EWING SARCOMA IN NEPAL: Investigators reported what they believe to be the first prospective clinical trial providing state-of-the-art chemotherapy to patients with Ewing sarcoma in Nepal. They treated 20 newly diagnosed patients with combination chemotherapy, including a course of etoposide and ifosfamide during external-beam radiotherapy. Radiotherapy was the only available treatment modality for local tumor control because advanced tumor-orthopedic services are not available in Nepal.

The 11 females and 9 males enrolled ranged in age from 6 to 37 years.

The treatment protocol—based on the Nepali-Norwegian Ewing Sarcoma Study treatment initiative— consisted of:

• Cyclophosphamide (1,200 mg/m2 as a 30-minute intravenous [IV] infusion)
• Doxorubicin (40 mg/m2/d as a 4-hour IV infusion on days 1 and 2; total dose, 80 mg/m2 in 2 days; total cumulative dose, 400 mg/m2)
• Etoposide (150 mg/m2/d as a 2-hour IV infusion; total dose, 450 mg/m2 in 3 days)
• Ifosfamide (3,000 mg/m2 over 21 to 24 hours as a 3-day continuous IV infusion; total dose, 9,000 mg/m2 in 3 days)
• Vincristine (1.5 mg/m2 IV push; maximum, 2 mg)

Patients received 5 courses of chemotherapy, then radiotherapy twice daily for 4 weeks for a total accumulated 54-Gy dose with a course of etoposide and ifosfamide, followed by 6 additional courses of chemotherapy.

Patients had primary tumors in the following sites: femur (n = 4), pubic bone (n = 1), fibula (n = 1), thoracic wall or costae (n = 4), clavicle (n = 1), craniofacial bone (n = 3), humerus (n = 3), forearm (n = 1), musculus sartorius with invasion into adjacent femur (n = 1), and uterine cervix (n = 1).

Eleven patients completed the entire treatment regimen, 6 of whom had no evidence of disease at a median follow-up of 2.3 years (range, 1.3 to 3.1 years). Four of them died of metastatic disease, and 1 experienced a recurrence 6 months later.

Three patients died due to chemotherapy- related toxicity, and 6 patients did not complete the treatment protocol, 4 of whom experienced progressive disease, were lost to follow-up, and presumed dead.

The investigators concluded that radiotherapy as the sole local treatment modality in combination with chemotherapy is feasible. They observed no fractures among the 15 patients who received radiotherapy.

SOURCE: Jha AK, Neupane P, Pradhan M, et al. Ewing sarcoma in Nepal treated with combined chemotherapy and definitive radiotherapy. J Glob Oncol. 2019;5:1-10.

PEDIATRIC SOFT TISSUE AND BONE SARCOMAS IN TANZANIA: In this retrospective review, investigators documented the epidemiologic and clinical features of pediatric sarcomas in the largest pediatric oncology center in Tanzania—Muhimbili National Hospital. Their objective in collecting the data was to compare the results with those of other countries and ultimately prioritize treatment protocols and resources for the more common pediatric sarcomas in Tanzania. Prior to this study, no data existed on the frequency and types most commonly seen in the country.

Between 2011 and 2016, the investigators collected information on 135 pediatric cases seen at the hospital. Eighty-nine cases (66%) were soft tissue sarcomas (STS) and 46 (34%) were bone sarcomas. Most patients, they reported, presented with a painless swelling.

Investigators found that, as in other countries, embryonal rhabdomyosarcoma accounted for the majority (75%) of all sarcomas seen in this study and osteosarcoma accounted for most (87%) bone sarcomas. However, unlike pediatric sarcomas in other countries, few cases of Ewing sarcoma were diagnosed during the study period.

An important disparity between Tanzania and other countries is that most patients in Tanzania present with advanced- stage disease, when the possibility of curative therapy is vastly reduced. Investigators found the lung to be the most common site of distant metastasis.

Other clinical and tumor characteristics reported in this study included:

• Slight female predominance (51%)
• Mean age, 6.3 years
• 42% of STS patients were younger than 5 years (n = 37)
• 46% of bone sarcoma patients were 10 to 15 years old (n = 21)
• Head and neck were the most common sites for STS
• Extremities were the most common sites for bone sarcomas
• Most patients presented with large tumors (>5 cm for STS and >8 cm for bone sarcomas).

The investigators believe these findings and others they reported will help them adapt treatment protocols used in Europe and America so that they will be most appropriate for their patients.

SOURCE: Siwillis EM, Dharse NJ, Scanlan T, et al. Pediatric soft tissue and bone sarcomas in Tanzania: Epidemiology and clinical features. J Glob Oncol. 2019;5:1-6.

PEDIATRIC OSTEOSARCOMA IN LEBANON: Investigators at a single institution in Lebanon reported a similar survival rate for newly diagnosed patients with pediatric osteosarcoma treated at their center as for those treated in more developed countries. In a retrospective review of the medical records of 38 patients treated at the American University of Beirut Medical Center between August 2001 and May 2012, they determined the 5-year overall survival (OS) for all patients to be 74% and the event-free survival (EFS), 62%. Patients with localized disease had a 5-year OS of 81% and an EFS of 68%. Patients with metastatic disease had OS and EFS rates of about 42%.

All patients with localized disease received chemotherapy according to the Pediatric Oncology Group 9351 protocol, which consisted of cisplatin, doxorubicin, and methotrexate. If patients had metastatic disease or tumor necrosis less than 90%, they also received ifosfamide and etoposide.

Patients were a mean age of 12.9 years at diagnosis and there were an equal number of male and female patients. Most patients (n=34) had a primary tumor site affecting the long bones around the knee.

Six patients had metastatic disease to the lungs, and 3 patients had multifocal bone disease with lung metastases.

Thirty-three patients (86.8%) underwent surgical resection after 2 courses of induction chemotherapy. Twenty-two (66.7%) of these patients had a delay in local tumor control of more than 4 weeks. And 12 patients (31.5%) had tumor necrosis of less than 90%.

The investigators analyzed the prognostic importance of age, sex, metastatic disease, tumor site, delay in local control, and degree of tumor necrosis. Bivariate analysis revealed that only the degree of tumor necrosis was a statistically significant adverse prognostic factor for EFS (P=.001) and OS (P=.002).

SOURCE: Abou Ali B, Salman M, Ghanem KM, et al. Clinical prognostic factors and outcome in pediatric osteosarcoma: Effect of delay in local control and degree of necrosis in a multidisciplinary setting in Lebanon. J Glob Oncol. 2019;5:1-8.

EWING SARCOMA IN NEPAL: Investigators reported what they believe to be the first prospective clinical trial providing state-of-the-art chemotherapy to patients with Ewing sarcoma in Nepal. They treated 20 newly diagnosed patients with combination chemotherapy, including a course of etoposide and ifosfamide during external-beam radiotherapy. Radiotherapy was the only available treatment modality for local tumor control because advanced tumor-orthopedic services are not available in Nepal.

The 11 females and 9 males enrolled ranged in age from 6 to 37 years.

The treatment protocol—based on the Nepali-Norwegian Ewing Sarcoma Study treatment initiative— consisted of:

• Cyclophosphamide (1,200 mg/m2 as a 30-minute intravenous [IV] infusion)
• Doxorubicin (40 mg/m2/d as a 4-hour IV infusion on days 1 and 2; total dose, 80 mg/m2 in 2 days; total cumulative dose, 400 mg/m2)
• Etoposide (150 mg/m2/d as a 2-hour IV infusion; total dose, 450 mg/m2 in 3 days)
• Ifosfamide (3,000 mg/m2 over 21 to 24 hours as a 3-day continuous IV infusion; total dose, 9,000 mg/m2 in 3 days)
• Vincristine (1.5 mg/m2 IV push; maximum, 2 mg)

Patients received 5 courses of chemotherapy, then radiotherapy twice daily for 4 weeks for a total accumulated 54-Gy dose with a course of etoposide and ifosfamide, followed by 6 additional courses of chemotherapy.

Patients had primary tumors in the following sites: femur (n = 4), pubic bone (n = 1), fibula (n = 1), thoracic wall or costae (n = 4), clavicle (n = 1), craniofacial bone (n = 3), humerus (n = 3), forearm (n = 1), musculus sartorius with invasion into adjacent femur (n = 1), and uterine cervix (n = 1).

Eleven patients completed the entire treatment regimen, 6 of whom had no evidence of disease at a median follow-up of 2.3 years (range, 1.3 to 3.1 years). Four of them died of metastatic disease, and 1 experienced a recurrence 6 months later.

Three patients died due to chemotherapy- related toxicity, and 6 patients did not complete the treatment protocol, 4 of whom experienced progressive disease, were lost to follow-up, and presumed dead.

The investigators concluded that radiotherapy as the sole local treatment modality in combination with chemotherapy is feasible. They observed no fractures among the 15 patients who received radiotherapy.

SOURCE: Jha AK, Neupane P, Pradhan M, et al. Ewing sarcoma in Nepal treated with combined chemotherapy and definitive radiotherapy. J Glob Oncol. 2019;5:1-10.

PEDIATRIC SOFT TISSUE AND BONE SARCOMAS IN TANZANIA: In this retrospective review, investigators documented the epidemiologic and clinical features of pediatric sarcomas in the largest pediatric oncology center in Tanzania—Muhimbili National Hospital. Their objective in collecting the data was to compare the results with those of other countries and ultimately prioritize treatment protocols and resources for the more common pediatric sarcomas in Tanzania. Prior to this study, no data existed on the frequency and types most commonly seen in the country.

Between 2011 and 2016, the investigators collected information on 135 pediatric cases seen at the hospital. Eighty-nine cases (66%) were soft tissue sarcomas (STS) and 46 (34%) were bone sarcomas. Most patients, they reported, presented with a painless swelling.

Investigators found that, as in other countries, embryonal rhabdomyosarcoma accounted for the majority (75%) of all sarcomas seen in this study and osteosarcoma accounted for most (87%) bone sarcomas. However, unlike pediatric sarcomas in other countries, few cases of Ewing sarcoma were diagnosed during the study period.

