Langerhans cell histiocytosis with lung involvement in isolation and multisystem disease: Staging, natural history, and comparative survival.

Langerhans cell histiocytosis (LCH) is a histiocytic neoplasm that can involve the lungs as single system (LCH-SSL) or multisystem disease (LCH-MSL). The role of full-body radiographic staging to determine whether patients have LCH-SSL or LCH-MSL is unclear. Long-term outcomes of LCH-SSL versus LCH-MSL and multisystem without lung involvement (LCH-MSNL) are unknown. A retrospective study of adult LCH patients seen at our center from January 2000 to 2020 was performed. In Part 1, we addressed utility of whole-body staging imaging among those presenting with isolated pulmonary signs or symptoms. Staging was defined as fluorodeoxyglucose positron emission tomography-computed tomography (CT) or whole-body CT obtained within 3 months of diagnosis. In Part 2, we examined the frequency of developing extra-pulmonary disease over time and mortality in patients with LCH-SSL. In Part 3, we compared the overall survival of LCH-SSL, LCH-MSL, and LCH-MSNL. Part 1: 240 patients with LCH were identified. A total of 112 (47%) had pulmonary signs or symptoms at presentation. Thirty-four (30%) underwent radiographic staging and only one showed evidence of extra-pulmonary disease. Part 2: 108 (45%) were LCH-SSL. Median follow-up duration of 4.5 years (95% confidence interval [CI]: 2.9-6.0). None developed extra-pulmonary disease. Part 3: 5-year survival: 94% (95% CI: 84%-98%) for LCH-SSL, 78% (95% CI: 59%-90%) for LCH-MSL, and 75% (95% CI: 53%-89%) for LCH-MSNL. LCH patients presenting with isolated pulmonary signs or symptoms rarely have extra-pulmonary involvement at the time of diagnosis and generally do not develop extra-pulmonary progression. LCH-SSL has the best overall survival, while LCH-MSL and LCH-MSNL have similar clinical outcomes.

Efficacy of BRAF-Inhibitor Therapy in BRAFV600E -Mutated Adult Langerhans Cell Histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare histiocytic neoplasm. To date, there is a lack of U.S. Food and Drug Administration-approved treatments in adult LCH to establish optimal first-line therapy. We conducted a retrospective, single-center case series evaluating the use of BRAF inhibitors in adult patients with BRAFV600E - LCH proven by biopsy. Our case series is the first to report the use of BRAF inhibitors as first-line therapy in adults with LCH. We also report the efficacy with single-agent dabrafenib in adult LCH. All but one of our patients had favorable response to targeted therapy.

Neulasta Onpro: a coup de grâce?

With the rapid decline in average sales price of reference pegfilgrastim products due to biosimilar competition, health care institutions and payers may grapple with coverage of Neulasta Onpro.

Analysis of Medicare Expenditure for Discarded Infused Cancer Therapeutics From 2017-2020.

OBJECTIVE: To explore patterns in Medicare reimbursement for wasted oncologic and hematologic infusion drugs from 2017 to 2020 and estimate the savings that implementation of the Infrastructure Investment and Jobs Act (IIJA) would have had. METHODS: Using the publicly available Medicare Part B Discarded Drug Units database, we analyzed reimbursement data for discarded antineoplastic and hematology therapies from 2017 to 2020. RESULTS: Medicare Part B utilization data was extracted for 77 therapies. From 2017 to 2020, the median annual dollar value of discarded therapies was $590 million. Every year, bortezomib, azacitidine, cabazitaxel, and decitabine were among the most wasted products, an average 24% waste. The IIJA policy would have impacted a median of 20 oncology agents and resulted in median annual refund of $172 million. Had the top five most discarded therapies been redistributed, they could have treated 18,289 patients. The five most wasted drugs were all dosed by weight and distributed in single-use vials. CONCLUSION: The IIJA could potentially significantly reduce waste or encourage redistribution to treat thousands of additional patients. We propose that a fusion of fixed and weight-based dosing may help reduce wasteful medication administration by offering doses that better accommodate most patients. We anticipate that manufacturers will adapt to the IIJA perhaps by adjusting fixed doses or simply increasing drug prices. If price changes from dose delivery adjustment occur, rebates offered to pharmacy benefit managers and insurers will likely follow suit and may alter formulary positioning.

Autoimmune Hemolytic Anemia: Diagnosis and Differential Diagnosis.

The causes of hemolytic anemia are numerous and a systematic approach is critical for proper identification and classification. The direct antiglobulin test can establish the diagnosis and subclassify the majority of autoimmune hemolytic anemias. Further testing to identify the driver of AIHA can have significant implications in overall management. Advanced testing for rare nonimmune acquired hemolytic anemias or hereditary hemolytic anemias may be necessary if DAT testing is negative.

Trends in Prices of Drugs Used to Treat Metastatic Non-Small Cell Lung Cancer in the US From 2015 to 2020.

