The American Academy of Dermatology has issued a position statement to address the unique health care disparities faced by sexual and gender minority (SGM) people, including LGBTQ individuals.

Some of the unique dermatologic issues faced by SGM individuals include a disproportionate risk for skin cancer in men who have sex with men; higher rates of sexually transmitted infections such as HIV, anogenital dysplasia, and anal cancer; and management of complications such as acne or scarring stemming from medical and/or surgical gender-affirming treatments for transgender individuals. In addition, racial and ethnic minority persons who identify as SGM or LGBTQ face additional stigma and health care disparities.

“While the precise role of dermatology remains controversial regarding anal cancer screening, treatment, and surveillance in these populations, comprehensive skin examinations as well as appropriate counseling and referrals may be linked to earlier detection and improved outcomes,” the statement notes.

The AAD has already taken some steps in advancing the care of SGM individuals, including dedicated educational sessions and workshops at AAD meetings, formation of the AAD LGBTQ/SGM Health Expert Resource Group, incorporation of LGBTQ/SGM content into online AAD basic dermatology curriculum modules, revision of the AAD position statement on isotretinoin, and forthcoming book chapters and CME articles for the Journal of the American Academy of Dermatology.

In order to further commit to the care of diverse populations, the AAD recognized a series of 11 positions in accordance with the association’s “core values of patient-first medicine and visionary leadership,” such as recognizing and affirming the identity and dignity of LGBTQ/SGM individuals, opposing all bias and discrimination, endorsing policies and initiatives that ensure nondiscrimination, and supporting training in cultural humility and structural competency.

“Adequate training of medical professionals regarding the unique health care needs of LGBTQ/SGM people and ongoing research into best care practices are necessary to provide care that facilitates trust and resilience while ensuring the ability of LGBTQ/SGM individuals to thrive,” the statement says.

Find the full position statement on the AAD website.

[email protected]

The American Academy of Dermatology has issued a position statement to address the unique health care disparities faced by sexual and gender minority (SGM) people, including LGBTQ individuals.

Some of the unique dermatologic issues faced by SGM individuals include a disproportionate risk for skin cancer in men who have sex with men; higher rates of sexually transmitted infections such as HIV, anogenital dysplasia, and anal cancer; and management of complications such as acne or scarring stemming from medical and/or surgical gender-affirming treatments for transgender individuals. In addition, racial and ethnic minority persons who identify as SGM or LGBTQ face additional stigma and health care disparities.

“While the precise role of dermatology remains controversial regarding anal cancer screening, treatment, and surveillance in these populations, comprehensive skin examinations as well as appropriate counseling and referrals may be linked to earlier detection and improved outcomes,” the statement notes.

The AAD has already taken some steps in advancing the care of SGM individuals, including dedicated educational sessions and workshops at AAD meetings, formation of the AAD LGBTQ/SGM Health Expert Resource Group, incorporation of LGBTQ/SGM content into online AAD basic dermatology curriculum modules, revision of the AAD position statement on isotretinoin, and forthcoming book chapters and CME articles for the Journal of the American Academy of Dermatology.

In order to further commit to the care of diverse populations, the AAD recognized a series of 11 positions in accordance with the association’s “core values of patient-first medicine and visionary leadership,” such as recognizing and affirming the identity and dignity of LGBTQ/SGM individuals, opposing all bias and discrimination, endorsing policies and initiatives that ensure nondiscrimination, and supporting training in cultural humility and structural competency.

“Adequate training of medical professionals regarding the unique health care needs of LGBTQ/SGM people and ongoing research into best care practices are necessary to provide care that facilitates trust and resilience while ensuring the ability of LGBTQ/SGM individuals to thrive,” the statement says.

Find the full position statement on the AAD website.

[email protected]

The American Academy of Dermatology has issued a position statement to address the unique health care disparities faced by sexual and gender minority (SGM) people, including LGBTQ individuals.

Some of the unique dermatologic issues faced by SGM individuals include a disproportionate risk for skin cancer in men who have sex with men; higher rates of sexually transmitted infections such as HIV, anogenital dysplasia, and anal cancer; and management of complications such as acne or scarring stemming from medical and/or surgical gender-affirming treatments for transgender individuals. In addition, racial and ethnic minority persons who identify as SGM or LGBTQ face additional stigma and health care disparities.

“While the precise role of dermatology remains controversial regarding anal cancer screening, treatment, and surveillance in these populations, comprehensive skin examinations as well as appropriate counseling and referrals may be linked to earlier detection and improved outcomes,” the statement notes.

The AAD has already taken some steps in advancing the care of SGM individuals, including dedicated educational sessions and workshops at AAD meetings, formation of the AAD LGBTQ/SGM Health Expert Resource Group, incorporation of LGBTQ/SGM content into online AAD basic dermatology curriculum modules, revision of the AAD position statement on isotretinoin, and forthcoming book chapters and CME articles for the Journal of the American Academy of Dermatology.

In order to further commit to the care of diverse populations, the AAD recognized a series of 11 positions in accordance with the association’s “core values of patient-first medicine and visionary leadership,” such as recognizing and affirming the identity and dignity of LGBTQ/SGM individuals, opposing all bias and discrimination, endorsing policies and initiatives that ensure nondiscrimination, and supporting training in cultural humility and structural competency.

“Adequate training of medical professionals regarding the unique health care needs of LGBTQ/SGM people and ongoing research into best care practices are necessary to provide care that facilitates trust and resilience while ensuring the ability of LGBTQ/SGM individuals to thrive,” the statement says.

Find the full position statement on the AAD website.

[email protected]

An immune-related adverse event during initial treatment with an immune checkpoint inhibitor does not necessarily preclude a rechallenge, based on a review of outcomes in 93 patients with a variety of cancers who were part of a cohort study.

Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.

In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.

As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.

“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.

The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).

The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.

When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).

“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.

“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.

The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.

SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.

An immune-related adverse event during initial treatment with an immune checkpoint inhibitor does not necessarily preclude a rechallenge, based on a review of outcomes in 93 patients with a variety of cancers who were part of a cohort study.

Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.

In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.

As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.

“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.

The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).

The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.

When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).

“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.

“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.

The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.

SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.

An immune-related adverse event during initial treatment with an immune checkpoint inhibitor does not necessarily preclude a rechallenge, based on a review of outcomes in 93 patients with a variety of cancers who were part of a cohort study.

Rechallenge resulted in the recurrence of a grade 2 or higher immune-related adverse event (irAE) in 55% of rechallenged patients, but no deaths occurred, according to Audrey Simonaggio, MD, of the department of drug development at Gustave Roussy, Villejuif, France, and colleagues.

In those rechallenged patients who had a second irAE, the second event was not more severe than the first. “The rechallenge should first be assessed in a multidisciplinary team meeting with regard to each patient’s individual risk-reward ratio. ... We recommend close monitoring,” the researchers wrote in a study published in JAMA Oncology.

As there are no specific recommendations to guide the decision to rechallenge, the usefulness of the rechallenge was considered. The readministration could be delayed if the patient was in complete or excellent partial response. The existence of other therapeutic alternatives was also important as was the patient’s clinical state. Rechallenge was considered possible only after the grade of the initial irAE returned to 0 or 1.

“Because of life-threatening risk, we did not support rechallenge for cardiac (myocarditis) and neurologic irAEs [such] as Guillain-Barré syndrome, encephalitis, and severe myositis,” they said. CT scans were used to guide the decision to rechallenge in those with initial lung adverse events.

The cohort study included 93 consecutive adult patients who were referred over an 18-month period to the ImmunoTOX assessment board at the Gustave Roussy cancer center and followed for at least 1 year. The cohort was balanced for gender and ranged in age from 33 to 85 years, with a median age of 62.5 years. Melanoma was the predominant tumor (33%), followed by lung (16%), colorectal (9%), and lymphoma (9%).

The initial immune-related adverse event was a grade 2 event in 46% of patients, grade 3 in 39%, and grade 4 in 15%. Events included hepatitis (18%), skin toxicity (15%), pneumonitis (14%), colitis (12%), and arthralgia (7.5%). A rechallenge with the same anti–PD-1 or anti–PD-L1 was conducted in 43% of patients.

