable, surgeons must be aware of its anatomy to avoid unintentional damage. Hwang et al⁷ reported that the parotid duct and buccal branches of the facial nerves passed through the buccal extension in 26.3% of cadavers. The transbuccal approach is preferred over the sub–superficial muscular aponeurotic system approach largely because it avoids these structures. In addition, blunt dissection may further decrease chances of injury. Although the long-term effects are unknown, there is a potential risk for facial hollowing.³ The use of preprocedure ultrasonography to quantify the buccal fat pad may avoid overresection and enhanced potential for facial hollowing.⁶

Avoidance of Temporal Hollowing

Because the buccal fat pad extends into the temporal space, buccal fat pad reduction may lead to further temporal hollowing, contributing to an aged appearance. The authors’ technique addresses both midface and upper face contouring in one minimally invasive procedure. Temporal hollowing commonly has been corrected with autologous fat grafting from the thigh or abdomen, which leads to an additional scar at the donor site. Our technique relies on autologous adjacent fat transfer from previously removed buccal fat. In addition, compared with the use of hyaluronic acid fillers for temple reflation, fat transfer largely is safe and biocompatible. Major complications of autologous fat transfer to the temples include nodularity or fat clumping, fat necrosis, sensory or motor nerve damage, and edema or ecchymosis.⁴ Also, with time there will be ongoing hollowing of the temples as part of the aging process with soft tissue and bone resorption. Therefore, further volume restoration procedures may be required in the future to address these dynamic changes.

Conclusion

The buccal fat pad has been extensively used to reconstruct oral defects, including oroantral and cranial base defects, owing to its high vascularity.⁶ However, there also is great potential to utilize buccal fat for autologous fat transfer to improve temporal wasting. Further studies are needed to determine optimal technique as well as longer-term safety and efficacy of this procedure.

The buccal fat pad (Bichat fat pad) is a tubular-shaped collection of adipose tissue that occupies a prominent position in the midface. The buccal fat pad has been described as having 3 lobes: an anterior lobe, which is anterior to the masseter muscle; an intermediate lobe between the masseter and buccinator muscles; and a posterior lobe between the temporal masticatory space.¹ There are 4 extensions from the body of the buccal fat pad: the buccal, the sublevator, the melolabial, and the pterygoid. It is the buccal extension and main body that are removed intraorally to achieve midfacial and lower facial contouring, as these support the contours of the cheeks. The deep fat pad within the temporal fossa is a true extension of the buccal fat pad (Figure).² It has a complex relationship to the facial structures, with known variability in the positions of the buccal branch of the facial nerve and the parotid duct.³ The parotid duct travels over, superior to, or through the buccal extension 42%, 32%, and 26% of the time, respectively. The duct travels along the surface of the masseter, then pierces the buccinator to drain into the vestibule of the mouth at the second superior molar tooth. The buccal branch of the facial nerve travels on the surface of the buccal fat pad 73% of the time, whereas 27% of the time it travels deeper through the buccal extension.⁴ A study that used ultrasonography to map the surface anatomy path of the parotid duct in 50 healthy patients showed that the duct was within 1.5 cm of the middle half of a line between the lower border of the tragus and the oral commissure in 93% of individuals.⁵ We describe a technique in which part of the buccal fat pad is removed and the fat is transferred to the temple to achieve aesthetically pleasing facial contouring. We used a vertical line from the lateral canthus as a surface anatomy landmark to determine when the duct emerges from the gland and is most susceptible to injury.

Illustration by Ni-ka Ford, MS. Printed with permission from Mount Sinai Health System (New York, New York).

Operative Technique

Correct instrumentation is important to obtain appropriate anatomic exposure for this procedure. The surgical tray should include 4-0 poliglecaprone 25 suture, bite guards, a needle driver, a hemostat, surgical scissors, toothed forceps, a Beaver surgical handle with #15 blade, a protected diathermy needle, cotton tip applicators, and gauze.

Fat Harvest—With the patient supine, bite blocks are placed, and the buccal fat pad incision line is marked with a surgical marker. A 1-cm line is drawn approximately 4 cm posterior to the oral commissure by the buccal bite marks. The location is verified by balloting externally on the buccal fat pad on the cheek. The incision line is then anesthetized transorally with lidocaine and epinephrine-containing solution. The cheek is retracted laterally with Caldwell-Luc retractors, and a 1-cm incision is made and carried through the mucosa and superficial muscle using the Colorado needle. Scissors are then used to spread the deeper muscle fibers to expose the deeper fascia and fat pads. Metzenbaum scissors are used to gently spread the fat while the surgeon places pressure on the external cheek, manipulating the fat into the wound. Without excess traction, the walnut-sized portion of the fat pad that protrudes is grasped with Debakey forceps, gently teased into the field, clamped at its base with a curved hemostat, and excised. The stump is electrocoagulated with an extendable protected Colorado needle, with care to prevent inadvertent cauterization of the lips. The wound is closed with a single 4-0 poliglecaprone-25 suture.

A 5-cc Luer lock syringe is preloaded with 2 cc of normal saline and attached to another 5-cc Luer lock syringe via a female-female attachment. The excised fat is then placed in a 5-cc Luer lock syringe by removing the plunger. The plunger is then reinstalled, and the fat is injected back and forth approximately 30 times. The fat is centrifuged at 3500 rpm for 3 minutes. The purified fat is then transferred to a 1-cc Luer lock syringe attached to an 18-gauge needle.

Fat Injection—The authors use an 18-gauge needle to perform depot injections into the temporal fossae above the periosteum. This is a relatively safe area of the face to inject, but care must be taken to avoid injury to the superficial temporal artery. Between 1.5 and 3 cc of high-quality fat usually are administered to each temple.

Aftercare Instructions—The patient is instructed to have a soft diet for 24 to 48 hours and can return to work the next day. The patient also is given prophylactic antibiotics with Gram-negative coverage for 7 days (amoxicillin-clavulanate 875 mg/125 mg orally twice daily for 7 days).

Candidates for Buccal Fat Pad Reduction

Buccal fat pad reduction has become an increasingly popular technique for midface and lower face shaping to decrease the appearance of a round face. To achieve an aesthetically pleasing midface, surgeons should consider enhancing zygomatic eminences while emphasizing the border between the zygomatic prominence and cheek hollow.⁶ Selection criteria for buccal fat pad reduction are not well established. One study recommended avoiding the procedure in pregnant or lactating patients, patients with chronic illnesses, patients on blood-thinning agents, and patients younger than 18 years. In addition, this study suggested ensuring the malar fullness is in the anteromedial portion of the face, as posterolateral fullness may be due to masseter hypertrophy.⁶

Complications associated with buccal fat pad reduction include inadvertent damage to surrounding structures, including the buccal branch of the facial nerve and parotid duct. Because the location of the facial nerve in relation to the parotid duct is highly variable, surgeons must be aware of its anatomy to avoid unintentional damage. Hwang et al⁷ reported that the parotid duct and buccal branches of the facial nerves passed through the buccal extension in 26.3% of cadavers. The transbuccal approach is preferred over the sub–superficial muscular aponeurotic system approach largely because it avoids these structures. In addition, blunt dissection may further decrease chances of injury. Although the long-term effects are unknown, there is a potential risk for facial hollowing.³ The use of preprocedure ultrasonography to quantify the buccal fat pad may avoid overresection and enhanced potential for facial hollowing.⁶

Avoidance of Temporal Hollowing

Because the buccal fat pad extends into the temporal space, buccal fat pad reduction may lead to further temporal hollowing, contributing to an aged appearance. The authors’ technique addresses both midface and upper face contouring in one minimally invasive procedure. Temporal hollowing commonly has been corrected with autologous fat grafting from the thigh or abdomen, which leads to an additional scar at the donor site. Our technique relies on autologous adjacent fat transfer from previously removed buccal fat. In addition, compared with the use of hyaluronic acid fillers for temple reflation, fat transfer largely is safe and biocompatible. Major complications of autologous fat transfer to the temples include nodularity or fat clumping, fat necrosis, sensory or motor nerve damage, and edema or ecchymosis.⁴ Also, with time there will be ongoing hollowing of the temples as part of the aging process with soft tissue and bone resorption. Therefore, further volume restoration procedures may be required in the future to address these dynamic changes.

Conclusion

The buccal fat pad has been extensively used to reconstruct oral defects, including oroantral and cranial base defects, owing to its high vascularity.⁶ However, there also is great potential to utilize buccal fat for autologous fat transfer to improve temporal wasting. Further studies are needed to determine optimal technique as well as longer-term safety and efficacy of this procedure.

Consider the following clinical scenarios.

Ellen, a 42-year-old married woman, presents to Dr. H’s office with a recent increase in her migraines. She looks sad and worried.

Dr. H. walks into the room, introduces himself, and immediately opens the electronic record to review her medical history forms. Her migraine episodes have increased from once biweekly to 1 to 2 times weekly; with additional less intense headaches on many other days. She uses both a triptan and an over-the-counter medication to control the pain–she gets a limited number of sumatriptan each month and is beginning to escalate her OTC usage. Dr. H. asks her about the intensity and duration of her headaches, reviews her medication use, and questions her about associated symptoms such as nausea or light and sound sensitivity? Ellen responds with yes and no answers. Dr. H. reviews different medication options, prescribes an older preventative medication and renews her sumatriptan.

In the second scenario, Ellen is in Dr. J’s office. When Dr. J enters the doorway to her office, she introduces herself and is welcoming and seated in a less formal manner. Dr. J is making eye contact with Ellen and not looking at her computer.

Instead of asking her questions that require a yes or no reply, she asks Ellen to walk her through her migraine experiences. She learns that the patient has been under much stress with work, and hears about troubling family issues, and that she is worried about her increased number of headaches and decreased functionality. Dr. J says, let’s talk about options. She tells her the first thing is to optimize acute care in order treat the acute attacks effectively. Simply “taking” a medication is insufficient to know whether a patient is taking that medication optimally. She asks Ellen to take her through her process in treating a migraine.

Ellen, Dr. J surmises, has a penchant for treating any sensation associated with a possible approaching headache with OTCs, which needs to be curtailed. Her use of OTCs could be at medication overuse levels thereby contributing to her headaches. Dr. J explains and shows Ellen a simple headache diary. Dr. J then discusses the future: the two of them will develop a plan to control the migraine frequency for the long term. The plan will include ways to control the stressors in Ellen’s life. Dr. J provides Ellen with names of psychologists with expertise in cognitive behavior therapies and relaxation-based treatments; they can help Ellen manage stressors that could be impacting her headaches. Dr. J communicates that migraine management requires a comprehensive approach that can involve behavioral as well as pharmacological therapies to maximize both headache relief and reduce disability. 