An important disparity between Tanzania and other countries is that most patients in Tanzania present with advanced- stage disease, when the possibility of curative therapy is vastly reduced. Investigators found the lung to be the most common site of distant metastasis.

Other clinical and tumor characteristics reported in this study included:

• Slight female predominance (51%)
• Mean age, 6.3 years
• 42% of STS patients were younger than 5 years (n = 37)
• 46% of bone sarcoma patients were 10 to 15 years old (n = 21)
• Head and neck were the most common sites for STS
• Extremities were the most common sites for bone sarcomas
• Most patients presented with large tumors (>5 cm for STS and >8 cm for bone sarcomas).

The investigators believe these findings and others they reported will help them adapt treatment protocols used in Europe and America so that they will be most appropriate for their patients.

SOURCE: Siwillis EM, Dharse NJ, Scanlan T, et al. Pediatric soft tissue and bone sarcomas in Tanzania: Epidemiology and clinical features. J Glob Oncol. 2019;5:1-6.

PEDIATRIC OSTEOSARCOMA IN LEBANON: Investigators at a single institution in Lebanon reported a similar survival rate for newly diagnosed patients with pediatric osteosarcoma treated at their center as for those treated in more developed countries. In a retrospective review of the medical records of 38 patients treated at the American University of Beirut Medical Center between August 2001 and May 2012, they determined the 5-year overall survival (OS) for all patients to be 74% and the event-free survival (EFS), 62%. Patients with localized disease had a 5-year OS of 81% and an EFS of 68%. Patients with metastatic disease had OS and EFS rates of about 42%.

All patients with localized disease received chemotherapy according to the Pediatric Oncology Group 9351 protocol, which consisted of cisplatin, doxorubicin, and methotrexate. If patients had metastatic disease or tumor necrosis less than 90%, they also received ifosfamide and etoposide.

Patients were a mean age of 12.9 years at diagnosis and there were an equal number of male and female patients. Most patients (n=34) had a primary tumor site affecting the long bones around the knee.

Six patients had metastatic disease to the lungs, and 3 patients had multifocal bone disease with lung metastases.

Thirty-three patients (86.8%) underwent surgical resection after 2 courses of induction chemotherapy. Twenty-two (66.7%) of these patients had a delay in local tumor control of more than 4 weeks. And 12 patients (31.5%) had tumor necrosis of less than 90%.

The investigators analyzed the prognostic importance of age, sex, metastatic disease, tumor site, delay in local control, and degree of tumor necrosis. Bivariate analysis revealed that only the degree of tumor necrosis was a statistically significant adverse prognostic factor for EFS (P=.001) and OS (P=.002).

SOURCE: Abou Ali B, Salman M, Ghanem KM, et al. Clinical prognostic factors and outcome in pediatric osteosarcoma: Effect of delay in local control and degree of necrosis in a multidisciplinary setting in Lebanon. J Glob Oncol. 2019;5:1-8.

EWING SARCOMA IN NEPAL: Investigators reported what they believe to be the first prospective clinical trial providing state-of-the-art chemotherapy to patients with Ewing sarcoma in Nepal. They treated 20 newly diagnosed patients with combination chemotherapy, including a course of etoposide and ifosfamide during external-beam radiotherapy. Radiotherapy was the only available treatment modality for local tumor control because advanced tumor-orthopedic services are not available in Nepal.

The 11 females and 9 males enrolled ranged in age from 6 to 37 years.

The treatment protocol—based on the Nepali-Norwegian Ewing Sarcoma Study treatment initiative— consisted of:

• Cyclophosphamide (1,200 mg/m2 as a 30-minute intravenous [IV] infusion)
• Doxorubicin (40 mg/m2/d as a 4-hour IV infusion on days 1 and 2; total dose, 80 mg/m2 in 2 days; total cumulative dose, 400 mg/m2)
• Etoposide (150 mg/m2/d as a 2-hour IV infusion; total dose, 450 mg/m2 in 3 days)
• Ifosfamide (3,000 mg/m2 over 21 to 24 hours as a 3-day continuous IV infusion; total dose, 9,000 mg/m2 in 3 days)
• Vincristine (1.5 mg/m2 IV push; maximum, 2 mg)

Patients received 5 courses of chemotherapy, then radiotherapy twice daily for 4 weeks for a total accumulated 54-Gy dose with a course of etoposide and ifosfamide, followed by 6 additional courses of chemotherapy.

Patients had primary tumors in the following sites: femur (n = 4), pubic bone (n = 1), fibula (n = 1), thoracic wall or costae (n = 4), clavicle (n = 1), craniofacial bone (n = 3), humerus (n = 3), forearm (n = 1), musculus sartorius with invasion into adjacent femur (n = 1), and uterine cervix (n = 1).

Eleven patients completed the entire treatment regimen, 6 of whom had no evidence of disease at a median follow-up of 2.3 years (range, 1.3 to 3.1 years). Four of them died of metastatic disease, and 1 experienced a recurrence 6 months later.

Three patients died due to chemotherapy- related toxicity, and 6 patients did not complete the treatment protocol, 4 of whom experienced progressive disease, were lost to follow-up, and presumed dead.

The investigators concluded that radiotherapy as the sole local treatment modality in combination with chemotherapy is feasible. They observed no fractures among the 15 patients who received radiotherapy.

SOURCE: Jha AK, Neupane P, Pradhan M, et al. Ewing sarcoma in Nepal treated with combined chemotherapy and definitive radiotherapy. J Glob Oncol. 2019;5:1-10.

PEDIATRIC SOFT TISSUE AND BONE SARCOMAS IN TANZANIA: In this retrospective review, investigators documented the epidemiologic and clinical features of pediatric sarcomas in the largest pediatric oncology center in Tanzania—Muhimbili National Hospital. Their objective in collecting the data was to compare the results with those of other countries and ultimately prioritize treatment protocols and resources for the more common pediatric sarcomas in Tanzania. Prior to this study, no data existed on the frequency and types most commonly seen in the country.

Between 2011 and 2016, the investigators collected information on 135 pediatric cases seen at the hospital. Eighty-nine cases (66%) were soft tissue sarcomas (STS) and 46 (34%) were bone sarcomas. Most patients, they reported, presented with a painless swelling.

Investigators found that, as in other countries, embryonal rhabdomyosarcoma accounted for the majority (75%) of all sarcomas seen in this study and osteosarcoma accounted for most (87%) bone sarcomas. However, unlike pediatric sarcomas in other countries, few cases of Ewing sarcoma were diagnosed during the study period.

An important disparity between Tanzania and other countries is that most patients in Tanzania present with advanced- stage disease, when the possibility of curative therapy is vastly reduced. Investigators found the lung to be the most common site of distant metastasis.

Other clinical and tumor characteristics reported in this study included:

• Slight female predominance (51%)
• Mean age, 6.3 years
• 42% of STS patients were younger than 5 years (n = 37)
• 46% of bone sarcoma patients were 10 to 15 years old (n = 21)
• Head and neck were the most common sites for STS
• Extremities were the most common sites for bone sarcomas
• Most patients presented with large tumors (>5 cm for STS and >8 cm for bone sarcomas).

The investigators believe these findings and others they reported will help them adapt treatment protocols used in Europe and America so that they will be most appropriate for their patients.

SOURCE: Siwillis EM, Dharse NJ, Scanlan T, et al. Pediatric soft tissue and bone sarcomas in Tanzania: Epidemiology and clinical features. J Glob Oncol. 2019;5:1-6.

PEDIATRIC OSTEOSARCOMA IN LEBANON: Investigators at a single institution in Lebanon reported a similar survival rate for newly diagnosed patients with pediatric osteosarcoma treated at their center as for those treated in more developed countries. In a retrospective review of the medical records of 38 patients treated at the American University of Beirut Medical Center between August 2001 and May 2012, they determined the 5-year overall survival (OS) for all patients to be 74% and the event-free survival (EFS), 62%. Patients with localized disease had a 5-year OS of 81% and an EFS of 68%. Patients with metastatic disease had OS and EFS rates of about 42%.

All patients with localized disease received chemotherapy according to the Pediatric Oncology Group 9351 protocol, which consisted of cisplatin, doxorubicin, and methotrexate. If patients had metastatic disease or tumor necrosis less than 90%, they also received ifosfamide and etoposide.

Patients were a mean age of 12.9 years at diagnosis and there were an equal number of male and female patients. Most patients (n=34) had a primary tumor site affecting the long bones around the knee.

Six patients had metastatic disease to the lungs, and 3 patients had multifocal bone disease with lung metastases.

Thirty-three patients (86.8%) underwent surgical resection after 2 courses of induction chemotherapy. Twenty-two (66.7%) of these patients had a delay in local tumor control of more than 4 weeks. And 12 patients (31.5%) had tumor necrosis of less than 90%.

The investigators analyzed the prognostic importance of age, sex, metastatic disease, tumor site, delay in local control, and degree of tumor necrosis. Bivariate analysis revealed that only the degree of tumor necrosis was a statistically significant adverse prognostic factor for EFS (P=.001) and OS (P=.002).

SOURCE: Abou Ali B, Salman M, Ghanem KM, et al. Clinical prognostic factors and outcome in pediatric osteosarcoma: Effect of delay in local control and degree of necrosis in a multidisciplinary setting in Lebanon. J Glob Oncol. 2019;5:1-8.

Cognitive decline accelerates in the long term after patients develop coronary heart disease (CHD), according to the results of a large prospective study with a median of 12 years of follow-up.

“We found that incident CHD was significantly associated with faster post–CHD-diagnosis cognitive decline, but not pre–CHD-diagnosis or short-term cognitive decline after the event,” Wuxiang Xie, PhD, of Peking University Health Science Center, Beijing, and associates wrote in the Journal of the American College of Cardiology. Linear mixed models showed that cognitive decline sped up during the year after incident CHD.

Past research had suggested a link between accelerated cognitive decline and CHD, but the temporal pattern of the relationship was unclear. For the study, Dr. Xie and associates followed 7,888 adults from the English Longitudinal Study of Aging who were an average of 62 years old and had no history of stroke, MI, angina, or dementia (Alzheimer’s disease or otherwise). All participants underwent a baseline cognitive assessment for verbal memory, semantic fluency, and temporal orientation, plus a median of six follow-up assessments.