When compared with patients who were not rechallenged, there was no difference in median patient age, time to initial immune-related adverse event (five vs. three treatment cycles), event severity, or steroid use. With a median follow-up period of 14 months, the same or a different immune-related adverse event occurred in 22 patients (55%). A shorter time to the initial event was linked to the occurrence of a second event (9 vs. 15 weeks; P = .04).

“However, we did observe a trend toward a higher recurrence rate after a more severe initial irAE and a trend toward more frequent recurrence in patients treated with corticosteroids after the initial irAE,” the researchers wrote. “An anti–PD-1or anti–PD-L1 rechallenge after a grade 4 irAE should always be considered with caution.” Three of the five patients with these events were being treated for lymphoma, they said.

“As long as patients are closely monitored, anti–PD-1 or anti–PD-L1 rechallenge appears to have an acceptable toxic effect profile. Myocarditis and neurologic toxic effect should remain a contraindication. Rechallenge conditions require further investigation in a prospective clinical trial. ... Well-powered, prospective studies with a larger number of patients would be required to generate information on putative risk factors for the recurrence of irAEs. Our results highlighted the value of a review board, like ImmunoTOX, with intention to build a large irAE database and then establish evidence-based guidelines on the safety of a rechallenge,” the researchers concluded.

The study was supported by the Gustave Roussy cancer center and the Gustave Roussy immunotherapy program. Dr. Simonaggio had no relevant disclosures; several coauthors reported consultancy fees and research support from multiple drug companies.

SOURCE: Simonaggio A et al. JAMA Oncol. 2019 Jun 6. doi:10.1001/jamaoncol.2019.1022.

The Food and Drug Administration has approved two new formulations for the anti–interleukin-5 biologic mepolizumab (Nucala) for treatment of certain severe or rare forms of asthma, according to a press release from the drug’s developer. The biologic will now be available as an autoinjector and as a prefilled safety syringe.

The 100-mg subcutaneous mepolizumab injection is indicated as an add-on treatment for patients 12 years and older with severe eosinophilic asthma, and the three-dose 100-mg subcutaneous injections are indicated for the rare eosinophilic granulomatosis and polyangiitis, with the biologic administered every 4 weeks in either context. The release emphasizes that mepolizumab is not approved for acute bronchospasm or status asthmaticus. Health care professionals should first determine whether self-assisted administration or administration provided by a caregiver is appropriate, and then they should provide patients and/or caregivers with proper training in how to do so.

The approval is based on two open-label, single-arm, phase 3a studies that demonstrated successful administration was possible with these options among patients with severe eosinophilic asthma, at rates of 89%-95% in one study and 100% in the other. These results were followed by those of an open-label, parallel group, single-dose study that confirmed the pharmacokinetic and pharmacodynamic profiles of these new means of administration were comparable with those currently approved.

Mepolizumab is not indicated for those with a history of hypersensitivity to either mepolizumab or to the formulation’s excipients, such as anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, or rash. Any reductions of inhaled corticosteroids after initiation of mepolizumab should be gradual and under the supervision of a health care professional. Some infections by herpes zoster have been observed. The most common adverse reactions (occurring in 3% or more of patients and more often than with placebo) during the first 24 weeks of treatment were headache (19%), injection site reaction (8%), back pain (5%), fatigue (5%), influenza (3%), urinary tract infection (3%), abdominal pain upper (3%), pruritus (3%), eczema (3%), and muscle spasm (3%). Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved two new formulations for the anti–interleukin-5 biologic mepolizumab (Nucala) for treatment of certain severe or rare forms of asthma, according to a press release from the drug’s developer. The biologic will now be available as an autoinjector and as a prefilled safety syringe.

The 100-mg subcutaneous mepolizumab injection is indicated as an add-on treatment for patients 12 years and older with severe eosinophilic asthma, and the three-dose 100-mg subcutaneous injections are indicated for the rare eosinophilic granulomatosis and polyangiitis, with the biologic administered every 4 weeks in either context. The release emphasizes that mepolizumab is not approved for acute bronchospasm or status asthmaticus. Health care professionals should first determine whether self-assisted administration or administration provided by a caregiver is appropriate, and then they should provide patients and/or caregivers with proper training in how to do so.

The approval is based on two open-label, single-arm, phase 3a studies that demonstrated successful administration was possible with these options among patients with severe eosinophilic asthma, at rates of 89%-95% in one study and 100% in the other. These results were followed by those of an open-label, parallel group, single-dose study that confirmed the pharmacokinetic and pharmacodynamic profiles of these new means of administration were comparable with those currently approved.

Mepolizumab is not indicated for those with a history of hypersensitivity to either mepolizumab or to the formulation’s excipients, such as anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, or rash. Any reductions of inhaled corticosteroids after initiation of mepolizumab should be gradual and under the supervision of a health care professional. Some infections by herpes zoster have been observed. The most common adverse reactions (occurring in 3% or more of patients and more often than with placebo) during the first 24 weeks of treatment were headache (19%), injection site reaction (8%), back pain (5%), fatigue (5%), influenza (3%), urinary tract infection (3%), abdominal pain upper (3%), pruritus (3%), eczema (3%), and muscle spasm (3%). Full prescribing information can be found on the FDA website.

[email protected]

The Food and Drug Administration has approved two new formulations for the anti–interleukin-5 biologic mepolizumab (Nucala) for treatment of certain severe or rare forms of asthma, according to a press release from the drug’s developer. The biologic will now be available as an autoinjector and as a prefilled safety syringe.

The 100-mg subcutaneous mepolizumab injection is indicated as an add-on treatment for patients 12 years and older with severe eosinophilic asthma, and the three-dose 100-mg subcutaneous injections are indicated for the rare eosinophilic granulomatosis and polyangiitis, with the biologic administered every 4 weeks in either context. The release emphasizes that mepolizumab is not approved for acute bronchospasm or status asthmaticus. Health care professionals should first determine whether self-assisted administration or administration provided by a caregiver is appropriate, and then they should provide patients and/or caregivers with proper training in how to do so.

The approval is based on two open-label, single-arm, phase 3a studies that demonstrated successful administration was possible with these options among patients with severe eosinophilic asthma, at rates of 89%-95% in one study and 100% in the other. These results were followed by those of an open-label, parallel group, single-dose study that confirmed the pharmacokinetic and pharmacodynamic profiles of these new means of administration were comparable with those currently approved.

Mepolizumab is not indicated for those with a history of hypersensitivity to either mepolizumab or to the formulation’s excipients, such as anaphylaxis, angioedema, bronchospasm, hypotension, urticaria, or rash. Any reductions of inhaled corticosteroids after initiation of mepolizumab should be gradual and under the supervision of a health care professional. Some infections by herpes zoster have been observed. The most common adverse reactions (occurring in 3% or more of patients and more often than with placebo) during the first 24 weeks of treatment were headache (19%), injection site reaction (8%), back pain (5%), fatigue (5%), influenza (3%), urinary tract infection (3%), abdominal pain upper (3%), pruritus (3%), eczema (3%), and muscle spasm (3%). Full prescribing information can be found on the FDA website.

[email protected]

The advent of electronic medical records (EMRs) is arguably the most important technological revolution in modern medicine. The transition from paper documentation to EMRs has improved organization of medical records, consolidating all physician notes, orders, consultations, laboratory test results, and radiologic studies into a single accessible location.¹ However, this revolution has led to mixed consequences for patients, especially in the outpatient setting. The use of EMRs can facilitate questions, clarification, and discussion between patients and health care providers, prompted by the sections of the EMR. Unfortunately, patients too often encounter pressed-for-time, documentation-focused providers who may not even look up from the computer. Provider behaviors such as making eye contact, stopping typing during discussion of sensitive topics, and allowing patients to view the computer screen and using it as an educational tool are important for patients to have a positive care experience.² We envision further integration of current and future technology to overcome the challenges of outpatient care. We use a hypothetical patient encounter to illustrate what the future may hold.

Hypothetical Patient Encounter

An established patient, Ms. PS, comes to the dermatology clinic for a follow-up appointment and walks into an examination room (Figure). Prior to entering the room, the provider, Dr. FT, reviews Ms. PS’s history via a dermatology-specific EMR and reads that Ms. PS has a 1.5-year history of psoriasis and is considering other therapeutic options.