Migraine is a brain disease that can often be fueled by behavioral issues. Psychological stress, sleep problems, mood and anxiety issues can transform migraine from episodic to chronic. The operative word here is can. Patients with migraine who learn to better manage stress, employ simple relaxation strategies, and identify and treat comorbid psychiatric issues may show significant improvement. Migraine treatment can require more than one health care professional asheadache specialists, psychologists, perhaps psychiatrists, and sleep specialists may all be involved

Getting migraine under control often cannot be accomplished in just one visit; it can take time, as medications might need to be added or adjusted, sleep, diet, and physical activity modified along with stressors identified and managed. Helping patients optimize their acute treatment regimen is critical so they get quick relief while limiting overuse. Overuse of either prescription or OTC medications can lead to medication overuse headache (MOH). MOH can increase headache frequency and reduce the effectiveness of some preventive medications as well as other therapies. 

All these steps require good communication strategies by the physician and an understanding of the benefit of comprehensive treatment strategies that include behavioral therapies.

Helping motivation to change

Readiness to change will vary with different patients. Some people will be open to treating stress-related issues in an initial session while others will require many sessions in which the physician gently explores these concerns. It is helpful for the physician to ask open-ended questions, helping patients to “tell their stories.” The clinician needs to actively listen and accurately reflect patient’s thoughts and feelings (“it sounds like you…”) Avoiding overinterpretation and occasionally summarizing ensures clear communication. Both patients and physicians have identified high quality communication in the patient-physician relationship to be a key factor in adherence with acute headache medications.

Anxiety is common in migraine sufferers and predicts long-term migraine persistence. Some individuals with high levels of anxiety may overuse immediate relief medications because of worry about getting a migraine. Many migraineurs have a significant amount of fear about any sensation that may herald a migraine. Consequently, some medicate fear, preemptively. Patients also can fear side effects to new medications, thereby reducing their willingness to change existing therapy for a potentially more effective treatment.

Biological rhythms, sleep and coping skills

Managing migraine also includes managing consistent biological rhythms. The literature has shown that chronobiological issues can be a driver of headache frequency and may also contribute to mood and anxiety disorders. Studies have shown that a simple cognitive-behavioral treatment for insomnia has transformed many migraineurs from chronic migraine to episodic migraine. 

Studies have demonstrated that a combination of optimal medication and cognitive behavioral therapy can be very effective. Behavioral therapies increase self-efficacy, a belief that patients have the requisite skills to manage a complicated disorder like migraine. A few sessions of stress management training combined with preventive medications and maximizing acute care options may have significant added value—reducing migraine frequency and related disability and ensuring better disease-coping mechanisms.

Final notes

Migraine is a biobehavioral disorder and it is important for the clinician to evaluate a diverse set of factors and come up with a comprehensive plan. This is particularly important for the patient with high frequency migraine who exhibits stress-related factors and possible psychiatric comorbidities. There are numerous cognitive behavioral therapies incorporating relaxation strategies and stress management techniques that can be very effective in caring for these complicated patients.   

Consider the following clinical scenarios.

Ellen, a 42-year-old married woman, presents to Dr. H’s office with a recent increase in her migraines. She looks sad and worried.

Dr. H. walks into the room, introduces himself, and immediately opens the electronic record to review her medical history forms. Her migraine episodes have increased from once biweekly to 1 to 2 times weekly; with additional less intense headaches on many other days. She uses both a triptan and an over-the-counter medication to control the pain–she gets a limited number of sumatriptan each month and is beginning to escalate her OTC usage. Dr. H. asks her about the intensity and duration of her headaches, reviews her medication use, and questions her about associated symptoms such as nausea or light and sound sensitivity? Ellen responds with yes and no answers. Dr. H. reviews different medication options, prescribes an older preventative medication and renews her sumatriptan.

In the second scenario, Ellen is in Dr. J’s office. When Dr. J enters the doorway to her office, she introduces herself and is welcoming and seated in a less formal manner. Dr. J is making eye contact with Ellen and not looking at her computer.

Instead of asking her questions that require a yes or no reply, she asks Ellen to walk her through her migraine experiences. She learns that the patient has been under much stress with work, and hears about troubling family issues, and that she is worried about her increased number of headaches and decreased functionality. Dr. J says, let’s talk about options. She tells her the first thing is to optimize acute care in order treat the acute attacks effectively. Simply “taking” a medication is insufficient to know whether a patient is taking that medication optimally. She asks Ellen to take her through her process in treating a migraine.

Ellen, Dr. J surmises, has a penchant for treating any sensation associated with a possible approaching headache with OTCs, which needs to be curtailed. Her use of OTCs could be at medication overuse levels thereby contributing to her headaches. Dr. J explains and shows Ellen a simple headache diary. Dr. J then discusses the future: the two of them will develop a plan to control the migraine frequency for the long term. The plan will include ways to control the stressors in Ellen’s life. Dr. J provides Ellen with names of psychologists with expertise in cognitive behavior therapies and relaxation-based treatments; they can help Ellen manage stressors that could be impacting her headaches. Dr. J communicates that migraine management requires a comprehensive approach that can involve behavioral as well as pharmacological therapies to maximize both headache relief and reduce disability. 

Migraine is a brain disease that can often be fueled by behavioral issues. Psychological stress, sleep problems, mood and anxiety issues can transform migraine from episodic to chronic. The operative word here is can. Patients with migraine who learn to better manage stress, employ simple relaxation strategies, and identify and treat comorbid psychiatric issues may show significant improvement. Migraine treatment can require more than one health care professional asheadache specialists, psychologists, perhaps psychiatrists, and sleep specialists may all be involved

Getting migraine under control often cannot be accomplished in just one visit; it can take time, as medications might need to be added or adjusted, sleep, diet, and physical activity modified along with stressors identified and managed. Helping patients optimize their acute treatment regimen is critical so they get quick relief while limiting overuse. Overuse of either prescription or OTC medications can lead to medication overuse headache (MOH). MOH can increase headache frequency and reduce the effectiveness of some preventive medications as well as other therapies. 

All these steps require good communication strategies by the physician and an understanding of the benefit of comprehensive treatment strategies that include behavioral therapies.

Helping motivation to change

Readiness to change will vary with different patients. Some people will be open to treating stress-related issues in an initial session while others will require many sessions in which the physician gently explores these concerns. It is helpful for the physician to ask open-ended questions, helping patients to “tell their stories.” The clinician needs to actively listen and accurately reflect patient’s thoughts and feelings (“it sounds like you…”) Avoiding overinterpretation and occasionally summarizing ensures clear communication. Both patients and physicians have identified high quality communication in the patient-physician relationship to be a key factor in adherence with acute headache medications.

Anxiety is common in migraine sufferers and predicts long-term migraine persistence. Some individuals with high levels of anxiety may overuse immediate relief medications because of worry about getting a migraine. Many migraineurs have a significant amount of fear about any sensation that may herald a migraine. Consequently, some medicate fear, preemptively. Patients also can fear side effects to new medications, thereby reducing their willingness to change existing therapy for a potentially more effective treatment.

Biological rhythms, sleep and coping skills

Managing migraine also includes managing consistent biological rhythms. The literature has shown that chronobiological issues can be a driver of headache frequency and may also contribute to mood and anxiety disorders. Studies have shown that a simple cognitive-behavioral treatment for insomnia has transformed many migraineurs from chronic migraine to episodic migraine. 

Studies have demonstrated that a combination of optimal medication and cognitive behavioral therapy can be very effective. Behavioral therapies increase self-efficacy, a belief that patients have the requisite skills to manage a complicated disorder like migraine. A few sessions of stress management training combined with preventive medications and maximizing acute care options may have significant added value—reducing migraine frequency and related disability and ensuring better disease-coping mechanisms.

Final notes

Migraine is a biobehavioral disorder and it is important for the clinician to evaluate a diverse set of factors and come up with a comprehensive plan. This is particularly important for the patient with high frequency migraine who exhibits stress-related factors and possible psychiatric comorbidities. There are numerous cognitive behavioral therapies incorporating relaxation strategies and stress management techniques that can be very effective in caring for these complicated patients.   

Consider the following clinical scenarios.

Ellen, a 42-year-old married woman, presents to Dr. H’s office with a recent increase in her migraines. She looks sad and worried.

Dr. H. walks into the room, introduces himself, and immediately opens the electronic record to review her medical history forms. Her migraine episodes have increased from once biweekly to 1 to 2 times weekly; with additional less intense headaches on many other days. She uses both a triptan and an over-the-counter medication to control the pain–she gets a limited number of sumatriptan each month and is beginning to escalate her OTC usage. Dr. H. asks her about the intensity and duration of her headaches, reviews her medication use, and questions her about associated symptoms such as nausea or light and sound sensitivity? Ellen responds with yes and no answers. Dr. H. reviews different medication options, prescribes an older preventative medication and renews her sumatriptan.

In the second scenario, Ellen is in Dr. J’s office. When Dr. J enters the doorway to her office, she introduces herself and is welcoming and seated in a less formal manner. Dr. J is making eye contact with Ellen and not looking at her computer.

Instead of asking her questions that require a yes or no reply, she asks Ellen to walk her through her migraine experiences. She learns that the patient has been under much stress with work, and hears about troubling family issues, and that she is worried about her increased number of headaches and decreased functionality. Dr. J says, let’s talk about options. She tells her the first thing is to optimize acute care in order treat the acute attacks effectively. Simply “taking” a medication is insufficient to know whether a patient is taking that medication optimally. She asks Ellen to take her through her process in treating a migraine.

Ellen, Dr. J surmises, has a penchant for treating any sensation associated with a possible approaching headache with OTCs, which needs to be curtailed. Her use of OTCs could be at medication overuse levels thereby contributing to her headaches. Dr. J explains and shows Ellen a simple headache diary. Dr. J then discusses the future: the two of them will develop a plan to control the migraine frequency for the long term. The plan will include ways to control the stressors in Ellen’s life. Dr. J provides Ellen with names of psychologists with expertise in cognitive behavior therapies and relaxation-based treatments; they can help Ellen manage stressors that could be impacting her headaches. Dr. J communicates that migraine management requires a comprehensive approach that can involve behavioral as well as pharmacological therapies to maximize both headache relief and reduce disability. 