Importance: Oncology drug prices are a determinant of health disparities in the US and worldwide. Several new therapeutic agents for non-small cell lung cancer (NSCLC) have become available on the US market over the past decade. Although increased competition typically produces lower prices, competition among brand-name oncology drugs has not resulted in lower prices. Objective: To assess price changes in class-specific brand-name medications used to treat metastatic NSCLC in the US from 2015 to 2020. Design, Setting, and Participants: This cross-sectional study, conducted from August 13, 2015, to August 13, 2020, used data from the Micromedex Red Book and Medi-Span Price Rx databases. The study sample was limited to 17 brand-name medications used to treat metastatic NSCLC that were available for purchase before January 1, 2019. Main Outcomes and Measures: The main outcomes were trends over time in average wholesale prices and wholesale acquisition cost unit prices and the correlation in price among the multiple brand-name medications within each therapeutic class (immune checkpoint inhibitors, epidermal growth factor receptor inhibitors, anaplastic lymphoma kinase inhibitors, ROS1 inhibitors, BRAF inhibitors, and MEK inhibitors), measured using the Pearson correlation coefficient. The compounded annual growth rates of different medication costs were compared with the annual inflation rate and the consumer price index for prescription drugs. Results: For all drug classes, the Pearson correlation coefficient approached 1.0, indicating an increase in drug list prices despite within-class drug competition. The median Pearson correlation coefficient values were 0.964 (range, 0.951-0.994) for immune checkpoint inhibitors, 0.898 (range, 0.665-0.950) for epidermal growth factor receptor inhibitors, 0.999 (range, 0.982-0.999) for anaplastic lymphoma kinase inhibitors, and 0.999 for BRAF and MEK inhibitors. The median compounded annual growth rates for most drug costs were higher than the annual inflation rate and consumer price index for prescription drugs: 1.81% (range, 1.29%-2.13%) for immune checkpoint inhibitors, 2.56% (range, 2.38%-5.26%) for epidermal growth factor receptor inhibitors, 2.46% (range, 1.75%-4.66%) for anaplastic lymphoma kinase and ROS1 inhibitors, and 3.06% (range, 0%-3.06%) for BRAF and MEK inhibitors. Conclusions and Relevance: In this cross-sectional study, prices of brand-name medications for treatment of NSCLC increased in the US from 2015 to 2020 without evidence of price competition, raising concern about the affordability of promising oncology drugs. These findings suggest that drug pricing reform is needed.

Economic Cost and Sustainability of Oral Therapies in Precision Oncology.

PURPOSE: Precision oncology promises improved outcomes but the cost-effectiveness and accessibility of targeted therapies is debatable. We report price change patterns from 2015 to 2019 for several oral anticancer medications for common solid tumor malignancies. METHODS: We collected provider utilization and payment data from the public Medicare Part D database and extracted drug price information for commonly prescribed targeted oral anticancer agents for lung, breast, and prostate cancer. We then calculated median Pearson correlation coefficient values for various drugs (containing more than two data points) within each therapeutic class. We also calculated compound annual growth rates (CAGRs) for medication costs within each class and compared them with the consumer price index (CPI). RESULTS: Our study included six epidermal growth factor receptor inhibitors (EGFRi; one generic), five anaplastic lymphoma kinase inhibitors (ALKi), two B-Raf inhibitors (BRAFi), three hormonal agents (one generic), three cyclin-dependent kinases 4 and 6 inhibitors (CDK4/6i), two poly-ADP-ribose inhibitors (PARPi), and seven antiandrogen agents (two generic). The median (range) Pearson correlation coefficient values for cost of drugs within each therapeutic class were 0.967 (0.915-0.978) for EGFRi, 0.981 (0.966-0.989) for ALKi, 0.996 for BRAFi, 0.994 (0.992-0.999) for CDK4/6i, 0.855 for PARPi, and 0.442 (-0.522 to 0.962) for antiandrogens. Therapies with two or fewer data points (generic erlotinib, dacomitinib, abiraterone, apalutamide, and darolutamide) were excluded. The median CAGRs in costs over the 5-year period were 4.56% (EGFRi), 6.40% (ALKi), 2.58% (BRAFi), 5.48% (hormonal agents), 5.21% (CDK4/6i), 27.29% (PARPi), and 34.8% (antiandrogens). The CPI over 5 years was 2.26%/year, and the average inflation rate was 1.90%/year. CONCLUSION: The median CAGR in costs for modern oral precision-driven cancer therapeutic classes mostly outpaced CPI and the average inflation. Increase in cost within the same class should be weighed against incremental clinical benefit for the patients to ensure that rising costs do not limit access to targeted therapies.

Drug importation: limitations of current proposals and opportunities for improvement.

Drug importation is a policy proposal to help alleviate rising pharmaceutical prices. Restrictions on drug importation stem from the Federal Food, Drug, and Cosmetic Act but authorization of importation can be made by the Health and Human Services (HHS) Secretary. During the Trump administration a number of states passed laws to develop a drug importation programs, however, none have been authorized by HHS. Limitations of these importation programs include sole reliance on Canada, exclusion of high-cost drugs like biologics, and persistent legal hazard of the Personal Importation Program. Potential revisions to current law include expansion of countries approved for importation, inclusion of biologics, and codifying protection for personal importation. Drug importation policies are not a panacea to address rising pharmaceutical prices but may blunt prices while more permanent solutions are pursued.