Upon entering the room, Dr. FT tells Ms. PS that the visit is being recorded and transcribed. A large interactive screen is a key component of the examination room. A remote medical assistant is virtually present via video to transcribe and document the patient-provider interaction. There is potential for artificial intelligence to replace the remote medical assistant in the future. Wearable technology, including a smartwatch and Bluetooth headphones, allow the provider to record audio of the visit as well as through microphones on the interactive screen.

As the interaction begins, Ms. PS reports that her psoriasis is poorly controlled with her current regimen of topical steroids. Dr. FT inquires about Ms. PS’s current symptoms and psychosocial well-being. Dr. FT then performs a skin examination and is easily able to evaluate her skin vs prior visits, as clinical images from prior visits are automatically displayed on the interactive screen. Dr. FT also closely examines Ms. PS’s nails and conducts a joint examination, reminded by a notification on his wearable technology. After capturing clinical images of Ms. PS’s skin and nails with a secure EMR-connected tablet, Dr. FT briefly steps out of the room to allow Ms. PS to get dressed and feel more comfortable in the discussion to follow.

Once he reenters the examination room, Dr. FT initiates a discussion on next steps. Ms. PS’s pathology report and clinical images are displayed on the interactive screen, along with her most recent laboratory test results, which were completed prior to the visit in anticipation of changing therapies. Dr. FT presents Ms. PS with several evidence-based therapeutic options for psoriasis, and she expresses interest in methotrexate. Following the discussion, the remote medical assistant displays information about methotrexate on the interactive screen, including evidence for treatment of psoriasis, contraindications, laboratory monitoring requirements, and possible adverse effects for both the patient and provider to review together. Dr. FT reviews the laboratory test results displayed on the screen, specifically her transaminase levels, and confirms that methotrexate is an appropriate therapeutic option. After a full discussion of risks and benefits, Ms. PS chooses to initiate methotrexate treatment. Reminded by a notification on his wearable technology, Dr. FT follows evidence-based dosing guidelines and sends the prescription electronically to Ms. PS’s pharmacy, which concludes Ms. PS’s visit.

Analysis of the Patient Encounter

In this interaction, Dr. FT was able to fully engage with the patient, unencumbered by the demands of documentation. There were only a few instances when the provider looked at or touched the interactive screen. Furthermore, joint decision-making was optimized by allowing both the patient and provider to review diagnostic test results and current evidence-based therapeutic guidelines together through the interactive screen. Ms. PS goes home feeling satisfied that she received her provider’s complete attention and that they selected a therapeutic option supported by evidence. After the visit, the remote medial assistant’s transcript populates a patient note template, which Dr. FT reviews and amends to create the final note. Reducing the time required to write patient notes increases the speed at which Dr. FT can complete patient encounters and may improve clinic flow and productivity. In addition, a patient summary is generated from Dr. FT’s final note, with an emphasis on patient instructions, and is sent to Ms. PS.

Final Thoughts

Our proposed integration of currently available and future technology can help minimize documentation burdens on providers and improve patient-provider communication in the age of the EMR, thus optimizing patient satisfaction and outcomes.

The advent of electronic medical records (EMRs) is arguably the most important technological revolution in modern medicine. The transition from paper documentation to EMRs has improved organization of medical records, consolidating all physician notes, orders, consultations, laboratory test results, and radiologic studies into a single accessible location.¹ However, this revolution has led to mixed consequences for patients, especially in the outpatient setting. The use of EMRs can facilitate questions, clarification, and discussion between patients and health care providers, prompted by the sections of the EMR. Unfortunately, patients too often encounter pressed-for-time, documentation-focused providers who may not even look up from the computer. Provider behaviors such as making eye contact, stopping typing during discussion of sensitive topics, and allowing patients to view the computer screen and using it as an educational tool are important for patients to have a positive care experience.² We envision further integration of current and future technology to overcome the challenges of outpatient care. We use a hypothetical patient encounter to illustrate what the future may hold.

Hypothetical Patient Encounter

An established patient, Ms. PS, comes to the dermatology clinic for a follow-up appointment and walks into an examination room (Figure). Prior to entering the room, the provider, Dr. FT, reviews Ms. PS’s history via a dermatology-specific EMR and reads that Ms. PS has a 1.5-year history of psoriasis and is considering other therapeutic options.

Upon entering the room, Dr. FT tells Ms. PS that the visit is being recorded and transcribed. A large interactive screen is a key component of the examination room. A remote medical assistant is virtually present via video to transcribe and document the patient-provider interaction. There is potential for artificial intelligence to replace the remote medical assistant in the future. Wearable technology, including a smartwatch and Bluetooth headphones, allow the provider to record audio of the visit as well as through microphones on the interactive screen.

As the interaction begins, Ms. PS reports that her psoriasis is poorly controlled with her current regimen of topical steroids. Dr. FT inquires about Ms. PS’s current symptoms and psychosocial well-being. Dr. FT then performs a skin examination and is easily able to evaluate her skin vs prior visits, as clinical images from prior visits are automatically displayed on the interactive screen. Dr. FT also closely examines Ms. PS’s nails and conducts a joint examination, reminded by a notification on his wearable technology. After capturing clinical images of Ms. PS’s skin and nails with a secure EMR-connected tablet, Dr. FT briefly steps out of the room to allow Ms. PS to get dressed and feel more comfortable in the discussion to follow.

Once he reenters the examination room, Dr. FT initiates a discussion on next steps. Ms. PS’s pathology report and clinical images are displayed on the interactive screen, along with her most recent laboratory test results, which were completed prior to the visit in anticipation of changing therapies. Dr. FT presents Ms. PS with several evidence-based therapeutic options for psoriasis, and she expresses interest in methotrexate. Following the discussion, the remote medical assistant displays information about methotrexate on the interactive screen, including evidence for treatment of psoriasis, contraindications, laboratory monitoring requirements, and possible adverse effects for both the patient and provider to review together. Dr. FT reviews the laboratory test results displayed on the screen, specifically her transaminase levels, and confirms that methotrexate is an appropriate therapeutic option. After a full discussion of risks and benefits, Ms. PS chooses to initiate methotrexate treatment. Reminded by a notification on his wearable technology, Dr. FT follows evidence-based dosing guidelines and sends the prescription electronically to Ms. PS’s pharmacy, which concludes Ms. PS’s visit.

Analysis of the Patient Encounter

In this interaction, Dr. FT was able to fully engage with the patient, unencumbered by the demands of documentation. There were only a few instances when the provider looked at or touched the interactive screen. Furthermore, joint decision-making was optimized by allowing both the patient and provider to review diagnostic test results and current evidence-based therapeutic guidelines together through the interactive screen. Ms. PS goes home feeling satisfied that she received her provider’s complete attention and that they selected a therapeutic option supported by evidence. After the visit, the remote medial assistant’s transcript populates a patient note template, which Dr. FT reviews and amends to create the final note. Reducing the time required to write patient notes increases the speed at which Dr. FT can complete patient encounters and may improve clinic flow and productivity. In addition, a patient summary is generated from Dr. FT’s final note, with an emphasis on patient instructions, and is sent to Ms. PS.

Final Thoughts

Our proposed integration of currently available and future technology can help minimize documentation burdens on providers and improve patient-provider communication in the age of the EMR, thus optimizing patient satisfaction and outcomes.

The advent of electronic medical records (EMRs) is arguably the most important technological revolution in modern medicine. The transition from paper documentation to EMRs has improved organization of medical records, consolidating all physician notes, orders, consultations, laboratory test results, and radiologic studies into a single accessible location.¹ However, this revolution has led to mixed consequences for patients, especially in the outpatient setting. The use of EMRs can facilitate questions, clarification, and discussion between patients and health care providers, prompted by the sections of the EMR. Unfortunately, patients too often encounter pressed-for-time, documentation-focused providers who may not even look up from the computer. Provider behaviors such as making eye contact, stopping typing during discussion of sensitive topics, and allowing patients to view the computer screen and using it as an educational tool are important for patients to have a positive care experience.² We envision further integration of current and future technology to overcome the challenges of outpatient care. We use a hypothetical patient encounter to illustrate what the future may hold.

Hypothetical Patient Encounter

An established patient, Ms. PS, comes to the dermatology clinic for a follow-up appointment and walks into an examination room (Figure). Prior to entering the room, the provider, Dr. FT, reviews Ms. PS’s history via a dermatology-specific EMR and reads that Ms. PS has a 1.5-year history of psoriasis and is considering other therapeutic options.