Migraine is a brain disease that can often be fueled by behavioral issues. Psychological stress, sleep problems, mood and anxiety issues can transform migraine from episodic to chronic. The operative word here is can. Patients with migraine who learn to better manage stress, employ simple relaxation strategies, and identify and treat comorbid psychiatric issues may show significant improvement. Migraine treatment can require more than one health care professional asheadache specialists, psychologists, perhaps psychiatrists, and sleep specialists may all be involved

Getting migraine under control often cannot be accomplished in just one visit; it can take time, as medications might need to be added or adjusted, sleep, diet, and physical activity modified along with stressors identified and managed. Helping patients optimize their acute treatment regimen is critical so they get quick relief while limiting overuse. Overuse of either prescription or OTC medications can lead to medication overuse headache (MOH). MOH can increase headache frequency and reduce the effectiveness of some preventive medications as well as other therapies. 

All these steps require good communication strategies by the physician and an understanding of the benefit of comprehensive treatment strategies that include behavioral therapies.

Helping motivation to change

Readiness to change will vary with different patients. Some people will be open to treating stress-related issues in an initial session while others will require many sessions in which the physician gently explores these concerns. It is helpful for the physician to ask open-ended questions, helping patients to “tell their stories.” The clinician needs to actively listen and accurately reflect patient’s thoughts and feelings (“it sounds like you…”) Avoiding overinterpretation and occasionally summarizing ensures clear communication. Both patients and physicians have identified high quality communication in the patient-physician relationship to be a key factor in adherence with acute headache medications.

Anxiety is common in migraine sufferers and predicts long-term migraine persistence. Some individuals with high levels of anxiety may overuse immediate relief medications because of worry about getting a migraine. Many migraineurs have a significant amount of fear about any sensation that may herald a migraine. Consequently, some medicate fear, preemptively. Patients also can fear side effects to new medications, thereby reducing their willingness to change existing therapy for a potentially more effective treatment.

Biological rhythms, sleep and coping skills

Managing migraine also includes managing consistent biological rhythms. The literature has shown that chronobiological issues can be a driver of headache frequency and may also contribute to mood and anxiety disorders. Studies have shown that a simple cognitive-behavioral treatment for insomnia has transformed many migraineurs from chronic migraine to episodic migraine. 

Studies have demonstrated that a combination of optimal medication and cognitive behavioral therapy can be very effective. Behavioral therapies increase self-efficacy, a belief that patients have the requisite skills to manage a complicated disorder like migraine. A few sessions of stress management training combined with preventive medications and maximizing acute care options may have significant added value—reducing migraine frequency and related disability and ensuring better disease-coping mechanisms.

Final notes

Migraine is a biobehavioral disorder and it is important for the clinician to evaluate a diverse set of factors and come up with a comprehensive plan. This is particularly important for the patient with high frequency migraine who exhibits stress-related factors and possible psychiatric comorbidities. There are numerous cognitive behavioral therapies incorporating relaxation strategies and stress management techniques that can be very effective in caring for these complicated patients.   

In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.

But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.

Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.

Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.

If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.

“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”

The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.

The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.

CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.

The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.

CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.

A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”

In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.

In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.

The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.

In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.

Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.

Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.

“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.

Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.

Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.

Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.

“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.

But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.

Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.

Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.

If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.

“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”

The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.

The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.

CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.

The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.

CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.

A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”

In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.

In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.

The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.

In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.

Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.

Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.

“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.

Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.

Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.

Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.

“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

In 2014, when the Food and Drug Administration found serious problems with a life-sustaining heart pump, its warning letter to the manufacturer threatened to notify other federal health agencies about the inspection’s findings.

But for years, no such alert ever went out. Instead, the agency added the warning letter to an online database alongside thousands of others, following its typical procedures, an FDA spokesperson said.

Agencies such as the Centers for Medicare & Medicaid Services and the U.S. Department of Veterans Affairs went on paying to implant the HeartWare Ventricular Assist Device, or HVAD, in new patients even though federal inspectors had found problems with the device linked to patient deaths and injuries.

Taxpayer dollars continued to flow to the original device maker, HeartWare, and then to the company that acquired it in 2016, Medtronic, for 7 years while the issues raised in the warning letter remained unresolved.

If crucial safety information in FDA warning letters doesn’t make it to other arms of the government responsible for deciding which medical devices to pay for, experts said patients are the ones put at risk.

“It’s clearly a breakdown of communication,” said Dr. Rita Redberg, a cardiologist at the University of California, San Francisco, who researches medical device safety and regulation. “It’s not just the money, obviously. It’s people’s lives.”

The FDA acknowledged that it doesn’t directly notify other agencies when it issues warning letters, pointing instead to its online database, which is accessible to both government officials and the public. “The FDA’s decisions are intended to be patient-centric with the health and safety of device users as our highest priority,” the agency spokesperson said in an email.

The HeartWare letter was removed from the public database about 2 years ago, even though the problems remained unresolved and patients were still receiving implants. The database clears out letters that are more than 5 years old.

CMS, which oversees the Medicare and Medicaid programs, would not say why it continued paying for a device that didn’t meet government standards. It directed questions about the HeartWare warning letter to the FDA. “CMS does not have oversight of the manufacturing and related safety assessments of a medical device manufacturer,” a spokesperson said in an email.

The spokesperson noted that CMS requires heart pump patients to have specialized medical teams managing their care, which should monitor FDA communications regarding safety of devices.

CMS doesn’t track data on devices by manufacturer, so it’s essentially impossible to calculate its total spending on HVADs. One 2018 medical journal study found that Medicare and Medicaid paid for more than half the cost of all heart pump implants from 2009 to 2014. If that rate of spending continued, CMS may have spent more than $400 million on implanting HVADs since 2014.

A spokesperson for the VA said his agency was never notified about the HeartWare warning letter. The VA paid HeartWare and Medtronic more than $3 million after the FDA issued the letter in 2014. It offered this explanation for why: “It’s important to note that FDA Warning Letters are notifications issued to manufacturers found to be in significant violation of federal regulations. They are not product recalls.”

In the case of the HVAD, the FDA’s failure to make sure its warning reached beyond the manufacturer may have had life-and-death consequences.

In August, ProPublica reported that federal inspectors continued finding problems at the HVAD’s manufacturing plant for years. Meanwhile, the FDA received thousands of reports of suspicious deaths and injuries and more than a dozen high-risk safety alerts from the manufacturer.

The documents detailed one horrifying device failure after another. A father of four died after his device suddenly failed and his teenage daughter couldn’t resuscitate him. Another patient’s heart tissue was charred after a pump short-circuited and overheated. A teenager died after vomiting blood as his mother struggled to restart a defective pump.

In June, Medtronic ended sales and implants of the device, citing new data that showed patients with HVADs had a higher rate of deaths and strokes than those with a competing heart pump.

Medtronic declined to comment for this story. It has previously said it believed that after the 2014 warning letter the benefits of the HVAD still outweighed the risks for patients with severe heart failure.

Experts said the lack of communication between federal agencies when serious device problems are found is baffling but not surprising. It fits a broader trend of device regulators focusing more on evaluating new products than monitoring the ones already on the market.

“The priority is to get more medical devices out there, paid for and getting used,” said Dr. Joseph Ross, a professor of medicine and public health at Yale University who studies medical device regulation.

Other U.S. health care regulators move more forcefully when providers and suppliers don’t meet the government’s minimum safety requirements for an extended period, putting patients at risk.

Take hospitals. When inspectors find a facility is not meeting safety standards, CMS can issue an immediate jeopardy citation and, if problems aren’t fixed, move to withhold federal payments, which make up substantial portions of most hospitals’ revenues. In the rare cases when hospitals don’t take sufficient action, CMS follows through and revokes funding.

Redberg, the UCSF cardiologist, said the lack of similar action for medical devices offers a clear “opportunity for improvement.” At minimum, the FDA could establish processes to directly inform other agencies when it issues warning letters and finds serious problems with devices being sold in the United States.

“If the agency’s mission is to protect public health, they would want to do these things and move quickly,” she said.

This story was originally published on ProPublica. ProPublica is a nonprofit newsroom that investigates abuses of power. Sign up to receive their biggest stories as soon as they’re published.

The dopamine receptors of the brain get their fair share amid the didactics we receive in residency. From discussions of antipsychotics and schizophrenia to stimulants and ADHD, dopamine plays a key role. Depending on the program and interest of faculty, methamphetamine may get its own lecture or be mixed in with other stimulants of abuse. During that discussion, a comment might be made in passing on the impact of methamphetamine on sexual desire and activity.

Experiences in the emergency department caring for patients who are intoxicated from methamphetamine then effectively make up for any gaps in trainees’ knowledge base. From patients engaging in self-pleasing pursuits in the emergency room to unfiltered reports of sexual exploits and desires, the impact of methamphetamine on sexual behavior quickly becomes apparent. Those experiences are later reinforced when residents are exposed to more long-term rehabilitation programs and have more in-depth conversations with patients about the sex-culture surrounding methamphetamine.

It is common to hear that, under the influence of methamphetamine, any available body will become an acceptable sexual partner – at times resulting in significant regrets, dangerous sexual activity, and complicated questions surrounding consent. Some early studies have found up to 72% increase in risky sexual behavior in methamphetamine users.¹ This is particularly problematic as society has recently taken on the difficult and important work to re-examine the role and nature of consent in sexual activities. This falls within the larger #MeToo movement and has led to advocating for harsher sentencing of sexual offenders.

Yet simultaneously, society has also reconsidered its approach to apportioning blame on drug users.² This shift to a more compassionate stance has resulted in a desire to treat and care for a disorder, rather than punish and condemn a poor choice. As forensic psychiatrists, we have noted this significant change. Where substance use disorders were once considered a risk factor for recidivism, they are now considered a disability that not only warrants treatment but can also diminish the share of blame one may be responsible for.

The convergence of those two societal movements often plays out in the courtroom, and in our experience when faced with those two opposing viewpoints, triers of fact (judges and juries) often favor punishing sexual offense over empathizing with an addictive disorder. While certainly not implying methamphetamine use condones sexual offense, we do posit the particular relationship between methamphetamine use and sexual activity should be explained to those entrusted with deciding guilt.