In all, 480 (6%) participants developed CHD during follow-up. Their rate of cognitive decline remained constant before and immediately after their CHD diagnosis, but in subsequent years, they experienced significant accelerations in loss of global cognitive function, verbal memory, and temporal orientation even after accounting for time and many demographic and clinical variables. For example, the slope representing temporal change in global cognitive score decreased by a mean of 0.039 per year, compared with the pre-CHD slope (slope difference, –0.039; 95% confidence interval, –0.063 to –0.015; P =. 002). Semantic fluency also declined faster after CHD, but the difference, compared with before CHD, did not reach statistical significance (P = .11).

Individuals without CHD showed no such accelerations in cognitive decline throughout follow-up in adjusted models, the researchers wrote. “Based on repeated cognitive measurements over a long follow-up period, this study revealed a reliable and robust trajectory of cognitive decline [after CHD]. Future studies are warranted to determine the precise mechanisms linking incident CHD to cognitive decline.”

Funders included the National Natural Science Foundation of China, the Beijing Natural Science Foundation, and the Newton International Fellowship from the Academy of Medical Sciences. The researchers reported having no relevant financial disclosures.

SOURCE: Xie W et al. J Amer Coll Cardiol. 2019 Jun 17. doi: 10.1016/j.jacc.2019.04.019.

Cognitive decline accelerates in the long term after patients develop coronary heart disease (CHD), according to the results of a large prospective study with a median of 12 years of follow-up.

“We found that incident CHD was significantly associated with faster post–CHD-diagnosis cognitive decline, but not pre–CHD-diagnosis or short-term cognitive decline after the event,” Wuxiang Xie, PhD, of Peking University Health Science Center, Beijing, and associates wrote in the Journal of the American College of Cardiology. Linear mixed models showed that cognitive decline sped up during the year after incident CHD.

Past research had suggested a link between accelerated cognitive decline and CHD, but the temporal pattern of the relationship was unclear. For the study, Dr. Xie and associates followed 7,888 adults from the English Longitudinal Study of Aging who were an average of 62 years old and had no history of stroke, MI, angina, or dementia (Alzheimer’s disease or otherwise). All participants underwent a baseline cognitive assessment for verbal memory, semantic fluency, and temporal orientation, plus a median of six follow-up assessments.

In all, 480 (6%) participants developed CHD during follow-up. Their rate of cognitive decline remained constant before and immediately after their CHD diagnosis, but in subsequent years, they experienced significant accelerations in loss of global cognitive function, verbal memory, and temporal orientation even after accounting for time and many demographic and clinical variables. For example, the slope representing temporal change in global cognitive score decreased by a mean of 0.039 per year, compared with the pre-CHD slope (slope difference, –0.039; 95% confidence interval, –0.063 to –0.015; P =. 002). Semantic fluency also declined faster after CHD, but the difference, compared with before CHD, did not reach statistical significance (P = .11).

Individuals without CHD showed no such accelerations in cognitive decline throughout follow-up in adjusted models, the researchers wrote. “Based on repeated cognitive measurements over a long follow-up period, this study revealed a reliable and robust trajectory of cognitive decline [after CHD]. Future studies are warranted to determine the precise mechanisms linking incident CHD to cognitive decline.”

Funders included the National Natural Science Foundation of China, the Beijing Natural Science Foundation, and the Newton International Fellowship from the Academy of Medical Sciences. The researchers reported having no relevant financial disclosures.

SOURCE: Xie W et al. J Amer Coll Cardiol. 2019 Jun 17. doi: 10.1016/j.jacc.2019.04.019.

Cognitive decline accelerates in the long term after patients develop coronary heart disease (CHD), according to the results of a large prospective study with a median of 12 years of follow-up.

“We found that incident CHD was significantly associated with faster post–CHD-diagnosis cognitive decline, but not pre–CHD-diagnosis or short-term cognitive decline after the event,” Wuxiang Xie, PhD, of Peking University Health Science Center, Beijing, and associates wrote in the Journal of the American College of Cardiology. Linear mixed models showed that cognitive decline sped up during the year after incident CHD.

Past research had suggested a link between accelerated cognitive decline and CHD, but the temporal pattern of the relationship was unclear. For the study, Dr. Xie and associates followed 7,888 adults from the English Longitudinal Study of Aging who were an average of 62 years old and had no history of stroke, MI, angina, or dementia (Alzheimer’s disease or otherwise). All participants underwent a baseline cognitive assessment for verbal memory, semantic fluency, and temporal orientation, plus a median of six follow-up assessments.

In all, 480 (6%) participants developed CHD during follow-up. Their rate of cognitive decline remained constant before and immediately after their CHD diagnosis, but in subsequent years, they experienced significant accelerations in loss of global cognitive function, verbal memory, and temporal orientation even after accounting for time and many demographic and clinical variables. For example, the slope representing temporal change in global cognitive score decreased by a mean of 0.039 per year, compared with the pre-CHD slope (slope difference, –0.039; 95% confidence interval, –0.063 to –0.015; P =. 002). Semantic fluency also declined faster after CHD, but the difference, compared with before CHD, did not reach statistical significance (P = .11).

Individuals without CHD showed no such accelerations in cognitive decline throughout follow-up in adjusted models, the researchers wrote. “Based on repeated cognitive measurements over a long follow-up period, this study revealed a reliable and robust trajectory of cognitive decline [after CHD]. Future studies are warranted to determine the precise mechanisms linking incident CHD to cognitive decline.”

Funders included the National Natural Science Foundation of China, the Beijing Natural Science Foundation, and the Newton International Fellowship from the Academy of Medical Sciences. The researchers reported having no relevant financial disclosures.

SOURCE: Xie W et al. J Amer Coll Cardiol. 2019 Jun 17. doi: 10.1016/j.jacc.2019.04.019.

Long-term genetically low levels of LDL cholesterol, by means of functional variants in the PCSK9 gene, were associated with a reduced risk of CV mortality, but not all-cause mortality, in a large cohort of individuals.

ktsimage/Thinkstock

“We tested the hypothesis that genetically low LDL cholesterol due to PCSK9 [proprotein convertase subtilisin/kexin type 9] variation is causally associated with low cardiovascular and all-cause mortality in a general population of Northern European ancestry,” wrote Marianne Benn, MD, DMSc, and colleagues. The findings were published in the Journal of the American College of Cardiology.

The researchers conducted a large-scale genetic analysis of 109,566 persons from the Copenhagen City Heart Study and Copenhagen General Population Study. In addition, the team included a validation cohort of 431,043 individuals from the UK Biobank.

The median duration of follow-up was 10 years (0-42 years), and the median age at study entry was 57 years.

Study participants were genotyped for several PCSK9 variants and a weighted allele score based the effects of LDL cholesterol, individual allele frequency, and number of variant alleles was calculated for each subject.

Weighted scores were categorized into five stepwise noncontinuous score ranges, with lower levels of LDL cholesterol linked to higher allele scores.

After analysis, the researchers found that a growing number of PCSK9 alleles were associated with lower levels of LDL cholesterol up to 0.61 mmol/L (P for trend less than .001) and reduced CV mortality (P = .001), but not with reduced all-cause mortality (P = .11).

“Our genetic data did not show a reduction in risk of all-cause mortality, and only showed a reduction in risk of all-cause mortality in statin trials and not in the PCSK9-inhibitor trials meta-analyzed,” the researchers wrote. “This may be explained by the low frequency of cardiovascular disease in the 2 populations studied,” they explained.

One key limitation was the homogeneous makeup of the study population. Dr. Benn and colleagues acknowledged this could limit the generalizability of the results.

“Long-term LDL cholesterol treatment (e.g., with PCSK9 inhibitors), may translate into reductions in cardiovascular mortality,” they concluded.

The study was supported by the Danish Council for Independent Research, Medical Sciences, Johan Boserup, and the Lise Boserup’s Fund. The authors reported no conflicts of interest.

SOURCE: Benn M et al. JACC. 2019 Jun 17. doi: 10.1016/j.jacc.2019.03.517

Long-term genetically low levels of LDL cholesterol, by means of functional variants in the PCSK9 gene, were associated with a reduced risk of CV mortality, but not all-cause mortality, in a large cohort of individuals.

ktsimage/Thinkstock

“We tested the hypothesis that genetically low LDL cholesterol due to PCSK9 [proprotein convertase subtilisin/kexin type 9] variation is causally associated with low cardiovascular and all-cause mortality in a general population of Northern European ancestry,” wrote Marianne Benn, MD, DMSc, and colleagues. The findings were published in the Journal of the American College of Cardiology.

The researchers conducted a large-scale genetic analysis of 109,566 persons from the Copenhagen City Heart Study and Copenhagen General Population Study. In addition, the team included a validation cohort of 431,043 individuals from the UK Biobank.

The median duration of follow-up was 10 years (0-42 years), and the median age at study entry was 57 years.

Study participants were genotyped for several PCSK9 variants and a weighted allele score based the effects of LDL cholesterol, individual allele frequency, and number of variant alleles was calculated for each subject.

Weighted scores were categorized into five stepwise noncontinuous score ranges, with lower levels of LDL cholesterol linked to higher allele scores.

After analysis, the researchers found that a growing number of PCSK9 alleles were associated with lower levels of LDL cholesterol up to 0.61 mmol/L (P for trend less than .001) and reduced CV mortality (P = .001), but not with reduced all-cause mortality (P = .11).

“Our genetic data did not show a reduction in risk of all-cause mortality, and only showed a reduction in risk of all-cause mortality in statin trials and not in the PCSK9-inhibitor trials meta-analyzed,” the researchers wrote. “This may be explained by the low frequency of cardiovascular disease in the 2 populations studied,” they explained.

One key limitation was the homogeneous makeup of the study population. Dr. Benn and colleagues acknowledged this could limit the generalizability of the results.

“Long-term LDL cholesterol treatment (e.g., with PCSK9 inhibitors), may translate into reductions in cardiovascular mortality,” they concluded.

The study was supported by the Danish Council for Independent Research, Medical Sciences, Johan Boserup, and the Lise Boserup’s Fund. The authors reported no conflicts of interest.