Upon entering the room, Dr. FT tells Ms. PS that the visit is being recorded and transcribed. A large interactive screen is a key component of the examination room. A remote medical assistant is virtually present via video to transcribe and document the patient-provider interaction. There is potential for artificial intelligence to replace the remote medical assistant in the future. Wearable technology, including a smartwatch and Bluetooth headphones, allow the provider to record audio of the visit as well as through microphones on the interactive screen.

As the interaction begins, Ms. PS reports that her psoriasis is poorly controlled with her current regimen of topical steroids. Dr. FT inquires about Ms. PS’s current symptoms and psychosocial well-being. Dr. FT then performs a skin examination and is easily able to evaluate her skin vs prior visits, as clinical images from prior visits are automatically displayed on the interactive screen. Dr. FT also closely examines Ms. PS’s nails and conducts a joint examination, reminded by a notification on his wearable technology. After capturing clinical images of Ms. PS’s skin and nails with a secure EMR-connected tablet, Dr. FT briefly steps out of the room to allow Ms. PS to get dressed and feel more comfortable in the discussion to follow.

Once he reenters the examination room, Dr. FT initiates a discussion on next steps. Ms. PS’s pathology report and clinical images are displayed on the interactive screen, along with her most recent laboratory test results, which were completed prior to the visit in anticipation of changing therapies. Dr. FT presents Ms. PS with several evidence-based therapeutic options for psoriasis, and she expresses interest in methotrexate. Following the discussion, the remote medical assistant displays information about methotrexate on the interactive screen, including evidence for treatment of psoriasis, contraindications, laboratory monitoring requirements, and possible adverse effects for both the patient and provider to review together. Dr. FT reviews the laboratory test results displayed on the screen, specifically her transaminase levels, and confirms that methotrexate is an appropriate therapeutic option. After a full discussion of risks and benefits, Ms. PS chooses to initiate methotrexate treatment. Reminded by a notification on his wearable technology, Dr. FT follows evidence-based dosing guidelines and sends the prescription electronically to Ms. PS’s pharmacy, which concludes Ms. PS’s visit.

Analysis of the Patient Encounter

In this interaction, Dr. FT was able to fully engage with the patient, unencumbered by the demands of documentation. There were only a few instances when the provider looked at or touched the interactive screen. Furthermore, joint decision-making was optimized by allowing both the patient and provider to review diagnostic test results and current evidence-based therapeutic guidelines together through the interactive screen. Ms. PS goes home feeling satisfied that she received her provider’s complete attention and that they selected a therapeutic option supported by evidence. After the visit, the remote medial assistant’s transcript populates a patient note template, which Dr. FT reviews and amends to create the final note. Reducing the time required to write patient notes increases the speed at which Dr. FT can complete patient encounters and may improve clinic flow and productivity. In addition, a patient summary is generated from Dr. FT’s final note, with an emphasis on patient instructions, and is sent to Ms. PS.

Final Thoughts

Our proposed integration of currently available and future technology can help minimize documentation burdens on providers and improve patient-provider communication in the age of the EMR, thus optimizing patient satisfaction and outcomes.

As an academic nurse practitioner hospitalist with faculty and leadership roles, I found that HM19 had many important and helpful topics that apply directly to my practice.

The “Onboarding Best Practices” session provided specific examples and tips for clinical ramp up, enculturation, and orienting staff to an academic career. As a result of this talk, I began the process of establishing a formal enculturation activity for new hires that includes a panel of senior advanced practice provider (APP) hospitalists to give career path advice.

The “Adaptive Leadership for Hospitalists” workshop provided the opportunity to practice emotional intelligence and effective communication in managing routine and difficult leadership interactions. The “Practice Models/Models of Care for Optimal Integration of NPs and PAs” presentation provided insight into variable team structures at other institutions that could be considered for improved efficiency in my group. The “Academic NP/PA” session provided ideas for how to apply for faculty positions in academic institutions. It also gave APPs who have faculty appointment specific illustrations of using current educational, quality improvement, and research projects to promote. I particularly found the “What Mentorship Has Meant to Me” talk significant. It gave practical essential advice on making sure there is chemistry and trust when seeking a mentor and staying engaged to be a successful mentee.

APPs, whether practicing in academic, private, or community settings, should attend the SHM Annual Conference. SHM is very inclusive and proud of APPs as colleagues and leaders. There are topics that directly apply to the needs of APP hospitalists – including career advancement – and that create excitement for APP practice in hospital medicine.

The Annual Conference also provides the very unique opportunity to meet and establish relationships with APP and physician colleagues and leaders nationwide. These relationships lend to career advancing opportunities for collaboration in clinical excellence, education, quality improvement, research, and leadership.
 

Dr. Apodaca is assistant professor and nurse practitioner hospitalist at the University of New Mexico. She is one of the first APPNP/PAs to receive faculty appointment at UNM. She serves as codirector of the UNM APP Hospital Medicine Fellowship and director of the APP Hospital Medicine Team. She is also the president of the New Mexico Chapter of SHM and is the first APP at her institution to achieve designation as a Fellow in Hospital Medicine.

As an academic nurse practitioner hospitalist with faculty and leadership roles, I found that HM19 had many important and helpful topics that apply directly to my practice.

The “Onboarding Best Practices” session provided specific examples and tips for clinical ramp up, enculturation, and orienting staff to an academic career. As a result of this talk, I began the process of establishing a formal enculturation activity for new hires that includes a panel of senior advanced practice provider (APP) hospitalists to give career path advice.

The “Adaptive Leadership for Hospitalists” workshop provided the opportunity to practice emotional intelligence and effective communication in managing routine and difficult leadership interactions. The “Practice Models/Models of Care for Optimal Integration of NPs and PAs” presentation provided insight into variable team structures at other institutions that could be considered for improved efficiency in my group. The “Academic NP/PA” session provided ideas for how to apply for faculty positions in academic institutions. It also gave APPs who have faculty appointment specific illustrations of using current educational, quality improvement, and research projects to promote. I particularly found the “What Mentorship Has Meant to Me” talk significant. It gave practical essential advice on making sure there is chemistry and trust when seeking a mentor and staying engaged to be a successful mentee.

APPs, whether practicing in academic, private, or community settings, should attend the SHM Annual Conference. SHM is very inclusive and proud of APPs as colleagues and leaders. There are topics that directly apply to the needs of APP hospitalists – including career advancement – and that create excitement for APP practice in hospital medicine.

The Annual Conference also provides the very unique opportunity to meet and establish relationships with APP and physician colleagues and leaders nationwide. These relationships lend to career advancing opportunities for collaboration in clinical excellence, education, quality improvement, research, and leadership.
 

Dr. Apodaca is assistant professor and nurse practitioner hospitalist at the University of New Mexico. She is one of the first APPNP/PAs to receive faculty appointment at UNM. She serves as codirector of the UNM APP Hospital Medicine Fellowship and director of the APP Hospital Medicine Team. She is also the president of the New Mexico Chapter of SHM and is the first APP at her institution to achieve designation as a Fellow in Hospital Medicine.

As an academic nurse practitioner hospitalist with faculty and leadership roles, I found that HM19 had many important and helpful topics that apply directly to my practice.

The “Onboarding Best Practices” session provided specific examples and tips for clinical ramp up, enculturation, and orienting staff to an academic career. As a result of this talk, I began the process of establishing a formal enculturation activity for new hires that includes a panel of senior advanced practice provider (APP) hospitalists to give career path advice.

The “Adaptive Leadership for Hospitalists” workshop provided the opportunity to practice emotional intelligence and effective communication in managing routine and difficult leadership interactions. The “Practice Models/Models of Care for Optimal Integration of NPs and PAs” presentation provided insight into variable team structures at other institutions that could be considered for improved efficiency in my group. The “Academic NP/PA” session provided ideas for how to apply for faculty positions in academic institutions. It also gave APPs who have faculty appointment specific illustrations of using current educational, quality improvement, and research projects to promote. I particularly found the “What Mentorship Has Meant to Me” talk significant. It gave practical essential advice on making sure there is chemistry and trust when seeking a mentor and staying engaged to be a successful mentee.