Examples of such problems are extremely common. A routine case involves IK,³ a 48-year-old male without significant history of legal problems, arrested for indecent exposure. His history of mental illness is closely intertwined with a history of substance use, leading to many psychiatric hospitalizations for methamphetamine-induced psychosis. After many hospitalizations he was placed in an assertive community treatment (ACT) team.

One day, IK is approached by an industrious drug dealer who frequents multiple board-and-cares in search for customers interested in relapsing. IK uses methamphetamine and within hours finds himself having walked miles away, naked, in the middle of an RV park. He subsequently describes the experience of unrelenting sexual desire, accompanied by ideas of reference involving billboards encouraging him to demonstrate his sexual prowess, as well as auditory hallucinations of women cheering him on. This leads to him pleasing himself publicly and his subsequent arrest.

Interviewing IK, 3 months later, he is embarrassed and apologetic. He is cognizant of the inappropriate nature of the incident and the foolishness of his actions. However, when asked whether he considers himself a sexual offender, he protests that he would never act in such a manner if not under the influence of methamphetamine. He points to his lack of significant sexual urges when sober, his lack of prior sexual offense, his lack of sexually violent offense, and his lack of unusual sexual interests.

It is unclear to us how society will or should adjudicate on such a case. It is not under the purview of forensic psychiatry to become a trier of fact. However, psychiatry should have a better working framework of how to discuss and conceptualize such situations, especially considering the dire consequences for those involved.

While any criminal conviction already has the potential to destroy a person’s life, sexual crimes bring particularly serious consequences. Entry into the national sex offender registry, in addition to carrying an unshakable stigma, comes with additional degrees of lost freedom. These individuals are prohibited from living or working in areas that have children in proximity, subjecting them to the outskirts of society and greatly restricting any chance of economic escape from poverty. Parks, libraries, and shopping malls can become off limits. Privacy for these individuals is nonexistent; from websites they visit to where they travel physically can be monitored. Even where they live and a detailed physical description are often easily accessible by members of their community.

When should it be permissible to consider sex offender status for someone on the grounds of a mental illness? A patient with obsessive-compulsive disorder might have sadistic obsessions and compulsions to commit violent sexual acts, which, along with being repugnant to society, are entirely ego-dystonic to the suffering patient. Psychosis is often characterized as involving a loss of insight and impaired reality testing. If society accepts insanity as grounds to mitigate sentencing, then why not permit it for grounds to wave the designation of sex offender to those with certain disorders, including substance use disorder? Wherever we come down on this issue, it is a sad fact that in practically no other medical field can a person be sentenced for having a disease.

Should IK have to register as a sex offender? Regardless of the circumstances, he did publicly masturbate. Society has determined that public sexual displays are a crime worth carrying the pariah status of sex offender – why should an exception be made for methamphetamine use? On the other hand, it is difficult to claim that IK’s behavior was entirely of his own free will. Most triers of fact will have never experienced that amount of dopamine reward. They can’t attest to the remaining free will after experiencing more pleasurable salience and positive reinforcement than ever naturally possible.

How we deal with the behavioral consequences, and other sequelae, of methamphetamine use is a growing problem. Access to and use of methamphetamine is no longer reserved for soldiers patrolling the jungles of Vietnam. Once thought to be a scourge of the West Coast, methamphetamine is now widely available throughout the United States.⁴ The use of methamphetamine is likely to continue to expand as society keeps pursuing the decriminalizing of drug use. Psychiatrists practicing in areas heavily affected by methamphetamine see firsthand the burden it places on community resources in the form of increased psychosis, emergency room utilization, medical resource strain, and encounters with police.⁵

The presence of mental illness is tied to a small but statistically significant risk of violence. However, substance use is a well-established risk factor for violence.⁶ What is often missed is that many sexual offenders have not committed a violent offense. However, like IK, they have been charged with indecent exposure or other nonviolent sexual offenses, such as prostitution and solicitation. Those nonviolent offenses are driven by poor judgment and impulsivity, the trademarks of substance use. The answer cannot be to incarcerate, and eventually add to the sex offender registry, the growing number of these individuals.

Yet, as psychiatrists, we seem at a loss for how to treat these patients. The prescription of allowing them to spend a night in the ED with a complementary sandwich garnished with olanzapine often feels like enabling. Substance use treatment programs are too limited, and the wait list is rarely shorter than the time it takes our patient to purchase their next hit.

There are no effective pharmacologic treatments for methamphetamine use disorder.⁷ The recommendations of cognitive-behavioral therapy, family and group therapy, contingency management, and a 12-step program may be sufficient for the most motivated and well-supported patients but are inadequate for the vast majority.⁸ As much as we want to laud the merits of community psychiatry and the ACT [assertive community treatment] model of care, it is hard to carry that banner while confronted with the reality these patients face on a day-to-day basis during any shift in the emergency room. Eventually the countless encounters with homeless, helplessly meth-addicted patients ending in discharge back to the streets begins to tarnish the bright rhetoric surrounding community care, which starts to sound more and more like abandonment of patients to suffer in futility.⁹

It is not up to forensic psychiatrists, or even psychiatry as a whole, to fix the myriad of inadequacies surrounding how society handles those suffering from methamphetamine addiction. However, it is essential for psychiatry to study and educate society on the interaction of methamphetamine use and sexual behavior. There has been some exploration into other risk factors for paraphilic behavior while under the influence of substances, but there is a dearth of information on this topic. Establishing a nomenclature called “substance-induced paraphilia” might be a way to bring clarity to such instances in both a forensic and general psychiatric setting.

Dr. Compton is a psychiatry resident at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research. Dr. Compton has no conflicts of interest. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. He has no conflicts of interest.

References

1. Psychol Addict Behav. 2016;30(2)147-57.

2. Monitor Psychol. 2019;50(6).

3. IK’s case has been modified in certain ways to maintain confidentiality.

4. J Psychoactive Drugs. 2000;(2):137-41.

5. Acad Emerg Med. 2020 Nov;27(11):1116-25.

6. Swanson JW. Mental disorder, substance abuse, and community violence: An epidemiological approach, in: Monahan J and Steadman HJ, eds. “Violence and Mental Disorder: Developments in Risk Assessment” (Chicago: University of Chicago Press, 1994, pp. 101-36).

7. Addiction. 2004 Jun;99(6)708-17.

8. Am Fam Physician. 2007 Oct 15;76(8):1169-74.

9. Perspect Biol Med. 2021;64(1)70-81.

The dopamine receptors of the brain get their fair share amid the didactics we receive in residency. From discussions of antipsychotics and schizophrenia to stimulants and ADHD, dopamine plays a key role. Depending on the program and interest of faculty, methamphetamine may get its own lecture or be mixed in with other stimulants of abuse. During that discussion, a comment might be made in passing on the impact of methamphetamine on sexual desire and activity.

Experiences in the emergency department caring for patients who are intoxicated from methamphetamine then effectively make up for any gaps in trainees’ knowledge base. From patients engaging in self-pleasing pursuits in the emergency room to unfiltered reports of sexual exploits and desires, the impact of methamphetamine on sexual behavior quickly becomes apparent. Those experiences are later reinforced when residents are exposed to more long-term rehabilitation programs and have more in-depth conversations with patients about the sex-culture surrounding methamphetamine.

It is common to hear that, under the influence of methamphetamine, any available body will become an acceptable sexual partner – at times resulting in significant regrets, dangerous sexual activity, and complicated questions surrounding consent. Some early studies have found up to 72% increase in risky sexual behavior in methamphetamine users.¹ This is particularly problematic as society has recently taken on the difficult and important work to re-examine the role and nature of consent in sexual activities. This falls within the larger #MeToo movement and has led to advocating for harsher sentencing of sexual offenders.

Yet simultaneously, society has also reconsidered its approach to apportioning blame on drug users.² This shift to a more compassionate stance has resulted in a desire to treat and care for a disorder, rather than punish and condemn a poor choice. As forensic psychiatrists, we have noted this significant change. Where substance use disorders were once considered a risk factor for recidivism, they are now considered a disability that not only warrants treatment but can also diminish the share of blame one may be responsible for.

The convergence of those two societal movements often plays out in the courtroom, and in our experience when faced with those two opposing viewpoints, triers of fact (judges and juries) often favor punishing sexual offense over empathizing with an addictive disorder. While certainly not implying methamphetamine use condones sexual offense, we do posit the particular relationship between methamphetamine use and sexual activity should be explained to those entrusted with deciding guilt.

Examples of such problems are extremely common. A routine case involves IK,³ a 48-year-old male without significant history of legal problems, arrested for indecent exposure. His history of mental illness is closely intertwined with a history of substance use, leading to many psychiatric hospitalizations for methamphetamine-induced psychosis. After many hospitalizations he was placed in an assertive community treatment (ACT) team.

One day, IK is approached by an industrious drug dealer who frequents multiple board-and-cares in search for customers interested in relapsing. IK uses methamphetamine and within hours finds himself having walked miles away, naked, in the middle of an RV park. He subsequently describes the experience of unrelenting sexual desire, accompanied by ideas of reference involving billboards encouraging him to demonstrate his sexual prowess, as well as auditory hallucinations of women cheering him on. This leads to him pleasing himself publicly and his subsequent arrest.

Interviewing IK, 3 months later, he is embarrassed and apologetic. He is cognizant of the inappropriate nature of the incident and the foolishness of his actions. However, when asked whether he considers himself a sexual offender, he protests that he would never act in such a manner if not under the influence of methamphetamine. He points to his lack of significant sexual urges when sober, his lack of prior sexual offense, his lack of sexually violent offense, and his lack of unusual sexual interests.

It is unclear to us how society will or should adjudicate on such a case. It is not under the purview of forensic psychiatry to become a trier of fact. However, psychiatry should have a better working framework of how to discuss and conceptualize such situations, especially considering the dire consequences for those involved.

While any criminal conviction already has the potential to destroy a person’s life, sexual crimes bring particularly serious consequences. Entry into the national sex offender registry, in addition to carrying an unshakable stigma, comes with additional degrees of lost freedom. These individuals are prohibited from living or working in areas that have children in proximity, subjecting them to the outskirts of society and greatly restricting any chance of economic escape from poverty. Parks, libraries, and shopping malls can become off limits. Privacy for these individuals is nonexistent; from websites they visit to where they travel physically can be monitored. Even where they live and a detailed physical description are often easily accessible by members of their community.