SOURCE: Benn M et al. JACC. 2019 Jun 17. doi: 10.1016/j.jacc.2019.03.517

Long-term genetically low levels of LDL cholesterol, by means of functional variants in the PCSK9 gene, were associated with a reduced risk of CV mortality, but not all-cause mortality, in a large cohort of individuals.

ktsimage/Thinkstock

“We tested the hypothesis that genetically low LDL cholesterol due to PCSK9 [proprotein convertase subtilisin/kexin type 9] variation is causally associated with low cardiovascular and all-cause mortality in a general population of Northern European ancestry,” wrote Marianne Benn, MD, DMSc, and colleagues. The findings were published in the Journal of the American College of Cardiology.

The researchers conducted a large-scale genetic analysis of 109,566 persons from the Copenhagen City Heart Study and Copenhagen General Population Study. In addition, the team included a validation cohort of 431,043 individuals from the UK Biobank.

The median duration of follow-up was 10 years (0-42 years), and the median age at study entry was 57 years.

Study participants were genotyped for several PCSK9 variants and a weighted allele score based the effects of LDL cholesterol, individual allele frequency, and number of variant alleles was calculated for each subject.

Weighted scores were categorized into five stepwise noncontinuous score ranges, with lower levels of LDL cholesterol linked to higher allele scores.

After analysis, the researchers found that a growing number of PCSK9 alleles were associated with lower levels of LDL cholesterol up to 0.61 mmol/L (P for trend less than .001) and reduced CV mortality (P = .001), but not with reduced all-cause mortality (P = .11).

“Our genetic data did not show a reduction in risk of all-cause mortality, and only showed a reduction in risk of all-cause mortality in statin trials and not in the PCSK9-inhibitor trials meta-analyzed,” the researchers wrote. “This may be explained by the low frequency of cardiovascular disease in the 2 populations studied,” they explained.

One key limitation was the homogeneous makeup of the study population. Dr. Benn and colleagues acknowledged this could limit the generalizability of the results.

“Long-term LDL cholesterol treatment (e.g., with PCSK9 inhibitors), may translate into reductions in cardiovascular mortality,” they concluded.

The study was supported by the Danish Council for Independent Research, Medical Sciences, Johan Boserup, and the Lise Boserup’s Fund. The authors reported no conflicts of interest.

SOURCE: Benn M et al. JACC. 2019 Jun 17. doi: 10.1016/j.jacc.2019.03.517

SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.

Doug Brunk/MDedge News

“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”

Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.

Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.

During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).

Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).

When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.

Doug Brunk/MDedge News

“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”

Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.

Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.

During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).

Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).

When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.

[email protected]

SAN DIEGO – Patients on rivaroxaban had significantly higher rates of GI bleeding, compared with those taking apixaban or dabigatran, results from a large population-based study showed.

Doug Brunk/MDedge News

“This may be due to the fact that rivaroxaban is administered as a single daily dose as opposed to the other two non–vitamin K anticoagulants [NOACs], which are given twice daily,” lead study author Arnar B. Ingason said at the annual Digestive Disease Week. “This may lead to a greater variance in plasma drug concentration, making these patients more susceptible to bleeding.”

Mr. Ingason, a medical student at the University of Iceland, Reykjavik, said that although several studies have compared warfarin with NOACs, it remains unclear which NOAC has the most favorable GI profile. In an effort to improve the research in this area, he and his associates performed a nationwide, population-based study during March 2014–Jan. 2018 to compare the GI bleeding risk of patients receiving rivaroxaban to that of a combined pool of patients receiving either apixaban or dabigatran. They drew from the Icelandic Medicine Registry, which contains all outpatient drug prescriptions in the country. Next, the researchers linked the personal identification numbers of patients to the Landspitali University diagnoses registry, which includes more than 90% of all patients hospitalized for GI bleeding. They used 1:1 nearest neighbor propensity score for matching and Kaplan-Meier survival estimates and Cox regression to compare rates of GI bleeding. The study outcome of interest was any clinically relevant GI bleeding.

Mr. Ingason reported that the baseline characteristics were similar between the rivaroxaban group and the apixaban/dabigatran group. They matched for several variables, including age, sex, Charlson score, the proportion being anticoagulant naive, moderate to severe renal disease, moderate to severe liver disease, any prior bleeding, and any prior thrombotic events.

During the study period, 3,473 patients received rivaroxaban, 1,901 received apixaban, and 1,086 received dabigatran. After propensity score matching, the researchers compared 2,635 patients who received rivaroxaban with 2,365 patients who received either apixaban or dabigatran. They found that patients in the rivaroxaban group had significantly higher rates of GI bleeding, compared with in the apixaban/dabigatran group (1.2 and. 0.6 events per 100 patient-years, respectively). This yielded a hazard ratio of 2.02, “which means that patients receiving rivaroxaban are twice as likely to get GI bleeding compared to patients on apixaban or dabigatran,” Mr. Ingason said. When the researchers examined the entire unmatched cohort of patients, the rivaroxaban group also had significantly higher rates of GI bleeding, compared with the apixaban/dabigatran group (1.0 and 0.6 events per 100 patient-years; HR, 1.75).

Mr. Ingason and his colleagues observed that patients in the rivaroxaban group had higher rates of GI bleeding, compared with the apixaban/dabigatran group, during the entire follow-up period. At the end of year 4, the rivaroxaban group had a 4% cumulative event rate of GI bleeding, compared with 1.8% for the apixaban/dabigatran group, a highly significant difference at P = .0057).

When a meeting attendee asked Mr. Ingason why patients taking apixaban or dabigatran were combined into one group, he said that it was done to increase the power of their study. “Our theory was that rivaroxaban was different because it is administered as a single daily dose, while the others are given twice daily,” he said. The researchers reported having no financial disclosures.

[email protected]

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Cardiac implantable electronic devices (CIEDs) – cardiac pacemakers and implantable cardioverter defibrillators –are an established treatment for the management of cardiac dysrhythmias in millions of patients. Complications occur in up to 15%, some of which may present first to the dermatologist.

The differential diagnosis of dermatoses overlying pacemakers includes infection, irritant or allergic contact dermatitis, reticular telangiectatic erythema (caused by local venous obstruction and pressure dermatitis), and impending skin erosion/device extrusion.

Erosion and extrusion is a major complication with significant morbidity and mortality. The two main causes are pressure necrosis and infection. Pressure necrosis is influenced by the size of the device, complexity of the connections, and technical skill with which the pacemaker chest wall pocket is created.

After extrusion, the pacemaker should be considered contaminated and removed, and the necrotic tissue debrided. If infected, a prolonged course of appropriate antibiotic therapy is indicated. A bacterial culture in the patient presented here was negative.

Pocket infection of CIEDs is rare and may manifest as erythema, tenderness, drainage, erosion, or pruritus above the site of the pacemaker, along with systemic symptoms and signs, including fever, chills, or malaise. Some may have just the systemic symptoms. Fewer than half of patients with CIED infection present within 1 year of their last procedure.

Ruptured epidermal cysts usually manifest as acute swelling, inflammation, and tenderness of previously long-standing asymptomatic epidermal cysts. There may be drainage of malodorous keratinous and purulent debris. They are typically not infected. Treatment includes incision and drainage for fluctuant lesions or intralesional corticosteroid injection for early, nonfluctuant cases.

Allergic contact dermatitis to metal may be seen with implantable devices. Patch testing to various metal allergens can be helpful in determining if any allergy is present.

This case and photo were submitted by Michael Stierstorfer, MD, East Penn Dermatology, North Wales, Pa.

Dr. Bilu Martin is a board-certified dermatologist in private practice at Premier Dermatology, in Aventura, Fla. More diagnostic cases are available at mdedge.com/dermatology. To submit a case for possible publication, send an email to [email protected].

Young patients might be at increased risk of suicidal behavior, unintentional overdose, injuries, and traffic incidents during treatment periods with gabapentinoids, compared with periods without treatment with those medications, a cohort study of almost 200,000 people shows. Pregabalin is associated with higher hazards of those outcomes than is gabapentin, and the associations are strongest in patients aged 15-24 years, the researchers reported.

“If our findings are triangulated with other forms of evidence, clinical guidelines may need review regarding prescriptions for young people and those with substance use disorders,” wrote Yasmina Molero, PhD, and associates. “Further restrictions for off-label prescription may need consideration.” The study was published in BMJ.

The use of gabapentinoids has risen in the United States (JAMA Intern Med. 2018;178[2]:292-4), and overdose deaths tied to gabapentin have led some states to explore reclassification of the drug as a controlled substance (Risk Manag Healthc Policy. 2018;11:109-16). In the United Kingdom, gabapentinoids are being reclassified as a class C controlled drug because of concerns about the risk of addiction, overdose, and safety, wrote Dr. Molero of the department of psychiatry at Warneford Hospital at the University of Oxford, England, and associates.

To study associations between gabapentinoids and adverse outcomes related to coordination, mental health, and criminality, Dr. Molero and her associates analyzed data from 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for pregabalin or gabapentin between 2006 and 2013. The researchers included patients aged 15 years and older in their analyses.

They examined suicidal behavior, unintentional overdoses, head or body injuries, road traffic incidents and offenses, and arrests for violent crime using the Swedish Patient Register and the National Crime Register. In addition, they defined suicidal behavior as emergency hospital visits attributable to self-injurious behavior or suicide attempt, or death by suicide. Unintentional overdoses were defined as emergency hospital visits or death attributable to poisoning by illicit drugs, medications, or biologic substances; accidental poisoning by noxious substances; or acute intoxications and overdoses by alcohol and illicit drugs, excluding intentional self-poisoning, wrote Dr. Molero, who is affiliated with the Karolinska Institute in Stockholm, and her associates.

Of the nearly 192,000 participants who collected prescriptions of gabapentinoids on at least two consecutive occasions, 120,664 received pregabalin, and 85,360 received gabapentin; 14,051 of the participants received both drugs. Fifty-nine percent were women, and most patients were aged 45 or older.

During the study period, 10,026 participants (5.2%) were treated for suicidal behavior or died from suicide, 17,144 participants (8.9%) experienced an unintentional overdose, and 12,070 participants (6.3%) had a road traffic incident or offense. In addition, 70,522 participants (36.7%) had head or body injuries, and 7,984 participants (4.1%) were arrested for a violent crime.