APPs, whether practicing in academic, private, or community settings, should attend the SHM Annual Conference. SHM is very inclusive and proud of APPs as colleagues and leaders. There are topics that directly apply to the needs of APP hospitalists – including career advancement – and that create excitement for APP practice in hospital medicine.

The Annual Conference also provides the very unique opportunity to meet and establish relationships with APP and physician colleagues and leaders nationwide. These relationships lend to career advancing opportunities for collaboration in clinical excellence, education, quality improvement, research, and leadership.
 

Dr. Apodaca is assistant professor and nurse practitioner hospitalist at the University of New Mexico. She is one of the first APPNP/PAs to receive faculty appointment at UNM. She serves as codirector of the UNM APP Hospital Medicine Fellowship and director of the APP Hospital Medicine Team. She is also the president of the New Mexico Chapter of SHM and is the first APP at her institution to achieve designation as a Fellow in Hospital Medicine.

Among patients with moderate to severe ulcerative colitis, a median of 1.4 years and up to 4.4 years of tofacitinib therapy was safe apart from a dose-related increase in risk of herpes zoster infection, according to an integrated analysis of data from five clinical trials.

clsgraphics/iStockphoto

Compared with placebo, a 5-mg twice-daily maintenance dose of tofacitinib (Xeljanz) produced a 2.1-fold greater risk of herpes zoster infection (95% confidence interval, 0.4-6.0), while a 10-mg, twice-daily dose produced a statistically significant 6.6-fold increase in incidence (95% CI, 3.2-12.2).

With the exception of the higher incidence rate of herpes zoster, “in the overall cohort, the safety profile of tofacitinib was generally similar to that of tumor necrosis factor inhibitor therapies,” wrote William J. Sandborn, MD, director of the inflammatory bowel disease center and professor of medicine, at the University of California, San Diego, and associates. The findings were published in Clinical Gastroenterology and Hepatology.

Tofacitinib is an oral, small-molecular Janus kinase inhibitor approved in the United States for treating moderate to severe ulcerative colitis, as well as rheumatoid and psoriatic arthritis. The recommended ulcerative colitis dose is 10 mg twice daily for at least 8 weeks (induction therapy) followed by 5 or 10 mg twice daily (maintenance). The safety of tofacitinib has been studied in patients with rheumatoid arthritis through 9 years of treatment. To begin a similar undertaking in ulcerative colitis, Dr. Sandborn and associates pooled data from three 8-week, double-blind, placebo-controlled induction trials, as well as one 52-week, double-blind, placebo-controlled maintenance trial and one ongoing open-label trial. All patients received twice-daily tofacitinib (5 mg or 10 mg) or placebo.

Among 1,157 tofacitinib recipients in the pooled analysis, 84% received an average of 10 mg twice daily. For every 100 person-years of tofacitinib exposure, there were an estimated 2.0 serious infections, 1.3 opportunistic infections, 4.1 herpes zoster infections, 1.4 malignancies (including nonmelanoma skin cancer, which had an incidence of 0.7), 0.2 major adverse cardiovascular events, and 0.2 gastrointestinal perforations. The likelihood of these events did not increase with time on tofacitinib, the researchers said.

SOURCE: Sandborn WJ et al. Clin Gastroenterol Hepatol. 2018 Nov 23. doi: 10.1016/j.cgh.2018.11.035.

Among patients with moderate to severe ulcerative colitis, a median of 1.4 years and up to 4.4 years of tofacitinib therapy was safe apart from a dose-related increase in risk of herpes zoster infection, according to an integrated analysis of data from five clinical trials.

clsgraphics/iStockphoto

Compared with placebo, a 5-mg twice-daily maintenance dose of tofacitinib (Xeljanz) produced a 2.1-fold greater risk of herpes zoster infection (95% confidence interval, 0.4-6.0), while a 10-mg, twice-daily dose produced a statistically significant 6.6-fold increase in incidence (95% CI, 3.2-12.2).

With the exception of the higher incidence rate of herpes zoster, “in the overall cohort, the safety profile of tofacitinib was generally similar to that of tumor necrosis factor inhibitor therapies,” wrote William J. Sandborn, MD, director of the inflammatory bowel disease center and professor of medicine, at the University of California, San Diego, and associates. The findings were published in Clinical Gastroenterology and Hepatology.

Tofacitinib is an oral, small-molecular Janus kinase inhibitor approved in the United States for treating moderate to severe ulcerative colitis, as well as rheumatoid and psoriatic arthritis. The recommended ulcerative colitis dose is 10 mg twice daily for at least 8 weeks (induction therapy) followed by 5 or 10 mg twice daily (maintenance). The safety of tofacitinib has been studied in patients with rheumatoid arthritis through 9 years of treatment. To begin a similar undertaking in ulcerative colitis, Dr. Sandborn and associates pooled data from three 8-week, double-blind, placebo-controlled induction trials, as well as one 52-week, double-blind, placebo-controlled maintenance trial and one ongoing open-label trial. All patients received twice-daily tofacitinib (5 mg or 10 mg) or placebo.

Among 1,157 tofacitinib recipients in the pooled analysis, 84% received an average of 10 mg twice daily. For every 100 person-years of tofacitinib exposure, there were an estimated 2.0 serious infections, 1.3 opportunistic infections, 4.1 herpes zoster infections, 1.4 malignancies (including nonmelanoma skin cancer, which had an incidence of 0.7), 0.2 major adverse cardiovascular events, and 0.2 gastrointestinal perforations. The likelihood of these events did not increase with time on tofacitinib, the researchers said.

SOURCE: Sandborn WJ et al. Clin Gastroenterol Hepatol. 2018 Nov 23. doi: 10.1016/j.cgh.2018.11.035.

Among patients with moderate to severe ulcerative colitis, a median of 1.4 years and up to 4.4 years of tofacitinib therapy was safe apart from a dose-related increase in risk of herpes zoster infection, according to an integrated analysis of data from five clinical trials.

clsgraphics/iStockphoto

Compared with placebo, a 5-mg twice-daily maintenance dose of tofacitinib (Xeljanz) produced a 2.1-fold greater risk of herpes zoster infection (95% confidence interval, 0.4-6.0), while a 10-mg, twice-daily dose produced a statistically significant 6.6-fold increase in incidence (95% CI, 3.2-12.2).

With the exception of the higher incidence rate of herpes zoster, “in the overall cohort, the safety profile of tofacitinib was generally similar to that of tumor necrosis factor inhibitor therapies,” wrote William J. Sandborn, MD, director of the inflammatory bowel disease center and professor of medicine, at the University of California, San Diego, and associates. The findings were published in Clinical Gastroenterology and Hepatology.

Tofacitinib is an oral, small-molecular Janus kinase inhibitor approved in the United States for treating moderate to severe ulcerative colitis, as well as rheumatoid and psoriatic arthritis. The recommended ulcerative colitis dose is 10 mg twice daily for at least 8 weeks (induction therapy) followed by 5 or 10 mg twice daily (maintenance). The safety of tofacitinib has been studied in patients with rheumatoid arthritis through 9 years of treatment. To begin a similar undertaking in ulcerative colitis, Dr. Sandborn and associates pooled data from three 8-week, double-blind, placebo-controlled induction trials, as well as one 52-week, double-blind, placebo-controlled maintenance trial and one ongoing open-label trial. All patients received twice-daily tofacitinib (5 mg or 10 mg) or placebo.

Among 1,157 tofacitinib recipients in the pooled analysis, 84% received an average of 10 mg twice daily. For every 100 person-years of tofacitinib exposure, there were an estimated 2.0 serious infections, 1.3 opportunistic infections, 4.1 herpes zoster infections, 1.4 malignancies (including nonmelanoma skin cancer, which had an incidence of 0.7), 0.2 major adverse cardiovascular events, and 0.2 gastrointestinal perforations. The likelihood of these events did not increase with time on tofacitinib, the researchers said.

SOURCE: Sandborn WJ et al. Clin Gastroenterol Hepatol. 2018 Nov 23. doi: 10.1016/j.cgh.2018.11.035.

Obesity promotes the localization of inducible nitric oxide synthase (iNOS) in hepatic lysosomes, leading to a cascade of downstream effects that include excess lysosomal nitric oxide production, reduced hepatic autophagy, and insulin resistance, investigators reported.