When should it be permissible to consider sex offender status for someone on the grounds of a mental illness? A patient with obsessive-compulsive disorder might have sadistic obsessions and compulsions to commit violent sexual acts, which, along with being repugnant to society, are entirely ego-dystonic to the suffering patient. Psychosis is often characterized as involving a loss of insight and impaired reality testing. If society accepts insanity as grounds to mitigate sentencing, then why not permit it for grounds to wave the designation of sex offender to those with certain disorders, including substance use disorder? Wherever we come down on this issue, it is a sad fact that in practically no other medical field can a person be sentenced for having a disease.

Should IK have to register as a sex offender? Regardless of the circumstances, he did publicly masturbate. Society has determined that public sexual displays are a crime worth carrying the pariah status of sex offender – why should an exception be made for methamphetamine use? On the other hand, it is difficult to claim that IK’s behavior was entirely of his own free will. Most triers of fact will have never experienced that amount of dopamine reward. They can’t attest to the remaining free will after experiencing more pleasurable salience and positive reinforcement than ever naturally possible.

How we deal with the behavioral consequences, and other sequelae, of methamphetamine use is a growing problem. Access to and use of methamphetamine is no longer reserved for soldiers patrolling the jungles of Vietnam. Once thought to be a scourge of the West Coast, methamphetamine is now widely available throughout the United States.⁴ The use of methamphetamine is likely to continue to expand as society keeps pursuing the decriminalizing of drug use. Psychiatrists practicing in areas heavily affected by methamphetamine see firsthand the burden it places on community resources in the form of increased psychosis, emergency room utilization, medical resource strain, and encounters with police.⁵

The presence of mental illness is tied to a small but statistically significant risk of violence. However, substance use is a well-established risk factor for violence.⁶ What is often missed is that many sexual offenders have not committed a violent offense. However, like IK, they have been charged with indecent exposure or other nonviolent sexual offenses, such as prostitution and solicitation. Those nonviolent offenses are driven by poor judgment and impulsivity, the trademarks of substance use. The answer cannot be to incarcerate, and eventually add to the sex offender registry, the growing number of these individuals.

Yet, as psychiatrists, we seem at a loss for how to treat these patients. The prescription of allowing them to spend a night in the ED with a complementary sandwich garnished with olanzapine often feels like enabling. Substance use treatment programs are too limited, and the wait list is rarely shorter than the time it takes our patient to purchase their next hit.

There are no effective pharmacologic treatments for methamphetamine use disorder.⁷ The recommendations of cognitive-behavioral therapy, family and group therapy, contingency management, and a 12-step program may be sufficient for the most motivated and well-supported patients but are inadequate for the vast majority.⁸ As much as we want to laud the merits of community psychiatry and the ACT [assertive community treatment] model of care, it is hard to carry that banner while confronted with the reality these patients face on a day-to-day basis during any shift in the emergency room. Eventually the countless encounters with homeless, helplessly meth-addicted patients ending in discharge back to the streets begins to tarnish the bright rhetoric surrounding community care, which starts to sound more and more like abandonment of patients to suffer in futility.⁹

It is not up to forensic psychiatrists, or even psychiatry as a whole, to fix the myriad of inadequacies surrounding how society handles those suffering from methamphetamine addiction. However, it is essential for psychiatry to study and educate society on the interaction of methamphetamine use and sexual behavior. There has been some exploration into other risk factors for paraphilic behavior while under the influence of substances, but there is a dearth of information on this topic. Establishing a nomenclature called “substance-induced paraphilia” might be a way to bring clarity to such instances in both a forensic and general psychiatric setting.

Dr. Compton is a psychiatry resident at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research. Dr. Compton has no conflicts of interest. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. He has no conflicts of interest.

References

1. Psychol Addict Behav. 2016;30(2)147-57.

2. Monitor Psychol. 2019;50(6).

3. IK’s case has been modified in certain ways to maintain confidentiality.

4. J Psychoactive Drugs. 2000;(2):137-41.

5. Acad Emerg Med. 2020 Nov;27(11):1116-25.

6. Swanson JW. Mental disorder, substance abuse, and community violence: An epidemiological approach, in: Monahan J and Steadman HJ, eds. “Violence and Mental Disorder: Developments in Risk Assessment” (Chicago: University of Chicago Press, 1994, pp. 101-36).

7. Addiction. 2004 Jun;99(6)708-17.

8. Am Fam Physician. 2007 Oct 15;76(8):1169-74.

9. Perspect Biol Med. 2021;64(1)70-81.

The dopamine receptors of the brain get their fair share amid the didactics we receive in residency. From discussions of antipsychotics and schizophrenia to stimulants and ADHD, dopamine plays a key role. Depending on the program and interest of faculty, methamphetamine may get its own lecture or be mixed in with other stimulants of abuse. During that discussion, a comment might be made in passing on the impact of methamphetamine on sexual desire and activity.

Experiences in the emergency department caring for patients who are intoxicated from methamphetamine then effectively make up for any gaps in trainees’ knowledge base. From patients engaging in self-pleasing pursuits in the emergency room to unfiltered reports of sexual exploits and desires, the impact of methamphetamine on sexual behavior quickly becomes apparent. Those experiences are later reinforced when residents are exposed to more long-term rehabilitation programs and have more in-depth conversations with patients about the sex-culture surrounding methamphetamine.

It is common to hear that, under the influence of methamphetamine, any available body will become an acceptable sexual partner – at times resulting in significant regrets, dangerous sexual activity, and complicated questions surrounding consent. Some early studies have found up to 72% increase in risky sexual behavior in methamphetamine users.¹ This is particularly problematic as society has recently taken on the difficult and important work to re-examine the role and nature of consent in sexual activities. This falls within the larger #MeToo movement and has led to advocating for harsher sentencing of sexual offenders.

Yet simultaneously, society has also reconsidered its approach to apportioning blame on drug users.² This shift to a more compassionate stance has resulted in a desire to treat and care for a disorder, rather than punish and condemn a poor choice. As forensic psychiatrists, we have noted this significant change. Where substance use disorders were once considered a risk factor for recidivism, they are now considered a disability that not only warrants treatment but can also diminish the share of blame one may be responsible for.

The convergence of those two societal movements often plays out in the courtroom, and in our experience when faced with those two opposing viewpoints, triers of fact (judges and juries) often favor punishing sexual offense over empathizing with an addictive disorder. While certainly not implying methamphetamine use condones sexual offense, we do posit the particular relationship between methamphetamine use and sexual activity should be explained to those entrusted with deciding guilt.

Examples of such problems are extremely common. A routine case involves IK,³ a 48-year-old male without significant history of legal problems, arrested for indecent exposure. His history of mental illness is closely intertwined with a history of substance use, leading to many psychiatric hospitalizations for methamphetamine-induced psychosis. After many hospitalizations he was placed in an assertive community treatment (ACT) team.

One day, IK is approached by an industrious drug dealer who frequents multiple board-and-cares in search for customers interested in relapsing. IK uses methamphetamine and within hours finds himself having walked miles away, naked, in the middle of an RV park. He subsequently describes the experience of unrelenting sexual desire, accompanied by ideas of reference involving billboards encouraging him to demonstrate his sexual prowess, as well as auditory hallucinations of women cheering him on. This leads to him pleasing himself publicly and his subsequent arrest.

Interviewing IK, 3 months later, he is embarrassed and apologetic. He is cognizant of the inappropriate nature of the incident and the foolishness of his actions. However, when asked whether he considers himself a sexual offender, he protests that he would never act in such a manner if not under the influence of methamphetamine. He points to his lack of significant sexual urges when sober, his lack of prior sexual offense, his lack of sexually violent offense, and his lack of unusual sexual interests.

It is unclear to us how society will or should adjudicate on such a case. It is not under the purview of forensic psychiatry to become a trier of fact. However, psychiatry should have a better working framework of how to discuss and conceptualize such situations, especially considering the dire consequences for those involved.

While any criminal conviction already has the potential to destroy a person’s life, sexual crimes bring particularly serious consequences. Entry into the national sex offender registry, in addition to carrying an unshakable stigma, comes with additional degrees of lost freedom. These individuals are prohibited from living or working in areas that have children in proximity, subjecting them to the outskirts of society and greatly restricting any chance of economic escape from poverty. Parks, libraries, and shopping malls can become off limits. Privacy for these individuals is nonexistent; from websites they visit to where they travel physically can be monitored. Even where they live and a detailed physical description are often easily accessible by members of their community.

When should it be permissible to consider sex offender status for someone on the grounds of a mental illness? A patient with obsessive-compulsive disorder might have sadistic obsessions and compulsions to commit violent sexual acts, which, along with being repugnant to society, are entirely ego-dystonic to the suffering patient. Psychosis is often characterized as involving a loss of insight and impaired reality testing. If society accepts insanity as grounds to mitigate sentencing, then why not permit it for grounds to wave the designation of sex offender to those with certain disorders, including substance use disorder? Wherever we come down on this issue, it is a sad fact that in practically no other medical field can a person be sentenced for having a disease.

Should IK have to register as a sex offender? Regardless of the circumstances, he did publicly masturbate. Society has determined that public sexual displays are a crime worth carrying the pariah status of sex offender – why should an exception be made for methamphetamine use? On the other hand, it is difficult to claim that IK’s behavior was entirely of his own free will. Most triers of fact will have never experienced that amount of dopamine reward. They can’t attest to the remaining free will after experiencing more pleasurable salience and positive reinforcement than ever naturally possible.

How we deal with the behavioral consequences, and other sequelae, of methamphetamine use is a growing problem. Access to and use of methamphetamine is no longer reserved for soldiers patrolling the jungles of Vietnam. Once thought to be a scourge of the West Coast, methamphetamine is now widely available throughout the United States.⁴ The use of methamphetamine is likely to continue to expand as society keeps pursuing the decriminalizing of drug use. Psychiatrists practicing in areas heavily affected by methamphetamine see firsthand the burden it places on community resources in the form of increased psychosis, emergency room utilization, medical resource strain, and encounters with police.⁵

The presence of mental illness is tied to a small but statistically significant risk of violence. However, substance use is a well-established risk factor for violence.⁶ What is often missed is that many sexual offenders have not committed a violent offense. However, like IK, they have been charged with indecent exposure or other nonviolent sexual offenses, such as prostitution and solicitation. Those nonviolent offenses are driven by poor judgment and impulsivity, the trademarks of substance use. The answer cannot be to incarcerate, and eventually add to the sex offender registry, the growing number of these individuals.