[email protected]

SOURCE: Molero Y et al. BMJ. 2019 Jun 12. doi: 10.1136/bmj.l2147.

Young patients might be at increased risk of suicidal behavior, unintentional overdose, injuries, and traffic incidents during treatment periods with gabapentinoids, compared with periods without treatment with those medications, a cohort study of almost 200,000 people shows. Pregabalin is associated with higher hazards of those outcomes than is gabapentin, and the associations are strongest in patients aged 15-24 years, the researchers reported.

“If our findings are triangulated with other forms of evidence, clinical guidelines may need review regarding prescriptions for young people and those with substance use disorders,” wrote Yasmina Molero, PhD, and associates. “Further restrictions for off-label prescription may need consideration.” The study was published in BMJ.

The use of gabapentinoids has risen in the United States (JAMA Intern Med. 2018;178[2]:292-4), and overdose deaths tied to gabapentin have led some states to explore reclassification of the drug as a controlled substance (Risk Manag Healthc Policy. 2018;11:109-16). In the United Kingdom, gabapentinoids are being reclassified as a class C controlled drug because of concerns about the risk of addiction, overdose, and safety, wrote Dr. Molero of the department of psychiatry at Warneford Hospital at the University of Oxford, England, and associates.

To study associations between gabapentinoids and adverse outcomes related to coordination, mental health, and criminality, Dr. Molero and her associates analyzed data from 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for pregabalin or gabapentin between 2006 and 2013. The researchers included patients aged 15 years and older in their analyses.

They examined suicidal behavior, unintentional overdoses, head or body injuries, road traffic incidents and offenses, and arrests for violent crime using the Swedish Patient Register and the National Crime Register. In addition, they defined suicidal behavior as emergency hospital visits attributable to self-injurious behavior or suicide attempt, or death by suicide. Unintentional overdoses were defined as emergency hospital visits or death attributable to poisoning by illicit drugs, medications, or biologic substances; accidental poisoning by noxious substances; or acute intoxications and overdoses by alcohol and illicit drugs, excluding intentional self-poisoning, wrote Dr. Molero, who is affiliated with the Karolinska Institute in Stockholm, and her associates.

Of the nearly 192,000 participants who collected prescriptions of gabapentinoids on at least two consecutive occasions, 120,664 received pregabalin, and 85,360 received gabapentin; 14,051 of the participants received both drugs. Fifty-nine percent were women, and most patients were aged 45 or older.

During the study period, 10,026 participants (5.2%) were treated for suicidal behavior or died from suicide, 17,144 participants (8.9%) experienced an unintentional overdose, and 12,070 participants (6.3%) had a road traffic incident or offense. In addition, 70,522 participants (36.7%) had head or body injuries, and 7,984 participants (4.1%) were arrested for a violent crime.

[email protected]

SOURCE: Molero Y et al. BMJ. 2019 Jun 12. doi: 10.1136/bmj.l2147.

Young patients might be at increased risk of suicidal behavior, unintentional overdose, injuries, and traffic incidents during treatment periods with gabapentinoids, compared with periods without treatment with those medications, a cohort study of almost 200,000 people shows. Pregabalin is associated with higher hazards of those outcomes than is gabapentin, and the associations are strongest in patients aged 15-24 years, the researchers reported.

“If our findings are triangulated with other forms of evidence, clinical guidelines may need review regarding prescriptions for young people and those with substance use disorders,” wrote Yasmina Molero, PhD, and associates. “Further restrictions for off-label prescription may need consideration.” The study was published in BMJ.

The use of gabapentinoids has risen in the United States (JAMA Intern Med. 2018;178[2]:292-4), and overdose deaths tied to gabapentin have led some states to explore reclassification of the drug as a controlled substance (Risk Manag Healthc Policy. 2018;11:109-16). In the United Kingdom, gabapentinoids are being reclassified as a class C controlled drug because of concerns about the risk of addiction, overdose, and safety, wrote Dr. Molero of the department of psychiatry at Warneford Hospital at the University of Oxford, England, and associates.

To study associations between gabapentinoids and adverse outcomes related to coordination, mental health, and criminality, Dr. Molero and her associates analyzed data from 191,973 people from the Swedish Prescribed Drug Register who collected prescriptions for pregabalin or gabapentin between 2006 and 2013. The researchers included patients aged 15 years and older in their analyses.

They examined suicidal behavior, unintentional overdoses, head or body injuries, road traffic incidents and offenses, and arrests for violent crime using the Swedish Patient Register and the National Crime Register. In addition, they defined suicidal behavior as emergency hospital visits attributable to self-injurious behavior or suicide attempt, or death by suicide. Unintentional overdoses were defined as emergency hospital visits or death attributable to poisoning by illicit drugs, medications, or biologic substances; accidental poisoning by noxious substances; or acute intoxications and overdoses by alcohol and illicit drugs, excluding intentional self-poisoning, wrote Dr. Molero, who is affiliated with the Karolinska Institute in Stockholm, and her associates.

Of the nearly 192,000 participants who collected prescriptions of gabapentinoids on at least two consecutive occasions, 120,664 received pregabalin, and 85,360 received gabapentin; 14,051 of the participants received both drugs. Fifty-nine percent were women, and most patients were aged 45 or older.

During the study period, 10,026 participants (5.2%) were treated for suicidal behavior or died from suicide, 17,144 participants (8.9%) experienced an unintentional overdose, and 12,070 participants (6.3%) had a road traffic incident or offense. In addition, 70,522 participants (36.7%) had head or body injuries, and 7,984 participants (4.1%) were arrested for a violent crime.

[email protected]

SOURCE: Molero Y et al. BMJ. 2019 Jun 12. doi: 10.1136/bmj.l2147.

Neoadjuvant and adjuvant targeted therapy with erlotinib (Tarceva) may outperform standard chemotherapy in patients with locally advanced non–small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, suggests the Chinese Thoracic Oncology Group’s EMERGING trial.

Investigators led by Wen-Zhao Zhong, MD, a professor at Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China, enrolled 72 patients with stage IIIA-N2 EGFR-mutant NSCLC in the phase 2 randomized controlled trial. The patients were randomized to receive either erlotinib, an EGFR tyrosine kinase inhibitor (TKI), or the chemotherapy doublet of gemcitabine (Gemzar) and cisplatin as both neoadjuvant and adjuvant therapy.

Results reported in the Journal of Clinical Oncology showed that the objective response rate was 54.1% with neoadjuvant erlotinib (median, 42 days of therapy) versus 34.3% with neoadjuvant chemotherapy (with most patients receiving two cycles). However, the difference was not significant (odds ratio, 2.26; P = .092).

None of the patients in either arm achieved a pathologic complete response, but 9.7% in the erlotinib arm achieved a major pathologic response (less than 10% residual viable tumor cells) versus none of those in the chemotherapy arm.

With a median follow-up of 14.1 months, median progression-free survival was 21.5 months with erlotinib, nearly double the 11.4 months seen with chemotherapy (hazard ratio for events, 0.39; P less than .001). Overall survival did not differ significantly but was immature at the time of analysis.

Adverse events were largely as expected for each therapy. Incidence of grade 3 or 4 adverse events was 0% with erlotinib versus 29.4% with chemotherapy.

“These results suggest that biomarker-guided neoadjuvant/adjuvant EGFR-TKI treatment strategies in stage IIIA-N2 NSCLC are promising,” Dr. Zhong and colleagues wrote. “Our promising findings warrant additional investigation.”

“The optimal duration of neoadjuvant TKI also warrants additional investigation to validate the role of perioperative TKI therapy in oncogene-driven NSCLC,” they concluded. “Future studies should investigate the translational value of sequential plasma and tissue samples in a neoadjuvant setting using multiomics-based assays to identify predictive characteristics of patients who would benefit from neoadjuvant targeted therapies and predict prognosis.”

Dr. Zhong disclosed receiving honoraria from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. The trial was supported by the Chinese Thoracic Oncology Group and Shanghai Roche Pharmaceutical.

SOURCE: Zhong W-Z et al. J Clin Oncol. 2019 June 13. doi: 10.1200/JCO.19.00075.

Neoadjuvant and adjuvant targeted therapy with erlotinib (Tarceva) may outperform standard chemotherapy in patients with locally advanced non–small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, suggests the Chinese Thoracic Oncology Group’s EMERGING trial.

Investigators led by Wen-Zhao Zhong, MD, a professor at Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China, enrolled 72 patients with stage IIIA-N2 EGFR-mutant NSCLC in the phase 2 randomized controlled trial. The patients were randomized to receive either erlotinib, an EGFR tyrosine kinase inhibitor (TKI), or the chemotherapy doublet of gemcitabine (Gemzar) and cisplatin as both neoadjuvant and adjuvant therapy.

Results reported in the Journal of Clinical Oncology showed that the objective response rate was 54.1% with neoadjuvant erlotinib (median, 42 days of therapy) versus 34.3% with neoadjuvant chemotherapy (with most patients receiving two cycles). However, the difference was not significant (odds ratio, 2.26; P = .092).

None of the patients in either arm achieved a pathologic complete response, but 9.7% in the erlotinib arm achieved a major pathologic response (less than 10% residual viable tumor cells) versus none of those in the chemotherapy arm.

With a median follow-up of 14.1 months, median progression-free survival was 21.5 months with erlotinib, nearly double the 11.4 months seen with chemotherapy (hazard ratio for events, 0.39; P less than .001). Overall survival did not differ significantly but was immature at the time of analysis.

Adverse events were largely as expected for each therapy. Incidence of grade 3 or 4 adverse events was 0% with erlotinib versus 29.4% with chemotherapy.

“These results suggest that biomarker-guided neoadjuvant/adjuvant EGFR-TKI treatment strategies in stage IIIA-N2 NSCLC are promising,” Dr. Zhong and colleagues wrote. “Our promising findings warrant additional investigation.”