“It is well known that in the context of obesity, chronic inflammation and lysosome dysfunction coexist in the liver,” wrote Qingwen Qian, PhD, of the University of Iowa in Iowa City and associates in Cellular and Molecular Gastroenterology and Hepatology. “Our studies suggest that lysosomal iNOS-mediated nitric oxide signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.” They noted that the findings could hasten the development of new treatments for metabolic diseases.

Lysosomes recycle autophagocytosed intracellular and extracellular material, which is crucial to maintain several types of homeostasis within the liver. Each hepatocyte has about 250 lysosomes, which help regulate nutrient sensing, glycogen metabolism, cholesterol trafficking, and viral defense.

Activation of iNOS is a hallmark of inflammation, and iNOS levels are known to be elevated in the livers of patients with hepatitis C, alcoholic cirrhosis, and alpha 1-anti-trypsin disorder, the researchers wrote. “At the cellular level, iNOS produces pathological nitric oxide [NO], which triggers downstream effects, such as aberrant S-nitrosylation. These downstream effects can disrupt the function of organelles such as the mitochondria and the endoplasmic reticulum.”

Studies indicate that pathologic NO impairs lysosomal function in neurodegenerative diseases, cardiovascular disease, nonalcoholic fatty liver disease, and kidney disease, Dr. Qian and associates noted. But it was unclear whether NO in hepatocytes was generated by local iNOS or localized to lysosomes.

The researchers therefore studied cell cultures of primary murine hepatocytes by measuring their lysosomal activity, autophagy levels, and NO levels. They also studied a murine model of diet-induced obesity in which 60% of calories were from fat. They performed glucose tolerance tests by means of intraperitoneal glucose injections and studied the effects of insulin infusion. Finally, they performed immunohistology, immunohistochemistry, electron microscopy, and measurements of nitrosylated proteins and lysosomal arginine in frozen liver sections from the mice. Lysosomal arginine is required to catalyze NO production in the setting of inflammation as observed in obesity. In fact, concomitant stimulation of lysosomal arginine transport and activation of mTOR (an enzyme which tightly regulates transcription factor EB) was sufficient to stimulate lysosomal NO production in hepatocytes even in the absence of an inflammatory stimulus; pointing to a central role for these processes.

The researchers found that a NO scavenger diminished lysosomal NO production, while overexpression of both mTOR and a lysomal arginine transporter upregulated lysosomal NO production and suppressed autophagy. In mice with diet-induced obesity, deleting iNOS also improved nitrosative stress in hepatic lysosomes, promoted lysosomal biogenesis by activating transcription factor EB, enhanced lysosomal function and autophagy, and improved hepatic insulin sensitivity. Improved insulin sensitivity diminished, however, when the researchers suppressed transcription factor EB or autophagy-related 7 (Atg7).

Usually, iNOS is primarily expressed in hepatic Kupffer cells, but obesity increases the expression of iNOS in hepatocytes, which promotes hepatic insulin resistance and inflammation, the researchers commented. Unpublished data indicate that deleting iNOS initially protects against obesity-linked fatty liver steatosis and insulin resistance, but that these benefits weaken over time. “Nevertheless, our data showed that liver-specific iNOS suppression has a protective role,” they wrote. “Specifically, we showed that iNOS inactivates transcription factor EB, and that suppression of transcription factor EB and Atg7 diminishes the improved hepatic insulin sensitivity by iNOS deletion.” Transcription factor EB both regulates autophagy and is a “key player in lipid metabolism,” they added. It remains unclear whether the metabolic effects of iNOS solely relate to autophagy, they noted.

Funders included the American Heart Association, American Diabetes Association, and National Institutes of Health. The researchers reported having no conflicts of interest.

SOURCE: Qingwen Qian, et al. Cell Molec Gastroenterol Hepatol. 2019;8(1):95-110.
 

Obesity promotes the localization of inducible nitric oxide synthase (iNOS) in hepatic lysosomes, leading to a cascade of downstream effects that include excess lysosomal nitric oxide production, reduced hepatic autophagy, and insulin resistance, investigators reported.

“It is well known that in the context of obesity, chronic inflammation and lysosome dysfunction coexist in the liver,” wrote Qingwen Qian, PhD, of the University of Iowa in Iowa City and associates in Cellular and Molecular Gastroenterology and Hepatology. “Our studies suggest that lysosomal iNOS-mediated nitric oxide signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.” They noted that the findings could hasten the development of new treatments for metabolic diseases.

Lysosomes recycle autophagocytosed intracellular and extracellular material, which is crucial to maintain several types of homeostasis within the liver. Each hepatocyte has about 250 lysosomes, which help regulate nutrient sensing, glycogen metabolism, cholesterol trafficking, and viral defense.

Activation of iNOS is a hallmark of inflammation, and iNOS levels are known to be elevated in the livers of patients with hepatitis C, alcoholic cirrhosis, and alpha 1-anti-trypsin disorder, the researchers wrote. “At the cellular level, iNOS produces pathological nitric oxide [NO], which triggers downstream effects, such as aberrant S-nitrosylation. These downstream effects can disrupt the function of organelles such as the mitochondria and the endoplasmic reticulum.”

Studies indicate that pathologic NO impairs lysosomal function in neurodegenerative diseases, cardiovascular disease, nonalcoholic fatty liver disease, and kidney disease, Dr. Qian and associates noted. But it was unclear whether NO in hepatocytes was generated by local iNOS or localized to lysosomes.

The researchers therefore studied cell cultures of primary murine hepatocytes by measuring their lysosomal activity, autophagy levels, and NO levels. They also studied a murine model of diet-induced obesity in which 60% of calories were from fat. They performed glucose tolerance tests by means of intraperitoneal glucose injections and studied the effects of insulin infusion. Finally, they performed immunohistology, immunohistochemistry, electron microscopy, and measurements of nitrosylated proteins and lysosomal arginine in frozen liver sections from the mice. Lysosomal arginine is required to catalyze NO production in the setting of inflammation as observed in obesity. In fact, concomitant stimulation of lysosomal arginine transport and activation of mTOR (an enzyme which tightly regulates transcription factor EB) was sufficient to stimulate lysosomal NO production in hepatocytes even in the absence of an inflammatory stimulus; pointing to a central role for these processes.

The researchers found that a NO scavenger diminished lysosomal NO production, while overexpression of both mTOR and a lysomal arginine transporter upregulated lysosomal NO production and suppressed autophagy. In mice with diet-induced obesity, deleting iNOS also improved nitrosative stress in hepatic lysosomes, promoted lysosomal biogenesis by activating transcription factor EB, enhanced lysosomal function and autophagy, and improved hepatic insulin sensitivity. Improved insulin sensitivity diminished, however, when the researchers suppressed transcription factor EB or autophagy-related 7 (Atg7).

Usually, iNOS is primarily expressed in hepatic Kupffer cells, but obesity increases the expression of iNOS in hepatocytes, which promotes hepatic insulin resistance and inflammation, the researchers commented. Unpublished data indicate that deleting iNOS initially protects against obesity-linked fatty liver steatosis and insulin resistance, but that these benefits weaken over time. “Nevertheless, our data showed that liver-specific iNOS suppression has a protective role,” they wrote. “Specifically, we showed that iNOS inactivates transcription factor EB, and that suppression of transcription factor EB and Atg7 diminishes the improved hepatic insulin sensitivity by iNOS deletion.” Transcription factor EB both regulates autophagy and is a “key player in lipid metabolism,” they added. It remains unclear whether the metabolic effects of iNOS solely relate to autophagy, they noted.

Funders included the American Heart Association, American Diabetes Association, and National Institutes of Health. The researchers reported having no conflicts of interest.

SOURCE: Qingwen Qian, et al. Cell Molec Gastroenterol Hepatol. 2019;8(1):95-110.
 

Obesity promotes the localization of inducible nitric oxide synthase (iNOS) in hepatic lysosomes, leading to a cascade of downstream effects that include excess lysosomal nitric oxide production, reduced hepatic autophagy, and insulin resistance, investigators reported.

“It is well known that in the context of obesity, chronic inflammation and lysosome dysfunction coexist in the liver,” wrote Qingwen Qian, PhD, of the University of Iowa in Iowa City and associates in Cellular and Molecular Gastroenterology and Hepatology. “Our studies suggest that lysosomal iNOS-mediated nitric oxide signaling disrupts hepatic lysosomal function, contributing to obesity-associated defective hepatic autophagy and insulin resistance.” They noted that the findings could hasten the development of new treatments for metabolic diseases.