Yet, as psychiatrists, we seem at a loss for how to treat these patients. The prescription of allowing them to spend a night in the ED with a complementary sandwich garnished with olanzapine often feels like enabling. Substance use treatment programs are too limited, and the wait list is rarely shorter than the time it takes our patient to purchase their next hit.

There are no effective pharmacologic treatments for methamphetamine use disorder.⁷ The recommendations of cognitive-behavioral therapy, family and group therapy, contingency management, and a 12-step program may be sufficient for the most motivated and well-supported patients but are inadequate for the vast majority.⁸ As much as we want to laud the merits of community psychiatry and the ACT [assertive community treatment] model of care, it is hard to carry that banner while confronted with the reality these patients face on a day-to-day basis during any shift in the emergency room. Eventually the countless encounters with homeless, helplessly meth-addicted patients ending in discharge back to the streets begins to tarnish the bright rhetoric surrounding community care, which starts to sound more and more like abandonment of patients to suffer in futility.⁹

It is not up to forensic psychiatrists, or even psychiatry as a whole, to fix the myriad of inadequacies surrounding how society handles those suffering from methamphetamine addiction. However, it is essential for psychiatry to study and educate society on the interaction of methamphetamine use and sexual behavior. There has been some exploration into other risk factors for paraphilic behavior while under the influence of substances, but there is a dearth of information on this topic. Establishing a nomenclature called “substance-induced paraphilia” might be a way to bring clarity to such instances in both a forensic and general psychiatric setting.

Dr. Compton is a psychiatry resident at University of California, San Diego. His background includes medical education, mental health advocacy, work with underserved populations, and brain cancer research. Dr. Compton has no conflicts of interest. Dr. Badre is a clinical and forensic psychiatrist in San Diego. He holds teaching positions at the University of California, San Diego, and the University of San Diego. He teaches medical education, psychopharmacology, ethics in psychiatry, and correctional care. Dr. Badre can be reached at his website, BadreMD.com. He has no conflicts of interest.

References

1. Psychol Addict Behav. 2016;30(2)147-57.

2. Monitor Psychol. 2019;50(6).

3. IK’s case has been modified in certain ways to maintain confidentiality.

4. J Psychoactive Drugs. 2000;(2):137-41.

5. Acad Emerg Med. 2020 Nov;27(11):1116-25.

6. Swanson JW. Mental disorder, substance abuse, and community violence: An epidemiological approach, in: Monahan J and Steadman HJ, eds. “Violence and Mental Disorder: Developments in Risk Assessment” (Chicago: University of Chicago Press, 1994, pp. 101-36).

7. Addiction. 2004 Jun;99(6)708-17.

8. Am Fam Physician. 2007 Oct 15;76(8):1169-74.

9. Perspect Biol Med. 2021;64(1)70-81.

Gastroenterology centers with higher adenoma detection rates (ADR) with the use of flexible sigmoidoscopy (FS) had a lower long-term colorectal cancer incidence and lower CRC mortality among its patients, according to a new study.

Detection and removal of polyps during colonoscopy screening is vital to the prevention of CRC, and previous research has shown that centers with higher detection rates are associated with lower rates of CRC diagnosis within 3-5 years after a negative screen.

In Clinical Gastroenterology and Hepatology, researchers led by Amanda J. Cross, PhD, a professor of cancer epidemiology at Imperial College London, published an analysis of the UK Flexible Sigmoidoscopy Screening Trial, which found that FS screening between the ages 55 and 64 led to a 35% reduction of CRC incidence and a 41% reduction in CRC over a mean follow-up 17.1 years. The screening program had no apparent effect on incidence and mortality of proximal cancers. The researchers speculated that this was because few patients underwent proximal examination during follow-up colonoscopy.

“Considering only 5% of participants were referred for follow-up colonoscopy and 4% were referred for surveillance, we conclude that the improved detection of adenomas at FS has a measurable impact on long-term distal CRC outcomes, even when there is infrequent colonoscopy use. It is possible that high detectors also were more adept at polypectomy than intermediate or low detectors, and achieved more complete resection of detected lesions,” the authors wrote.

The researchers analyzed data from 38,550 patients who underwent screening at 14 U.K. hospitals, between 1994 and 1999. A single endoscopist was responsible for nearly all FS screens performed at each participating hospital.

The mean patient age was 60 years, and 49% were male. The researchers calculated ADRs for each center using the percentage of patients who had at least one adenoma detected during screening, which included any distal adenomas discovered during follow-up colonoscopy.

The ADR overall was 12%. The researchers used multivariate logistic regression to rank individual centers as having high (15%; five centers), intermediate (12%; four centers), or low (9%; four centers) detection rates.

There was a strong association between detection rates of small adenomas and a center’s ADR (P < .001), but not for large or advanced adenomas. In the high-detector group, 6.2% of patients screened were referred to colonoscopy versus 4.5% in the intermediate group and 4.5% in the low group. About half of colonoscopies were conducted by the same endoscopist who performed FS.

During follow-up, the distal CRC incidence was 1.5% in the high ADR group, 1.4% in the intermediate group, and 1.7% in the low group, and mortality rates were 0.4%, 0.4%, and 0.5%, respectively.

Compared with unscreened controls, risk of distal CRC was lowest among individuals who underwent screening in the high ADR group (hazard ratio, 0.34; 95% confidence interval, 0.27-0.42), followed by the intermediate group (HR, 0.46; 95% CI, 0.36-0.59), and the low ADR group (HR, 0.55; 95% CI, 0.44-0.68; P < .05 for all).

Compared with unscreened controls, CRC mortality was lower among individuals who underwent screening in the high ADR group (HR, 0.22; 95% CI, 0.13-0.37), followed by the intermediate group (HR, 0.30; 95% CI, 0.17-0.55), and the low ADR group (HR, 0.54; 95% CI, 0.34-0.86; P < .05 for between group differences).

All-site CRC incidence followed similar trends, with the lowest risks in the high ADR group (HR, 0.58; 95% CI, 0.50-0.67), followed by intermediate ADR (HR, 0.65; 95% CI, 0.55-0.77) and low ADR groups (HR, 0.72; 95% CI, 0.61-0.85; between group differences not statistically significant).

All-site CRC mortality was lowest in the high ADR group (HR, 0.52; 95% CI, 0.39-0.69), followed by the intermediate group (HR, 0.53; 95% CI, 0.38-0.73), and the low ADR group (HR, 0.68; 95% CI, 0.51-0.92; between-group differences not statistically significant).

The number needed to screen (NNS) to prevent one CRC diagnosis was 78 in the high ADR group (95% CI, 61-106), 103 in the intermediate group (95% CI, 74-171), and 125 in the low ADR group (95% CI, 82-256). The NNS to prevent one CRC death was 226 (95% CI, 159-387), 247 (95% CI, 165-490), and 349 respectively (95% CI, 192-1,904).

However, the researchers also pointed out that efforts to increase ADR could result in more complications, such as perforations or gastrointestinal bleeding, as well as more frequent diagnosis and recommended surveillance for diminutive adenomas.

The study is limited by the fact that endoscopists were either gastroenterologists or surgeons and the study population was made up of individuals who desired screening.

The UK Flexible Sigmoidoscopy Screening Trial was funded by the UK Medical Research Council and the National Institute for Health Research. The authors disclosed no conflicts of interest.

Gastroenterology centers with higher adenoma detection rates (ADR) with the use of flexible sigmoidoscopy (FS) had a lower long-term colorectal cancer incidence and lower CRC mortality among its patients, according to a new study.

Detection and removal of polyps during colonoscopy screening is vital to the prevention of CRC, and previous research has shown that centers with higher detection rates are associated with lower rates of CRC diagnosis within 3-5 years after a negative screen.

In Clinical Gastroenterology and Hepatology, researchers led by Amanda J. Cross, PhD, a professor of cancer epidemiology at Imperial College London, published an analysis of the UK Flexible Sigmoidoscopy Screening Trial, which found that FS screening between the ages 55 and 64 led to a 35% reduction of CRC incidence and a 41% reduction in CRC over a mean follow-up 17.1 years. The screening program had no apparent effect on incidence and mortality of proximal cancers. The researchers speculated that this was because few patients underwent proximal examination during follow-up colonoscopy.

“Considering only 5% of participants were referred for follow-up colonoscopy and 4% were referred for surveillance, we conclude that the improved detection of adenomas at FS has a measurable impact on long-term distal CRC outcomes, even when there is infrequent colonoscopy use. It is possible that high detectors also were more adept at polypectomy than intermediate or low detectors, and achieved more complete resection of detected lesions,” the authors wrote.

The researchers analyzed data from 38,550 patients who underwent screening at 14 U.K. hospitals, between 1994 and 1999. A single endoscopist was responsible for nearly all FS screens performed at each participating hospital.

The mean patient age was 60 years, and 49% were male. The researchers calculated ADRs for each center using the percentage of patients who had at least one adenoma detected during screening, which included any distal adenomas discovered during follow-up colonoscopy.

The ADR overall was 12%. The researchers used multivariate logistic regression to rank individual centers as having high (15%; five centers), intermediate (12%; four centers), or low (9%; four centers) detection rates.

There was a strong association between detection rates of small adenomas and a center’s ADR (P < .001), but not for large or advanced adenomas. In the high-detector group, 6.2% of patients screened were referred to colonoscopy versus 4.5% in the intermediate group and 4.5% in the low group. About half of colonoscopies were conducted by the same endoscopist who performed FS.

During follow-up, the distal CRC incidence was 1.5% in the high ADR group, 1.4% in the intermediate group, and 1.7% in the low group, and mortality rates were 0.4%, 0.4%, and 0.5%, respectively.

Compared with unscreened controls, risk of distal CRC was lowest among individuals who underwent screening in the high ADR group (hazard ratio, 0.34; 95% confidence interval, 0.27-0.42), followed by the intermediate group (HR, 0.46; 95% CI, 0.36-0.59), and the low ADR group (HR, 0.55; 95% CI, 0.44-0.68; P < .05 for all).

Compared with unscreened controls, CRC mortality was lower among individuals who underwent screening in the high ADR group (HR, 0.22; 95% CI, 0.13-0.37), followed by the intermediate group (HR, 0.30; 95% CI, 0.17-0.55), and the low ADR group (HR, 0.54; 95% CI, 0.34-0.86; P < .05 for between group differences).