“The optimal duration of neoadjuvant TKI also warrants additional investigation to validate the role of perioperative TKI therapy in oncogene-driven NSCLC,” they concluded. “Future studies should investigate the translational value of sequential plasma and tissue samples in a neoadjuvant setting using multiomics-based assays to identify predictive characteristics of patients who would benefit from neoadjuvant targeted therapies and predict prognosis.”

Dr. Zhong disclosed receiving honoraria from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. The trial was supported by the Chinese Thoracic Oncology Group and Shanghai Roche Pharmaceutical.

SOURCE: Zhong W-Z et al. J Clin Oncol. 2019 June 13. doi: 10.1200/JCO.19.00075.

Neoadjuvant and adjuvant targeted therapy with erlotinib (Tarceva) may outperform standard chemotherapy in patients with locally advanced non–small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, suggests the Chinese Thoracic Oncology Group’s EMERGING trial.

Investigators led by Wen-Zhao Zhong, MD, a professor at Guangdong Provincial People’s Hospital and Guangdong Academy of Medical Sciences, Guangzhou, China, enrolled 72 patients with stage IIIA-N2 EGFR-mutant NSCLC in the phase 2 randomized controlled trial. The patients were randomized to receive either erlotinib, an EGFR tyrosine kinase inhibitor (TKI), or the chemotherapy doublet of gemcitabine (Gemzar) and cisplatin as both neoadjuvant and adjuvant therapy.

Results reported in the Journal of Clinical Oncology showed that the objective response rate was 54.1% with neoadjuvant erlotinib (median, 42 days of therapy) versus 34.3% with neoadjuvant chemotherapy (with most patients receiving two cycles). However, the difference was not significant (odds ratio, 2.26; P = .092).

None of the patients in either arm achieved a pathologic complete response, but 9.7% in the erlotinib arm achieved a major pathologic response (less than 10% residual viable tumor cells) versus none of those in the chemotherapy arm.

With a median follow-up of 14.1 months, median progression-free survival was 21.5 months with erlotinib, nearly double the 11.4 months seen with chemotherapy (hazard ratio for events, 0.39; P less than .001). Overall survival did not differ significantly but was immature at the time of analysis.

Adverse events were largely as expected for each therapy. Incidence of grade 3 or 4 adverse events was 0% with erlotinib versus 29.4% with chemotherapy.

“These results suggest that biomarker-guided neoadjuvant/adjuvant EGFR-TKI treatment strategies in stage IIIA-N2 NSCLC are promising,” Dr. Zhong and colleagues wrote. “Our promising findings warrant additional investigation.”

“The optimal duration of neoadjuvant TKI also warrants additional investigation to validate the role of perioperative TKI therapy in oncogene-driven NSCLC,” they concluded. “Future studies should investigate the translational value of sequential plasma and tissue samples in a neoadjuvant setting using multiomics-based assays to identify predictive characteristics of patients who would benefit from neoadjuvant targeted therapies and predict prognosis.”

Dr. Zhong disclosed receiving honoraria from AstraZeneca, Eli Lilly, Pfizer, Roche, and Sanofi. The trial was supported by the Chinese Thoracic Oncology Group and Shanghai Roche Pharmaceutical.

SOURCE: Zhong W-Z et al. J Clin Oncol. 2019 June 13. doi: 10.1200/JCO.19.00075.

Many performance improvement programs try to create a higher value health system by incentivizing physicians and health systems to behave in particular ways. These have often been pay-for-performance programs that offer bonuses or impose penalties depending on how providers perform on various metrics.

“In theory, this makes sense,” said Dhruv Khullar, MD, MPP, lead author of a JAMA article about the future of incentives, and assistant professor at Weill Cornell Medicine in New York. “But in practice, these programs have not been successful in consistently improving quality, and sometimes they have been counterproductive. In our article, we argued that focusing too narrowly on financial rewards is not the right strategy to improve health system performance – and is sometimes at odds with the physician professionalism and what really motivates most clinicians.”

Pay-for-performance programs suffer from several fundamental flaws: they focus too narrowly on financial incentives and use centralized accountability instead of local culture, for example, Dr. Khullar said.

“A better future state would involve capitalizing on physician professionalism through nonfinancial rewards, resources for quality improvement, team-based assessments, and emphasizing continuous learning and organizational culture,” he noted. Performance programs would take a more global view of clinical care by emphasizing culture, teams, trust, and learning. Such a system would allow hospitalists and other physicians to worry less about meeting specific metrics and focus more on providing high-quality care to their patients.

“I would hope physicians, payers, and administrators would reconsider some previously held beliefs about quality improvement, especially the idea that better quality requires giving people bonus payments or imposing financial penalties,” Dr. Khullar said. “We believe the next wave of performance improvement programs should entertain other paths to better quality, which are more in line with human motivation and physician professionalism.”
 

Reference

1. Khullar D, Wolfson D, Casalino LP. Professionalism, Performance, and the Future of Physician Incentives. JAMA. 2018 Nov 26 (Epub ahead of print). doi: 10.1001/jama.2018.17719. Accessed Dec. 11, 2018.

Many performance improvement programs try to create a higher value health system by incentivizing physicians and health systems to behave in particular ways. These have often been pay-for-performance programs that offer bonuses or impose penalties depending on how providers perform on various metrics.

“In theory, this makes sense,” said Dhruv Khullar, MD, MPP, lead author of a JAMA article about the future of incentives, and assistant professor at Weill Cornell Medicine in New York. “But in practice, these programs have not been successful in consistently improving quality, and sometimes they have been counterproductive. In our article, we argued that focusing too narrowly on financial rewards is not the right strategy to improve health system performance – and is sometimes at odds with the physician professionalism and what really motivates most clinicians.”

Pay-for-performance programs suffer from several fundamental flaws: they focus too narrowly on financial incentives and use centralized accountability instead of local culture, for example, Dr. Khullar said.

“A better future state would involve capitalizing on physician professionalism through nonfinancial rewards, resources for quality improvement, team-based assessments, and emphasizing continuous learning and organizational culture,” he noted. Performance programs would take a more global view of clinical care by emphasizing culture, teams, trust, and learning. Such a system would allow hospitalists and other physicians to worry less about meeting specific metrics and focus more on providing high-quality care to their patients.

“I would hope physicians, payers, and administrators would reconsider some previously held beliefs about quality improvement, especially the idea that better quality requires giving people bonus payments or imposing financial penalties,” Dr. Khullar said. “We believe the next wave of performance improvement programs should entertain other paths to better quality, which are more in line with human motivation and physician professionalism.”
 

Reference

1. Khullar D, Wolfson D, Casalino LP. Professionalism, Performance, and the Future of Physician Incentives. JAMA. 2018 Nov 26 (Epub ahead of print). doi: 10.1001/jama.2018.17719. Accessed Dec. 11, 2018.

Many performance improvement programs try to create a higher value health system by incentivizing physicians and health systems to behave in particular ways. These have often been pay-for-performance programs that offer bonuses or impose penalties depending on how providers perform on various metrics.

“In theory, this makes sense,” said Dhruv Khullar, MD, MPP, lead author of a JAMA article about the future of incentives, and assistant professor at Weill Cornell Medicine in New York. “But in practice, these programs have not been successful in consistently improving quality, and sometimes they have been counterproductive. In our article, we argued that focusing too narrowly on financial rewards is not the right strategy to improve health system performance – and is sometimes at odds with the physician professionalism and what really motivates most clinicians.”

Pay-for-performance programs suffer from several fundamental flaws: they focus too narrowly on financial incentives and use centralized accountability instead of local culture, for example, Dr. Khullar said.

“A better future state would involve capitalizing on physician professionalism through nonfinancial rewards, resources for quality improvement, team-based assessments, and emphasizing continuous learning and organizational culture,” he noted. Performance programs would take a more global view of clinical care by emphasizing culture, teams, trust, and learning. Such a system would allow hospitalists and other physicians to worry less about meeting specific metrics and focus more on providing high-quality care to their patients.

“I would hope physicians, payers, and administrators would reconsider some previously held beliefs about quality improvement, especially the idea that better quality requires giving people bonus payments or imposing financial penalties,” Dr. Khullar said. “We believe the next wave of performance improvement programs should entertain other paths to better quality, which are more in line with human motivation and physician professionalism.”
 

Reference

1. Khullar D, Wolfson D, Casalino LP. Professionalism, Performance, and the Future of Physician Incentives. JAMA. 2018 Nov 26 (Epub ahead of print). doi: 10.1001/jama.2018.17719. Accessed Dec. 11, 2018.

Two researchers have joined Stand Up To Cancer’s scientific advisory committee, which directs the organization’s research initiatives, reviews grant proposals, and oversees active grants.

One new committee member is John D. Carpten, PhD, of the University of Southern California in Los Angeles. Dr. Carpten’s research encompasses several cancer types and focuses on the use of genomic technologies and bioinformatics analysis.

The other new committee member is Roderic I. Pettigrew, MD, PhD, of Texas A&M University in College Station. Dr. Pettigrew is known for pioneering four-dimensional imaging of the cardiovascular system using MRI.

[email protected]

Two researchers have joined Stand Up To Cancer’s scientific advisory committee, which directs the organization’s research initiatives, reviews grant proposals, and oversees active grants.

One new committee member is John D. Carpten, PhD, of the University of Southern California in Los Angeles. Dr. Carpten’s research encompasses several cancer types and focuses on the use of genomic technologies and bioinformatics analysis.

The other new committee member is Roderic I. Pettigrew, MD, PhD, of Texas A&M University in College Station. Dr. Pettigrew is known for pioneering four-dimensional imaging of the cardiovascular system using MRI.

[email protected]

Two researchers have joined Stand Up To Cancer’s scientific advisory committee, which directs the organization’s research initiatives, reviews grant proposals, and oversees active grants.

One new committee member is John D. Carpten, PhD, of the University of Southern California in Los Angeles. Dr. Carpten’s research encompasses several cancer types and focuses on the use of genomic technologies and bioinformatics analysis.

The other new committee member is Roderic I. Pettigrew, MD, PhD, of Texas A&M University in College Station. Dr. Pettigrew is known for pioneering four-dimensional imaging of the cardiovascular system using MRI.