Lysosomes recycle autophagocytosed intracellular and extracellular material, which is crucial to maintain several types of homeostasis within the liver. Each hepatocyte has about 250 lysosomes, which help regulate nutrient sensing, glycogen metabolism, cholesterol trafficking, and viral defense.

Activation of iNOS is a hallmark of inflammation, and iNOS levels are known to be elevated in the livers of patients with hepatitis C, alcoholic cirrhosis, and alpha 1-anti-trypsin disorder, the researchers wrote. “At the cellular level, iNOS produces pathological nitric oxide [NO], which triggers downstream effects, such as aberrant S-nitrosylation. These downstream effects can disrupt the function of organelles such as the mitochondria and the endoplasmic reticulum.”

Studies indicate that pathologic NO impairs lysosomal function in neurodegenerative diseases, cardiovascular disease, nonalcoholic fatty liver disease, and kidney disease, Dr. Qian and associates noted. But it was unclear whether NO in hepatocytes was generated by local iNOS or localized to lysosomes.

The researchers therefore studied cell cultures of primary murine hepatocytes by measuring their lysosomal activity, autophagy levels, and NO levels. They also studied a murine model of diet-induced obesity in which 60% of calories were from fat. They performed glucose tolerance tests by means of intraperitoneal glucose injections and studied the effects of insulin infusion. Finally, they performed immunohistology, immunohistochemistry, electron microscopy, and measurements of nitrosylated proteins and lysosomal arginine in frozen liver sections from the mice. Lysosomal arginine is required to catalyze NO production in the setting of inflammation as observed in obesity. In fact, concomitant stimulation of lysosomal arginine transport and activation of mTOR (an enzyme which tightly regulates transcription factor EB) was sufficient to stimulate lysosomal NO production in hepatocytes even in the absence of an inflammatory stimulus; pointing to a central role for these processes.

The researchers found that a NO scavenger diminished lysosomal NO production, while overexpression of both mTOR and a lysomal arginine transporter upregulated lysosomal NO production and suppressed autophagy. In mice with diet-induced obesity, deleting iNOS also improved nitrosative stress in hepatic lysosomes, promoted lysosomal biogenesis by activating transcription factor EB, enhanced lysosomal function and autophagy, and improved hepatic insulin sensitivity. Improved insulin sensitivity diminished, however, when the researchers suppressed transcription factor EB or autophagy-related 7 (Atg7).

Usually, iNOS is primarily expressed in hepatic Kupffer cells, but obesity increases the expression of iNOS in hepatocytes, which promotes hepatic insulin resistance and inflammation, the researchers commented. Unpublished data indicate that deleting iNOS initially protects against obesity-linked fatty liver steatosis and insulin resistance, but that these benefits weaken over time. “Nevertheless, our data showed that liver-specific iNOS suppression has a protective role,” they wrote. “Specifically, we showed that iNOS inactivates transcription factor EB, and that suppression of transcription factor EB and Atg7 diminishes the improved hepatic insulin sensitivity by iNOS deletion.” Transcription factor EB both regulates autophagy and is a “key player in lipid metabolism,” they added. It remains unclear whether the metabolic effects of iNOS solely relate to autophagy, they noted.

Funders included the American Heart Association, American Diabetes Association, and National Institutes of Health. The researchers reported having no conflicts of interest.

SOURCE: Qingwen Qian, et al. Cell Molec Gastroenterol Hepatol. 2019;8(1):95-110.
 

Henry T. Lynch, MD, an eminent researcher and trailblazer in the field of hereditary cancers, died June 2, 2019, at age 91.

Born in 1928, Dr. Lynch joined the military at age 16, becoming a gunner in the U.S. Navy. After a stint as a professional boxer, he obtained his high school equivalent, then attended the University of Oklahoma as an undergraduate. After receiving his master’s degree from the University of Denver, he earned a PhD in human genetics from the University of Texas, Austin, and his medical degree from the University of Texas, Galveston.

In 1967, Dr. Lynch accepted a position at Creighton University, Omaha, Neb., where he would spend the rest of his career. He was the founder and director of the Hereditary Cancer Center at Creighton, served as chair of the institution’s Department of Preventive Medicine and Public Health, and was named the inaugural holder of the Charles F. and Mary C. Heider Endowed Chair in Cancer Research.

It was at Creighton that Dr. Lynch began his work on genetic causes of and familial susceptibility to certain cancers. Dr. Lynch created a hereditary cancer registry, and definitively identified several genetic cancer syndromes that persist through multiple familial generations.

Dr. Lynch is credited with identifying a strain of hereditary nonpolyposis colon cancer that was named after him – Lynch syndrome. He is also credited with the discovery of hereditary breast-ovarian cancer syndrome, which would eventually lead to the discovery of the BRCA gene.

Find the full remembrance on the ASCO website.

[email protected]

Henry T. Lynch, MD, an eminent researcher and trailblazer in the field of hereditary cancers, died June 2, 2019, at age 91.

Born in 1928, Dr. Lynch joined the military at age 16, becoming a gunner in the U.S. Navy. After a stint as a professional boxer, he obtained his high school equivalent, then attended the University of Oklahoma as an undergraduate. After receiving his master’s degree from the University of Denver, he earned a PhD in human genetics from the University of Texas, Austin, and his medical degree from the University of Texas, Galveston.

In 1967, Dr. Lynch accepted a position at Creighton University, Omaha, Neb., where he would spend the rest of his career. He was the founder and director of the Hereditary Cancer Center at Creighton, served as chair of the institution’s Department of Preventive Medicine and Public Health, and was named the inaugural holder of the Charles F. and Mary C. Heider Endowed Chair in Cancer Research.

It was at Creighton that Dr. Lynch began his work on genetic causes of and familial susceptibility to certain cancers. Dr. Lynch created a hereditary cancer registry, and definitively identified several genetic cancer syndromes that persist through multiple familial generations.

Dr. Lynch is credited with identifying a strain of hereditary nonpolyposis colon cancer that was named after him – Lynch syndrome. He is also credited with the discovery of hereditary breast-ovarian cancer syndrome, which would eventually lead to the discovery of the BRCA gene.

Find the full remembrance on the ASCO website.

[email protected]

Henry T. Lynch, MD, an eminent researcher and trailblazer in the field of hereditary cancers, died June 2, 2019, at age 91.

Born in 1928, Dr. Lynch joined the military at age 16, becoming a gunner in the U.S. Navy. After a stint as a professional boxer, he obtained his high school equivalent, then attended the University of Oklahoma as an undergraduate. After receiving his master’s degree from the University of Denver, he earned a PhD in human genetics from the University of Texas, Austin, and his medical degree from the University of Texas, Galveston.

In 1967, Dr. Lynch accepted a position at Creighton University, Omaha, Neb., where he would spend the rest of his career. He was the founder and director of the Hereditary Cancer Center at Creighton, served as chair of the institution’s Department of Preventive Medicine and Public Health, and was named the inaugural holder of the Charles F. and Mary C. Heider Endowed Chair in Cancer Research.

It was at Creighton that Dr. Lynch began his work on genetic causes of and familial susceptibility to certain cancers. Dr. Lynch created a hereditary cancer registry, and definitively identified several genetic cancer syndromes that persist through multiple familial generations.

Dr. Lynch is credited with identifying a strain of hereditary nonpolyposis colon cancer that was named after him – Lynch syndrome. He is also credited with the discovery of hereditary breast-ovarian cancer syndrome, which would eventually lead to the discovery of the BRCA gene.

Find the full remembrance on the ASCO website.

[email protected]

CHICAGO – New data suggest pembrolizumab can increase 5-year overall survival (OS) for patients with advanced non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

In the phase 1b KEYNOTE-001 trial, the 5-year OS rate was 23.2% in treatment-naive patients and 15.5% in previously treated patients. This is in comparison to the 5.5% average 5-year OS rate observed in NSCLC patients who receive standard chemotherapy (Noone AM et al. SEER Cancer Statistics Review, 1975-2015).

“In total, the data confirm that pembrolizumab has the potential to improve long-term outcomes for both treatment-naive and previously treated patients with advanced non–small cell lung cancer,” said Edward B. Garon, MD, of the University of California, Los Angeles.