All-site CRC incidence followed similar trends, with the lowest risks in the high ADR group (HR, 0.58; 95% CI, 0.50-0.67), followed by intermediate ADR (HR, 0.65; 95% CI, 0.55-0.77) and low ADR groups (HR, 0.72; 95% CI, 0.61-0.85; between group differences not statistically significant).

All-site CRC mortality was lowest in the high ADR group (HR, 0.52; 95% CI, 0.39-0.69), followed by the intermediate group (HR, 0.53; 95% CI, 0.38-0.73), and the low ADR group (HR, 0.68; 95% CI, 0.51-0.92; between-group differences not statistically significant).

The number needed to screen (NNS) to prevent one CRC diagnosis was 78 in the high ADR group (95% CI, 61-106), 103 in the intermediate group (95% CI, 74-171), and 125 in the low ADR group (95% CI, 82-256). The NNS to prevent one CRC death was 226 (95% CI, 159-387), 247 (95% CI, 165-490), and 349 respectively (95% CI, 192-1,904).

However, the researchers also pointed out that efforts to increase ADR could result in more complications, such as perforations or gastrointestinal bleeding, as well as more frequent diagnosis and recommended surveillance for diminutive adenomas.

The study is limited by the fact that endoscopists were either gastroenterologists or surgeons and the study population was made up of individuals who desired screening.

The UK Flexible Sigmoidoscopy Screening Trial was funded by the UK Medical Research Council and the National Institute for Health Research. The authors disclosed no conflicts of interest.

Gastroenterology centers with higher adenoma detection rates (ADR) with the use of flexible sigmoidoscopy (FS) had a lower long-term colorectal cancer incidence and lower CRC mortality among its patients, according to a new study.

Detection and removal of polyps during colonoscopy screening is vital to the prevention of CRC, and previous research has shown that centers with higher detection rates are associated with lower rates of CRC diagnosis within 3-5 years after a negative screen.

In Clinical Gastroenterology and Hepatology, researchers led by Amanda J. Cross, PhD, a professor of cancer epidemiology at Imperial College London, published an analysis of the UK Flexible Sigmoidoscopy Screening Trial, which found that FS screening between the ages 55 and 64 led to a 35% reduction of CRC incidence and a 41% reduction in CRC over a mean follow-up 17.1 years. The screening program had no apparent effect on incidence and mortality of proximal cancers. The researchers speculated that this was because few patients underwent proximal examination during follow-up colonoscopy.

“Considering only 5% of participants were referred for follow-up colonoscopy and 4% were referred for surveillance, we conclude that the improved detection of adenomas at FS has a measurable impact on long-term distal CRC outcomes, even when there is infrequent colonoscopy use. It is possible that high detectors also were more adept at polypectomy than intermediate or low detectors, and achieved more complete resection of detected lesions,” the authors wrote.

The researchers analyzed data from 38,550 patients who underwent screening at 14 U.K. hospitals, between 1994 and 1999. A single endoscopist was responsible for nearly all FS screens performed at each participating hospital.

The mean patient age was 60 years, and 49% were male. The researchers calculated ADRs for each center using the percentage of patients who had at least one adenoma detected during screening, which included any distal adenomas discovered during follow-up colonoscopy.

The ADR overall was 12%. The researchers used multivariate logistic regression to rank individual centers as having high (15%; five centers), intermediate (12%; four centers), or low (9%; four centers) detection rates.

There was a strong association between detection rates of small adenomas and a center’s ADR (P < .001), but not for large or advanced adenomas. In the high-detector group, 6.2% of patients screened were referred to colonoscopy versus 4.5% in the intermediate group and 4.5% in the low group. About half of colonoscopies were conducted by the same endoscopist who performed FS.

During follow-up, the distal CRC incidence was 1.5% in the high ADR group, 1.4% in the intermediate group, and 1.7% in the low group, and mortality rates were 0.4%, 0.4%, and 0.5%, respectively.

Compared with unscreened controls, risk of distal CRC was lowest among individuals who underwent screening in the high ADR group (hazard ratio, 0.34; 95% confidence interval, 0.27-0.42), followed by the intermediate group (HR, 0.46; 95% CI, 0.36-0.59), and the low ADR group (HR, 0.55; 95% CI, 0.44-0.68; P < .05 for all).

Compared with unscreened controls, CRC mortality was lower among individuals who underwent screening in the high ADR group (HR, 0.22; 95% CI, 0.13-0.37), followed by the intermediate group (HR, 0.30; 95% CI, 0.17-0.55), and the low ADR group (HR, 0.54; 95% CI, 0.34-0.86; P < .05 for between group differences).

All-site CRC incidence followed similar trends, with the lowest risks in the high ADR group (HR, 0.58; 95% CI, 0.50-0.67), followed by intermediate ADR (HR, 0.65; 95% CI, 0.55-0.77) and low ADR groups (HR, 0.72; 95% CI, 0.61-0.85; between group differences not statistically significant).

All-site CRC mortality was lowest in the high ADR group (HR, 0.52; 95% CI, 0.39-0.69), followed by the intermediate group (HR, 0.53; 95% CI, 0.38-0.73), and the low ADR group (HR, 0.68; 95% CI, 0.51-0.92; between-group differences not statistically significant).

The number needed to screen (NNS) to prevent one CRC diagnosis was 78 in the high ADR group (95% CI, 61-106), 103 in the intermediate group (95% CI, 74-171), and 125 in the low ADR group (95% CI, 82-256). The NNS to prevent one CRC death was 226 (95% CI, 159-387), 247 (95% CI, 165-490), and 349 respectively (95% CI, 192-1,904).

However, the researchers also pointed out that efforts to increase ADR could result in more complications, such as perforations or gastrointestinal bleeding, as well as more frequent diagnosis and recommended surveillance for diminutive adenomas.

The study is limited by the fact that endoscopists were either gastroenterologists or surgeons and the study population was made up of individuals who desired screening.

The UK Flexible Sigmoidoscopy Screening Trial was funded by the UK Medical Research Council and the National Institute for Health Research. The authors disclosed no conflicts of interest.

The damage to the heart caused by a myocardial infarction is not just a result of ischemia caused by the blocked artery but is also brought about by bleeding in the myocardium after the artery has been opened, a new study suggests.

This observation is leading to new approaches to limiting infarct size and treating MI.

“In MI treatment, we have always focused on opening up the artery as quickly as possible to limit the myocardial damage caused by ischemia,” the study’s senior author, Rohan Dharmakumar, PhD, Indiana University, Indianapolis, told this news organization.

“We are pursuing a completely new approach focusing on limiting the damage after revascularization,” he said. “We are totally rethinking what a myocardial infarction is – what causes the injury and the time course of the injury – our results suggest that it’s not just ischemic damage and a lot of the harm is caused by hemorrhage after reperfusion.”

It has been known for many years that hemorrhage is often seen in the myocardium in large MIs, but it has not been established before now whether it contributes to the injury or not, Dr. Dharmakumar explained.

“This study was done to look at that – and we found that the hemorrhage drives a second layer of injury on top of the ischemia.”

Dr. Dharmakumar said this hemorrhage is part of the phenomenon known as reperfusion injury. “This has been known to exist for many years, but we haven’t fully understood all the factors contributing to it. Our results suggest that hemorrhage is a major component of reperfusion injury – probably the dominant factor,” he said.  

The researchers are now working on therapeutic approaches to try to prevent this hemorrhage and/or to minimize its effect.

“We are studying how hemorrhage drives damage and how to block these biological processes,” Dr. Dharmakumar said. “Our studies suggest that hemorrhage could account for up to half of the damage caused by a myocardial infarction. If we can limit that, we should be able to reduce the size of the infarct and this should translate into better long-term outcomes.

“I’m very excited about these results,” he added. “We are already seeing a remarkable improvement in animal models with some of the potential therapeutic approaches we are working on.”

The current study is published in the January 2022 issue of the Journal of the American College of Cardiology (JACC).

The authors explain that it is now recognized that reperfusion injury can contribute to increasing infarct size, which they refer to as “infarct surge.” Previous studies have also shown that reperfusion injury can contribute to as much as 50% of the final infarct size, but the factors contributing to the observed variability are not known, and previous attempts to limit infarct surge from reperfusion injury have failed.

They noted that after reperfusion, microvessels can remain obstructed, resulting in intramyocardial hemorrhage. They conducted the current study to investigate whether such hemorrhage causes expansion of the infarct.

They studied 70 patients with ST-segment elevation MI who were categorized with cardiovascular MRI to have intramyocardial hemorrhage or not following primary PCI, and for whom serial cardiac troponin measures were used to assess infarct size.

Results showed that while troponin levels were not different before reperfusion, patients with intramyocardial hemorrhage had significantly higher cardiac troponin levels after reperfusion and these levels peaked earlier than in patients without hemorrhage.

In animal models, those with intramyocardial hemorrhage had a more rapid expansion of myocardial necrosis than did those without hemorrhage, and within 72 hours of reperfusion, a fourfold greater loss in salvageable myocardium was evident in hemorrhagic MIs.

“We have shown that damage to the heart continues after revascularization as measured by rapidly increasing troponin levels in the hearts that have had a hemorrhage,” Dr. Dharmakumar said.

“Hemorrhage in the myocardium was associated with larger infarctions, and in infarcts causing the same area of myocardium to be at risk, those with hemorrhage after revascularization lost a lot more of the salvageable myocardium than those without hemorrhage,” he added.

Dr. Dharmakumar estimates that such hemorrhage occurs in about half of MIs after revascularization, with risk factors including male gender, anterior wall MIs, and smoking.

He pointed out that previous attempts to treat or prevent reperfusion injury have not been successful, probably because they have not been addressing the key mechanism. “We have not been looking at hemorrhage in this regard until now. This is because it is only recently that we have had the tools to be able to identify hemorrhage in the heart with the use of cardiac MRI.” 
 

Final frontier

In an accompanying editorial, Colin Berry, MBChB, University of Glasgow, and Borja Ibáñez, MD, Jiménez Díaz Foundation University Hospital, Madrid, said they applaud the investigators for providing new, mechanistic insights into a difficult clinical problem that has an unmet therapeutic need.

But they pointed out that it is difficult to completely dissect the impact of hemorrhage versus MI size on adverse remodeling, noting that it might be the case that more severe ischemia/reperfusion events are associated with large MI sizes and higher degree of hemorrhage.