[email protected]

Metatarsal bones are an unusual subsite for small bone involvement in osteosarcomas. This subgroup is often misdiagnosed and hence associated with significant treatment delays. The standard treatment of metatarsal osteosarcomas remains the same as for those treated at other sites, namely neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Limb salvage surgery or metatarsectomy in the foot is often a challenge owing to the poor compartmentalization of the disease. We hereby describe the case of a young girl with a metatarsal osteosarcoma who was managed with neoadjuvant chemotherapy and limb salvage surgery.

Introduction

Osteosarcomas are the most common primary malignant bone tumor in children and adolescents. Although predominantly occurring in pediatric and adolescent age groups, bimodal distribution (with a second incidence peak occurring in the sixth and seventh decades) is not uncommon.¹ Osteosarcomas of the foot and small bones represent a rare and distinct clinical entity. This must have been a well-known observation for years that led to Watson-Jones stating, “Sarcoma of this [metatarsal] bone has not yet been reported in thousands of years in any country.”² The incidence of osteosarcomas of the foot is estimated to be from 0.2% to 2%.³

These tumors, owing to their rarity, often lead to diagnostic dilemmas and hence treatment delays.⁴ They are usually mistaken for inflammatory conditions and often treated with—but not limited to—curettages and drainage procedures.⁵ The following case of osteosarcoma of the metatarsal bone in a young girl highlights the importance of having a high index of clinical suspicion prior to treatment.

Case Presentation and Summary

A 10-year-old girl visited our outpatient clinic with a painful progressive swelling on the dorsum of the left foot of 2 months’ duration. There was no history of antecedent trauma or fever. Physical examination revealed a bony hard swelling measuring around 5 x 6 cm on the dorsum of the left foot around the region of the second metatarsal. There was no regional lymphadenopathy or distal neurovascular deficit. She was evaluated with a plain radiograph that demonstrated a lytic lesion in the left second metatarsal associated with cortical destruction and periosteal reaction (Figure 1). A subsequent magnetic resonance image (MRI) revealed a bony lesion destroying part of the left second metatarsal with cortical destruction and marrow involvement and affecting the soft tissue around the adjacent third metatarsal (Figure 2). Needle biopsy showed chondroblastic osteosarcoma. Computed tomography (CT) of the thorax and bone scan were both negative for distant metastases.

She received 3 cycles of a MAP (highdose methotrexate, doxorubicin, and cisplatin) regimen as neoadjuvant chemotherapy. Response assessment scans showed partial response (Figures 3A and B). We performed a wide excision of the second and third metatarsal with reconstruction using a segment of non-vascularized fibular graft as rigid fixation (Figure 4). The postoperative period was uneventful. She was able to begin partial weight bearing on the fourth postoperative day and her sutures were removed on the twelfth postoperative day. She received adjuvant chemotherapy following surgery. The final histopathology report showed residual disease with Huvos grade III response (>90% necrosis) with all margins negative for malignancy (Figure 5). At present, the child is disease-free at 5 months of treatment completion and is undergoing regular follow-up visits.

Discussion

Metatarsal involvement amongst smallbone osteosarcomas is uncommon.³ There are about 32 cases of osteosarcomas reported in the literature from 1940 to 2018 involving the metatarsal bones (Table 1). According to a review article from the Mayo Clinic, the most common bone of the foot involved is the calcaneum.⁶ While the incidence of osteosarcomas of the foot as a whole is around 0.2% to 2%,3 metatarsal involvement is documented in 0.5% of these patients.⁷ However, a recent study depicted metatarsal involvement in 33% of all osteosarcomas of the foot.⁸

Osteosarcomas at conventional sites tend to have a bimodal age distribution with respect to disease affliction.⁹ Metatarsal osteosarcomas, however, are more common in an older age group.^4,10 Our patient is probably the second youngest reported case of metatarsal osteosarcoma in the literature.¹¹

Biscaglia et al propounded that osteosarcomas of the metatarsal were a distinct subgroup due to the rarity of occurrence, anatomical location, and prognosis.⁴ This often led to misdiagnosis and subsequent inadequate or inappropriate surgery. In six out of the ten cases (60%) described in Table 1, an incorrect pretreatment diagnosis was made that led to treatment delay. None, except one patient, received neoadjuvant chemotherapy, which is currently the standard of care. The average duration from symptom onset to diagnosis was found to be 2 years.⁴ However, in our case, the duration of symptoms was approximately 2 months.

Surgery for metatarsal osteosarcomas can be challenging, as the compartments of the foot are narrow spaces with poor demarcation. Limb salvage surgery in the form of metatarsectomy needs proper preoperative planning and execution. Neoadjuvant chemotherapy will serve to downstage the tumor within the fascial barriers of the metatarsal compartment.It has also been postulated that osteosarcoma of the foot may have a better prognosis and survival compared to other osteosarcoma subsites.¹⁰ This can be extrapolated from the fact that the majority are found to be low grade, and despite a long delay in treatment, there was no rapid increase in size and/or metastatic spread. However, tumor grade remains an important factor affecting survival— patients with higher grade tumors have worse survival.⁸

A number of differentials, including benign tumors, are to be kept in mind when diagnosing and treating such patients (Table 2). The most common benign tumors affecting the metatarsal are giant cell tumors (GCT) followed by chondromyxoid fibroma. Osteosarcomas and Ewing sarcomas constitute the malignant tumors.¹² Occasionally, infections like osteomyelitis of the small bones may mimic malignancy. The absence of an extensive soft tissue component and/or calcifications with the presence of bony changes (like sequestrum) favors a diagnosis of infection/osteomyelitis. In addition, clinical findings like fever, skin redness, and presence of a painful swelling (especially after onset of fever) point to an inflammatory pathology rather than malignancy. Stress fractures rarely simulate tumors. MRI showing marrow and soft tissue edema with a visible fracture line points to the diagnosis.

A plane radiograph showing cortical bone destruction with a soft tissue component and calcification should be considered suspicious and must be thoroughly evaluated prior to surgical treatment.¹³ In a young patient such as ours, the important differentials that need to be considered include Ewing sarcoma, chronic osteomyelitis, and eosinophilic granuloma, which can radiologically mimic osteosarcoma at this location.

Conclusions

Osteosarcoma of the metatarsal is rare. Our case remains unique as it reports the second youngest patient in the literature. Erroneous or delayed diagnosis resulting in inadequate tumor excision and limb loss (amputation) often occurs in a majority of the cases. Proper pretreatment radiological imaging becomes imperative, and when clinical suspicion is high, a needle biopsy must follow in those cases. Early diagnosis with administration of neoadjuvant chemotherapy may allow us to perform limb salvage surgery or wide excision in these cases.

Acknowledgement
We would like to thank Dr. Sithara Aravind, Associate Professor, Department of Pathology, Malabar Cancer Center, for the photomicrographs.

Metatarsal bones are an unusual subsite for small bone involvement in osteosarcomas. This subgroup is often misdiagnosed and hence associated with significant treatment delays. The standard treatment of metatarsal osteosarcomas remains the same as for those treated at other sites, namely neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Limb salvage surgery or metatarsectomy in the foot is often a challenge owing to the poor compartmentalization of the disease. We hereby describe the case of a young girl with a metatarsal osteosarcoma who was managed with neoadjuvant chemotherapy and limb salvage surgery.

Introduction

Osteosarcomas are the most common primary malignant bone tumor in children and adolescents. Although predominantly occurring in pediatric and adolescent age groups, bimodal distribution (with a second incidence peak occurring in the sixth and seventh decades) is not uncommon.¹ Osteosarcomas of the foot and small bones represent a rare and distinct clinical entity. This must have been a well-known observation for years that led to Watson-Jones stating, “Sarcoma of this [metatarsal] bone has not yet been reported in thousands of years in any country.”² The incidence of osteosarcomas of the foot is estimated to be from 0.2% to 2%.³

These tumors, owing to their rarity, often lead to diagnostic dilemmas and hence treatment delays.⁴ They are usually mistaken for inflammatory conditions and often treated with—but not limited to—curettages and drainage procedures.⁵ The following case of osteosarcoma of the metatarsal bone in a young girl highlights the importance of having a high index of clinical suspicion prior to treatment.

Case Presentation and Summary

A 10-year-old girl visited our outpatient clinic with a painful progressive swelling on the dorsum of the left foot of 2 months’ duration. There was no history of antecedent trauma or fever. Physical examination revealed a bony hard swelling measuring around 5 x 6 cm on the dorsum of the left foot around the region of the second metatarsal. There was no regional lymphadenopathy or distal neurovascular deficit. She was evaluated with a plain radiograph that demonstrated a lytic lesion in the left second metatarsal associated with cortical destruction and periosteal reaction (Figure 1). A subsequent magnetic resonance image (MRI) revealed a bony lesion destroying part of the left second metatarsal with cortical destruction and marrow involvement and affecting the soft tissue around the adjacent third metatarsal (Figure 2). Needle biopsy showed chondroblastic osteosarcoma. Computed tomography (CT) of the thorax and bone scan were both negative for distant metastases.

She received 3 cycles of a MAP (highdose methotrexate, doxorubicin, and cisplatin) regimen as neoadjuvant chemotherapy. Response assessment scans showed partial response (Figures 3A and B). We performed a wide excision of the second and third metatarsal with reconstruction using a segment of non-vascularized fibular graft as rigid fixation (Figure 4). The postoperative period was uneventful. She was able to begin partial weight bearing on the fourth postoperative day and her sutures were removed on the twelfth postoperative day. She received adjuvant chemotherapy following surgery. The final histopathology report showed residual disease with Huvos grade III response (>90% necrosis) with all margins negative for malignancy (Figure 5). At present, the child is disease-free at 5 months of treatment completion and is undergoing regular follow-up visits.