Dr. Garon and colleagues presented these results in a poster at the annual meeting of the American Society for Clinical Oncology, and the data were simultaneously published in the Journal of Clinical Oncology.

KEYNOTE-001 (NCT01295827) enrolled 550 patients with advanced NSCLC who had received no prior therapy (n = 101) or at least one prior line of therapy (n = 449). Initially, patients received pembrolizumab at varying doses depending on body weight, but the protocol was changed to a single dose of pembrolizumab at 200 mg every 3 weeks.

At a median follow-up of 60.6 months, 100 patients were still alive. Sixty patients had received at least 2 years of pembrolizumab, 14 of whom were treatment-naive at baseline, and 46 of whom were previously treated at baseline.

Five-year OS rates were best among patients who had high PD-L1 expression, which was defined as 50% or greater.

Among treatment-naive patients, the 5-year OS rate was 29.6% in PD-L1–high patients and 15.7% in PD-L1–low patients (expression of 1% to 49%). The median OS was 35.4 months and 19.5 months, respectively.

Among previously treated patients, the 5-year OS rate was 25.0% in PD-L1–high patients, 12.6% in patients with PD-L1 expression of 1%-49%, and 3.5% in patients with PD-L1 expression less than 1%. The median OS was 15.4 months, 8.5 months, and 8.6 months, respectively.

Among patients who received at least 2 years of pembrolizumab, the 5-year OS rate was 78.6% in the treatment-naive group and 75.8% in the previously treated group. The objective response rate was 86% and 91%, respectively. The rate of ongoing response at the data cutoff was 58% and 71%, respectively.

“The safety data did not show any unanticipated late toxicity, which I consider encouraging,” Dr. Garon noted.

He said rates of immune-mediated adverse events were similar at 3 years and 5 years of follow-up. At 5 years, 17% of patients (n = 92) had experienced an immune-related adverse event, the most common of which were hypothyroidism (9%), pneumonitis (5%), and hyperthyroidism (2%).

Dr. Garon disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis. KEYNOTE-001 was sponsored by Merck Sharp & Dohme Corp.

[email protected]

SOURCES: Garon E. et al. ASCO 2019, Abstract LBA9015; J Clin Oncol. 2019 June 2. doi: 10.1200/JCO.19.00934
 

CHICAGO – New data suggest pembrolizumab can increase 5-year overall survival (OS) for patients with advanced non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

In the phase 1b KEYNOTE-001 trial, the 5-year OS rate was 23.2% in treatment-naive patients and 15.5% in previously treated patients. This is in comparison to the 5.5% average 5-year OS rate observed in NSCLC patients who receive standard chemotherapy (Noone AM et al. SEER Cancer Statistics Review, 1975-2015).

“In total, the data confirm that pembrolizumab has the potential to improve long-term outcomes for both treatment-naive and previously treated patients with advanced non–small cell lung cancer,” said Edward B. Garon, MD, of the University of California, Los Angeles.

Dr. Garon and colleagues presented these results in a poster at the annual meeting of the American Society for Clinical Oncology, and the data were simultaneously published in the Journal of Clinical Oncology.

KEYNOTE-001 (NCT01295827) enrolled 550 patients with advanced NSCLC who had received no prior therapy (n = 101) or at least one prior line of therapy (n = 449). Initially, patients received pembrolizumab at varying doses depending on body weight, but the protocol was changed to a single dose of pembrolizumab at 200 mg every 3 weeks.

At a median follow-up of 60.6 months, 100 patients were still alive. Sixty patients had received at least 2 years of pembrolizumab, 14 of whom were treatment-naive at baseline, and 46 of whom were previously treated at baseline.

Five-year OS rates were best among patients who had high PD-L1 expression, which was defined as 50% or greater.

Among treatment-naive patients, the 5-year OS rate was 29.6% in PD-L1–high patients and 15.7% in PD-L1–low patients (expression of 1% to 49%). The median OS was 35.4 months and 19.5 months, respectively.

Among previously treated patients, the 5-year OS rate was 25.0% in PD-L1–high patients, 12.6% in patients with PD-L1 expression of 1%-49%, and 3.5% in patients with PD-L1 expression less than 1%. The median OS was 15.4 months, 8.5 months, and 8.6 months, respectively.

Among patients who received at least 2 years of pembrolizumab, the 5-year OS rate was 78.6% in the treatment-naive group and 75.8% in the previously treated group. The objective response rate was 86% and 91%, respectively. The rate of ongoing response at the data cutoff was 58% and 71%, respectively.

“The safety data did not show any unanticipated late toxicity, which I consider encouraging,” Dr. Garon noted.

He said rates of immune-mediated adverse events were similar at 3 years and 5 years of follow-up. At 5 years, 17% of patients (n = 92) had experienced an immune-related adverse event, the most common of which were hypothyroidism (9%), pneumonitis (5%), and hyperthyroidism (2%).

Dr. Garon disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis. KEYNOTE-001 was sponsored by Merck Sharp & Dohme Corp.

[email protected]

SOURCES: Garon E. et al. ASCO 2019, Abstract LBA9015; J Clin Oncol. 2019 June 2. doi: 10.1200/JCO.19.00934
 

CHICAGO – New data suggest pembrolizumab can increase 5-year overall survival (OS) for patients with advanced non–small cell lung cancer (NSCLC).

Jennifer Smith/MDedge News

In the phase 1b KEYNOTE-001 trial, the 5-year OS rate was 23.2% in treatment-naive patients and 15.5% in previously treated patients. This is in comparison to the 5.5% average 5-year OS rate observed in NSCLC patients who receive standard chemotherapy (Noone AM et al. SEER Cancer Statistics Review, 1975-2015).

“In total, the data confirm that pembrolizumab has the potential to improve long-term outcomes for both treatment-naive and previously treated patients with advanced non–small cell lung cancer,” said Edward B. Garon, MD, of the University of California, Los Angeles.

Dr. Garon and colleagues presented these results in a poster at the annual meeting of the American Society for Clinical Oncology, and the data were simultaneously published in the Journal of Clinical Oncology.

KEYNOTE-001 (NCT01295827) enrolled 550 patients with advanced NSCLC who had received no prior therapy (n = 101) or at least one prior line of therapy (n = 449). Initially, patients received pembrolizumab at varying doses depending on body weight, but the protocol was changed to a single dose of pembrolizumab at 200 mg every 3 weeks.

At a median follow-up of 60.6 months, 100 patients were still alive. Sixty patients had received at least 2 years of pembrolizumab, 14 of whom were treatment-naive at baseline, and 46 of whom were previously treated at baseline.

Five-year OS rates were best among patients who had high PD-L1 expression, which was defined as 50% or greater.

Among treatment-naive patients, the 5-year OS rate was 29.6% in PD-L1–high patients and 15.7% in PD-L1–low patients (expression of 1% to 49%). The median OS was 35.4 months and 19.5 months, respectively.

Among previously treated patients, the 5-year OS rate was 25.0% in PD-L1–high patients, 12.6% in patients with PD-L1 expression of 1%-49%, and 3.5% in patients with PD-L1 expression less than 1%. The median OS was 15.4 months, 8.5 months, and 8.6 months, respectively.

Among patients who received at least 2 years of pembrolizumab, the 5-year OS rate was 78.6% in the treatment-naive group and 75.8% in the previously treated group. The objective response rate was 86% and 91%, respectively. The rate of ongoing response at the data cutoff was 58% and 71%, respectively.

“The safety data did not show any unanticipated late toxicity, which I consider encouraging,” Dr. Garon noted.

He said rates of immune-mediated adverse events were similar at 3 years and 5 years of follow-up. At 5 years, 17% of patients (n = 92) had experienced an immune-related adverse event, the most common of which were hypothyroidism (9%), pneumonitis (5%), and hyperthyroidism (2%).

Dr. Garon disclosed relationships with AstraZeneca, Bristol-Myers Squibb, Dracen, Dynavax, Genentech, Iovance Biotherapeutics, Lilly, Merck, Mirati Therapeutics, Neon Therapeutics, and Novartis. KEYNOTE-001 was sponsored by Merck Sharp & Dohme Corp.

[email protected]

SOURCES: Garon E. et al. ASCO 2019, Abstract LBA9015; J Clin Oncol. 2019 June 2. doi: 10.1200/JCO.19.00934