However, they concluded that: “Intramyocardial hemorrhage represents the final frontier for preventing heart failure post-MI. It is readily detected using CMR, and clinical research of novel therapeutic approaches merits prioritization.”

This work was supported by grants from National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Dharmakumar and coauthor Robert Finney, PhD, have ownership interest in Cardiotheranostics. Dr. Berry is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GlaxoSmithKline, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health.

A version of this article first appeared on Medscape.com.

The damage to the heart caused by a myocardial infarction is not just a result of ischemia caused by the blocked artery but is also brought about by bleeding in the myocardium after the artery has been opened, a new study suggests.

This observation is leading to new approaches to limiting infarct size and treating MI.

“In MI treatment, we have always focused on opening up the artery as quickly as possible to limit the myocardial damage caused by ischemia,” the study’s senior author, Rohan Dharmakumar, PhD, Indiana University, Indianapolis, told this news organization.

“We are pursuing a completely new approach focusing on limiting the damage after revascularization,” he said. “We are totally rethinking what a myocardial infarction is – what causes the injury and the time course of the injury – our results suggest that it’s not just ischemic damage and a lot of the harm is caused by hemorrhage after reperfusion.”

It has been known for many years that hemorrhage is often seen in the myocardium in large MIs, but it has not been established before now whether it contributes to the injury or not, Dr. Dharmakumar explained.

“This study was done to look at that – and we found that the hemorrhage drives a second layer of injury on top of the ischemia.”

Dr. Dharmakumar said this hemorrhage is part of the phenomenon known as reperfusion injury. “This has been known to exist for many years, but we haven’t fully understood all the factors contributing to it. Our results suggest that hemorrhage is a major component of reperfusion injury – probably the dominant factor,” he said.  

The researchers are now working on therapeutic approaches to try to prevent this hemorrhage and/or to minimize its effect.

“We are studying how hemorrhage drives damage and how to block these biological processes,” Dr. Dharmakumar said. “Our studies suggest that hemorrhage could account for up to half of the damage caused by a myocardial infarction. If we can limit that, we should be able to reduce the size of the infarct and this should translate into better long-term outcomes.

“I’m very excited about these results,” he added. “We are already seeing a remarkable improvement in animal models with some of the potential therapeutic approaches we are working on.”

The current study is published in the January 2022 issue of the Journal of the American College of Cardiology (JACC).

The authors explain that it is now recognized that reperfusion injury can contribute to increasing infarct size, which they refer to as “infarct surge.” Previous studies have also shown that reperfusion injury can contribute to as much as 50% of the final infarct size, but the factors contributing to the observed variability are not known, and previous attempts to limit infarct surge from reperfusion injury have failed.

They noted that after reperfusion, microvessels can remain obstructed, resulting in intramyocardial hemorrhage. They conducted the current study to investigate whether such hemorrhage causes expansion of the infarct.

They studied 70 patients with ST-segment elevation MI who were categorized with cardiovascular MRI to have intramyocardial hemorrhage or not following primary PCI, and for whom serial cardiac troponin measures were used to assess infarct size.

Results showed that while troponin levels were not different before reperfusion, patients with intramyocardial hemorrhage had significantly higher cardiac troponin levels after reperfusion and these levels peaked earlier than in patients without hemorrhage.

In animal models, those with intramyocardial hemorrhage had a more rapid expansion of myocardial necrosis than did those without hemorrhage, and within 72 hours of reperfusion, a fourfold greater loss in salvageable myocardium was evident in hemorrhagic MIs.

“We have shown that damage to the heart continues after revascularization as measured by rapidly increasing troponin levels in the hearts that have had a hemorrhage,” Dr. Dharmakumar said.

“Hemorrhage in the myocardium was associated with larger infarctions, and in infarcts causing the same area of myocardium to be at risk, those with hemorrhage after revascularization lost a lot more of the salvageable myocardium than those without hemorrhage,” he added.

Dr. Dharmakumar estimates that such hemorrhage occurs in about half of MIs after revascularization, with risk factors including male gender, anterior wall MIs, and smoking.

He pointed out that previous attempts to treat or prevent reperfusion injury have not been successful, probably because they have not been addressing the key mechanism. “We have not been looking at hemorrhage in this regard until now. This is because it is only recently that we have had the tools to be able to identify hemorrhage in the heart with the use of cardiac MRI.” 
 

Final frontier

In an accompanying editorial, Colin Berry, MBChB, University of Glasgow, and Borja Ibáñez, MD, Jiménez Díaz Foundation University Hospital, Madrid, said they applaud the investigators for providing new, mechanistic insights into a difficult clinical problem that has an unmet therapeutic need.

But they pointed out that it is difficult to completely dissect the impact of hemorrhage versus MI size on adverse remodeling, noting that it might be the case that more severe ischemia/reperfusion events are associated with large MI sizes and higher degree of hemorrhage.

However, they concluded that: “Intramyocardial hemorrhage represents the final frontier for preventing heart failure post-MI. It is readily detected using CMR, and clinical research of novel therapeutic approaches merits prioritization.”

This work was supported by grants from National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Dharmakumar and coauthor Robert Finney, PhD, have ownership interest in Cardiotheranostics. Dr. Berry is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GlaxoSmithKline, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health.

A version of this article first appeared on Medscape.com.

The damage to the heart caused by a myocardial infarction is not just a result of ischemia caused by the blocked artery but is also brought about by bleeding in the myocardium after the artery has been opened, a new study suggests.

This observation is leading to new approaches to limiting infarct size and treating MI.

“In MI treatment, we have always focused on opening up the artery as quickly as possible to limit the myocardial damage caused by ischemia,” the study’s senior author, Rohan Dharmakumar, PhD, Indiana University, Indianapolis, told this news organization.

“We are pursuing a completely new approach focusing on limiting the damage after revascularization,” he said. “We are totally rethinking what a myocardial infarction is – what causes the injury and the time course of the injury – our results suggest that it’s not just ischemic damage and a lot of the harm is caused by hemorrhage after reperfusion.”

It has been known for many years that hemorrhage is often seen in the myocardium in large MIs, but it has not been established before now whether it contributes to the injury or not, Dr. Dharmakumar explained.

“This study was done to look at that – and we found that the hemorrhage drives a second layer of injury on top of the ischemia.”

Dr. Dharmakumar said this hemorrhage is part of the phenomenon known as reperfusion injury. “This has been known to exist for many years, but we haven’t fully understood all the factors contributing to it. Our results suggest that hemorrhage is a major component of reperfusion injury – probably the dominant factor,” he said.  

The researchers are now working on therapeutic approaches to try to prevent this hemorrhage and/or to minimize its effect.

“We are studying how hemorrhage drives damage and how to block these biological processes,” Dr. Dharmakumar said. “Our studies suggest that hemorrhage could account for up to half of the damage caused by a myocardial infarction. If we can limit that, we should be able to reduce the size of the infarct and this should translate into better long-term outcomes.

“I’m very excited about these results,” he added. “We are already seeing a remarkable improvement in animal models with some of the potential therapeutic approaches we are working on.”

The current study is published in the January 2022 issue of the Journal of the American College of Cardiology (JACC).

The authors explain that it is now recognized that reperfusion injury can contribute to increasing infarct size, which they refer to as “infarct surge.” Previous studies have also shown that reperfusion injury can contribute to as much as 50% of the final infarct size, but the factors contributing to the observed variability are not known, and previous attempts to limit infarct surge from reperfusion injury have failed.

They noted that after reperfusion, microvessels can remain obstructed, resulting in intramyocardial hemorrhage. They conducted the current study to investigate whether such hemorrhage causes expansion of the infarct.

They studied 70 patients with ST-segment elevation MI who were categorized with cardiovascular MRI to have intramyocardial hemorrhage or not following primary PCI, and for whom serial cardiac troponin measures were used to assess infarct size.

Results showed that while troponin levels were not different before reperfusion, patients with intramyocardial hemorrhage had significantly higher cardiac troponin levels after reperfusion and these levels peaked earlier than in patients without hemorrhage.

In animal models, those with intramyocardial hemorrhage had a more rapid expansion of myocardial necrosis than did those without hemorrhage, and within 72 hours of reperfusion, a fourfold greater loss in salvageable myocardium was evident in hemorrhagic MIs.

“We have shown that damage to the heart continues after revascularization as measured by rapidly increasing troponin levels in the hearts that have had a hemorrhage,” Dr. Dharmakumar said.

“Hemorrhage in the myocardium was associated with larger infarctions, and in infarcts causing the same area of myocardium to be at risk, those with hemorrhage after revascularization lost a lot more of the salvageable myocardium than those without hemorrhage,” he added.

Dr. Dharmakumar estimates that such hemorrhage occurs in about half of MIs after revascularization, with risk factors including male gender, anterior wall MIs, and smoking.

He pointed out that previous attempts to treat or prevent reperfusion injury have not been successful, probably because they have not been addressing the key mechanism. “We have not been looking at hemorrhage in this regard until now. This is because it is only recently that we have had the tools to be able to identify hemorrhage in the heart with the use of cardiac MRI.” 
 

Final frontier

In an accompanying editorial, Colin Berry, MBChB, University of Glasgow, and Borja Ibáñez, MD, Jiménez Díaz Foundation University Hospital, Madrid, said they applaud the investigators for providing new, mechanistic insights into a difficult clinical problem that has an unmet therapeutic need.

But they pointed out that it is difficult to completely dissect the impact of hemorrhage versus MI size on adverse remodeling, noting that it might be the case that more severe ischemia/reperfusion events are associated with large MI sizes and higher degree of hemorrhage.

However, they concluded that: “Intramyocardial hemorrhage represents the final frontier for preventing heart failure post-MI. It is readily detected using CMR, and clinical research of novel therapeutic approaches merits prioritization.”

This work was supported by grants from National Institutes of Health/National Heart, Lung, and Blood Institute. Dr. Dharmakumar and coauthor Robert Finney, PhD, have ownership interest in Cardiotheranostics. Dr. Berry is employed by the University of Glasgow, which holds consultancy and research agreements for his work with Abbott Vascular, AstraZeneca, Boehringer Ingelheim, Causeway Therapeutics, Coroventis, Genentech, GlaxoSmithKline, HeartFlow, Menarini, Neovasc, Siemens Healthcare, and Valo Health.

A version of this article first appeared on Medscape.com.