Discussion

Metatarsal involvement amongst smallbone osteosarcomas is uncommon.³ There are about 32 cases of osteosarcomas reported in the literature from 1940 to 2018 involving the metatarsal bones (Table 1). According to a review article from the Mayo Clinic, the most common bone of the foot involved is the calcaneum.⁶ While the incidence of osteosarcomas of the foot as a whole is around 0.2% to 2%,3 metatarsal involvement is documented in 0.5% of these patients.⁷ However, a recent study depicted metatarsal involvement in 33% of all osteosarcomas of the foot.⁸

Osteosarcomas at conventional sites tend to have a bimodal age distribution with respect to disease affliction.⁹ Metatarsal osteosarcomas, however, are more common in an older age group.^4,10 Our patient is probably the second youngest reported case of metatarsal osteosarcoma in the literature.¹¹

Biscaglia et al propounded that osteosarcomas of the metatarsal were a distinct subgroup due to the rarity of occurrence, anatomical location, and prognosis.⁴ This often led to misdiagnosis and subsequent inadequate or inappropriate surgery. In six out of the ten cases (60%) described in Table 1, an incorrect pretreatment diagnosis was made that led to treatment delay. None, except one patient, received neoadjuvant chemotherapy, which is currently the standard of care. The average duration from symptom onset to diagnosis was found to be 2 years.⁴ However, in our case, the duration of symptoms was approximately 2 months.

Surgery for metatarsal osteosarcomas can be challenging, as the compartments of the foot are narrow spaces with poor demarcation. Limb salvage surgery in the form of metatarsectomy needs proper preoperative planning and execution. Neoadjuvant chemotherapy will serve to downstage the tumor within the fascial barriers of the metatarsal compartment.It has also been postulated that osteosarcoma of the foot may have a better prognosis and survival compared to other osteosarcoma subsites.¹⁰ This can be extrapolated from the fact that the majority are found to be low grade, and despite a long delay in treatment, there was no rapid increase in size and/or metastatic spread. However, tumor grade remains an important factor affecting survival— patients with higher grade tumors have worse survival.⁸

A number of differentials, including benign tumors, are to be kept in mind when diagnosing and treating such patients (Table 2). The most common benign tumors affecting the metatarsal are giant cell tumors (GCT) followed by chondromyxoid fibroma. Osteosarcomas and Ewing sarcomas constitute the malignant tumors.¹² Occasionally, infections like osteomyelitis of the small bones may mimic malignancy. The absence of an extensive soft tissue component and/or calcifications with the presence of bony changes (like sequestrum) favors a diagnosis of infection/osteomyelitis. In addition, clinical findings like fever, skin redness, and presence of a painful swelling (especially after onset of fever) point to an inflammatory pathology rather than malignancy. Stress fractures rarely simulate tumors. MRI showing marrow and soft tissue edema with a visible fracture line points to the diagnosis.

A plane radiograph showing cortical bone destruction with a soft tissue component and calcification should be considered suspicious and must be thoroughly evaluated prior to surgical treatment.¹³ In a young patient such as ours, the important differentials that need to be considered include Ewing sarcoma, chronic osteomyelitis, and eosinophilic granuloma, which can radiologically mimic osteosarcoma at this location.

Conclusions

Osteosarcoma of the metatarsal is rare. Our case remains unique as it reports the second youngest patient in the literature. Erroneous or delayed diagnosis resulting in inadequate tumor excision and limb loss (amputation) often occurs in a majority of the cases. Proper pretreatment radiological imaging becomes imperative, and when clinical suspicion is high, a needle biopsy must follow in those cases. Early diagnosis with administration of neoadjuvant chemotherapy may allow us to perform limb salvage surgery or wide excision in these cases.

Acknowledgement
We would like to thank Dr. Sithara Aravind, Associate Professor, Department of Pathology, Malabar Cancer Center, for the photomicrographs.

Metatarsal bones are an unusual subsite for small bone involvement in osteosarcomas. This subgroup is often misdiagnosed and hence associated with significant treatment delays. The standard treatment of metatarsal osteosarcomas remains the same as for those treated at other sites, namely neoadjuvant chemotherapy followed by surgery and adjuvant chemotherapy. Limb salvage surgery or metatarsectomy in the foot is often a challenge owing to the poor compartmentalization of the disease. We hereby describe the case of a young girl with a metatarsal osteosarcoma who was managed with neoadjuvant chemotherapy and limb salvage surgery.

Introduction

Osteosarcomas are the most common primary malignant bone tumor in children and adolescents. Although predominantly occurring in pediatric and adolescent age groups, bimodal distribution (with a second incidence peak occurring in the sixth and seventh decades) is not uncommon.¹ Osteosarcomas of the foot and small bones represent a rare and distinct clinical entity. This must have been a well-known observation for years that led to Watson-Jones stating, “Sarcoma of this [metatarsal] bone has not yet been reported in thousands of years in any country.”² The incidence of osteosarcomas of the foot is estimated to be from 0.2% to 2%.³

These tumors, owing to their rarity, often lead to diagnostic dilemmas and hence treatment delays.⁴ They are usually mistaken for inflammatory conditions and often treated with—but not limited to—curettages and drainage procedures.⁵ The following case of osteosarcoma of the metatarsal bone in a young girl highlights the importance of having a high index of clinical suspicion prior to treatment.

Case Presentation and Summary

A 10-year-old girl visited our outpatient clinic with a painful progressive swelling on the dorsum of the left foot of 2 months’ duration. There was no history of antecedent trauma or fever. Physical examination revealed a bony hard swelling measuring around 5 x 6 cm on the dorsum of the left foot around the region of the second metatarsal. There was no regional lymphadenopathy or distal neurovascular deficit. She was evaluated with a plain radiograph that demonstrated a lytic lesion in the left second metatarsal associated with cortical destruction and periosteal reaction (Figure 1). A subsequent magnetic resonance image (MRI) revealed a bony lesion destroying part of the left second metatarsal with cortical destruction and marrow involvement and affecting the soft tissue around the adjacent third metatarsal (Figure 2). Needle biopsy showed chondroblastic osteosarcoma. Computed tomography (CT) of the thorax and bone scan were both negative for distant metastases.

She received 3 cycles of a MAP (highdose methotrexate, doxorubicin, and cisplatin) regimen as neoadjuvant chemotherapy. Response assessment scans showed partial response (Figures 3A and B). We performed a wide excision of the second and third metatarsal with reconstruction using a segment of non-vascularized fibular graft as rigid fixation (Figure 4). The postoperative period was uneventful. She was able to begin partial weight bearing on the fourth postoperative day and her sutures were removed on the twelfth postoperative day. She received adjuvant chemotherapy following surgery. The final histopathology report showed residual disease with Huvos grade III response (>90% necrosis) with all margins negative for malignancy (Figure 5). At present, the child is disease-free at 5 months of treatment completion and is undergoing regular follow-up visits.

Discussion

Metatarsal involvement amongst smallbone osteosarcomas is uncommon.³ There are about 32 cases of osteosarcomas reported in the literature from 1940 to 2018 involving the metatarsal bones (Table 1). According to a review article from the Mayo Clinic, the most common bone of the foot involved is the calcaneum.⁶ While the incidence of osteosarcomas of the foot as a whole is around 0.2% to 2%,3 metatarsal involvement is documented in 0.5% of these patients.⁷ However, a recent study depicted metatarsal involvement in 33% of all osteosarcomas of the foot.⁸

Osteosarcomas at conventional sites tend to have a bimodal age distribution with respect to disease affliction.⁹ Metatarsal osteosarcomas, however, are more common in an older age group.^4,10 Our patient is probably the second youngest reported case of metatarsal osteosarcoma in the literature.¹¹

Biscaglia et al propounded that osteosarcomas of the metatarsal were a distinct subgroup due to the rarity of occurrence, anatomical location, and prognosis.⁴ This often led to misdiagnosis and subsequent inadequate or inappropriate surgery. In six out of the ten cases (60%) described in Table 1, an incorrect pretreatment diagnosis was made that led to treatment delay. None, except one patient, received neoadjuvant chemotherapy, which is currently the standard of care. The average duration from symptom onset to diagnosis was found to be 2 years.⁴ However, in our case, the duration of symptoms was approximately 2 months.

Surgery for metatarsal osteosarcomas can be challenging, as the compartments of the foot are narrow spaces with poor demarcation. Limb salvage surgery in the form of metatarsectomy needs proper preoperative planning and execution. Neoadjuvant chemotherapy will serve to downstage the tumor within the fascial barriers of the metatarsal compartment.It has also been postulated that osteosarcoma of the foot may have a better prognosis and survival compared to other osteosarcoma subsites.¹⁰ This can be extrapolated from the fact that the majority are found to be low grade, and despite a long delay in treatment, there was no rapid increase in size and/or metastatic spread. However, tumor grade remains an important factor affecting survival— patients with higher grade tumors have worse survival.⁸

A number of differentials, including benign tumors, are to be kept in mind when diagnosing and treating such patients (Table 2). The most common benign tumors affecting the metatarsal are giant cell tumors (GCT) followed by chondromyxoid fibroma. Osteosarcomas and Ewing sarcomas constitute the malignant tumors.¹² Occasionally, infections like osteomyelitis of the small bones may mimic malignancy. The absence of an extensive soft tissue component and/or calcifications with the presence of bony changes (like sequestrum) favors a diagnosis of infection/osteomyelitis. In addition, clinical findings like fever, skin redness, and presence of a painful swelling (especially after onset of fever) point to an inflammatory pathology rather than malignancy. Stress fractures rarely simulate tumors. MRI showing marrow and soft tissue edema with a visible fracture line points to the diagnosis.

A plane radiograph showing cortical bone destruction with a soft tissue component and calcification should be considered suspicious and must be thoroughly evaluated prior to surgical treatment.¹³ In a young patient such as ours, the important differentials that need to be considered include Ewing sarcoma, chronic osteomyelitis, and eosinophilic granuloma, which can radiologically mimic osteosarcoma at this location.

Conclusions

Osteosarcoma of the metatarsal is rare. Our case remains unique as it reports the second youngest patient in the literature. Erroneous or delayed diagnosis resulting in inadequate tumor excision and limb loss (amputation) often occurs in a majority of the cases. Proper pretreatment radiological imaging becomes imperative, and when clinical suspicion is high, a needle biopsy must follow in those cases. Early diagnosis with administration of neoadjuvant chemotherapy may allow us to perform limb salvage surgery or wide excision in these cases.

Acknowledgement
We would like to thank Dr. Sithara Aravind, Associate Professor, Department of Pathology, Malabar Cancer Center, for the photomicrographs.