Life vs Loans: Does Debt Affect Career Satisfaction in Osteopathic Graduates?

BACKGROUND: The cost of undergraduate osteopathic medical education continues to grow. It is important to understand how the rising cost of matriculation negatively affects training and career satisfaction of entering students. OBJECTIVE: To better understand any association between level of educational debt and satisfaction with osteopathic medical education, career choice, and financial services. METHODS: Responses were analyzed from the American Association of Colleges of Osteopathic Medicine survey of pending medical school graduates from 2007 through 2016 regarding indebtedness and specialty selection. RESULTS: From 2007 to 2016, the mean educational debt level at graduation rose consistently among osteopathic graduates (from $155,698 to $240,331, respectively). In all years, there was no significant effect of debt quartile on satisfaction with choice of osteopathic medicine as a career. Quartile variable with debt did not show a significant effect on satisfaction with education experience in 2010, 2013, and 2016. Top quartile debt was associated with higher satisfaction with financial service departments in all years. CONCLUSION: Although debt has consistently increased for osteopathic medical graduates, it does not affect their satisfaction with either their educational experience or their choice of osteopathic medicine as a career.

How Trainees Finance Their Medical Education: Implications of Higher Education Act Reform.

CONTEXT: The Public Service Loan Forgiveness (PSLF) program is among several repayment programs currently available for recipients of federal student loans. Medical education debt has continued to expand at a rapid pace in the decade since PSLF was created. Proposed changes to the Higher Education Act would substantially transform how future medical trainees finance and repay medical education debt. OBJECTIVE: To better understand relationships between debt and personal stress, as well as between repayment- and forgiveness-program use, in the context of competing legislation. METHODS: Surveys were sent to all Accreditation Council for Graduate Medical Education-accredited internal medicine residency programs (osteopathic and allopathic). RESULTS: From a potential pool of 579 residents, data were obtained from 403 unique respondents (response rate, 69.6%) at 12 residency programs, for a program response rate of 2.2%. Of these respondents, 290 (71.9%) completed the demographic portion of the survey. Median education debt was $225,000. Residents with the top quartile of debt burden were more likely to use PSLF (odds ratio [OR], 3.27; P=.02), more likely to enter loan forbearance (OR, 2.14; P=.03), and indicated a higher level of stress (OR, 5.94; P<.001) compared with those in the second and third quartiles. CONCLUSION: Proposed legislative changes to the Higher Education Act would scale back loan repayment options and also eliminate PSLF for future borrowers. Our data suggest that higher debt burdens are associated with increased debt-related stress. Given program popularity and growing use, along with growing concerns of physician burnout, policy makers should weigh the potential downstream effects of policy change on prospective future physicians.

Choosing Primary Care: Factors Influencing Graduating Osteopathic Medical Students.

CONTEXT: Access to primary care (PC) improves health outcomes and decreases health care costs. The shortage of PC physicians and shifting physician workforce makes this an ongoing concern. Osteopathic medical schools are making strides to fill this void. Considering the critical need for PC physicians in the United States, this study aims to identify factors related to choosing a PC specialty. OBJECTIVE: To understand possible motivations of osteopathic medical students pursuing a career in PC specialties by examining the role of sex and the influence of 5 key factors in this decision. METHODS: Responses from the annual American Association of Colleges of Osteopathic Medicine graduate survey (2007-2016) were analyzed. Self-reported practice decision considerations of 5 key factors, including (1) intellectual and technical content, (2) debt level, (3) lifestyle, (4) prestige/income level, and (5) personal experience and abilities were summarized, and their subjective value was contrasted between osteopathic medicine graduates pursuing PC specialties vs those pursuing non-PC specialties. RESULTS: The mean percentage of graduates pursuing PC and non-PC specialties from 2007 to 2016 was 31.3% and 68.7%, respectively. Women were 1.75 times more likely to choose PC than men (95% CI, 1.62-1.89). Regardless of specialty choice, lifestyle was the most important factor each year (1027 for PC [75.3%] vs 320 for non-PC [63.3%] in 2016; P<.0001). Students entering PC were more likely to report prestige and income level to be "no or minor influence" compared with students entering non-PC specialties (P<.0001). Debt level was more likely to be a "major influence" to students choosing to enter non-PC specialties than to those entering PC (P<.0001), and the percentage of non-PC students has grown from 383 in 2007 (22.9%) to 833 in 2016 (30.6%). CONCLUSION: Sex was found to significantly influence a graduate's choice of specialty, and female graduates were more likely to enter practice in PC. Each of the 5 survey factors analyzed was significantly different between students entering PC and students entering non-PC specialties. Lifestyle was deemed a major influencing factor, and responses suggested that debt level is a strong influencing factor among students pursuing non-PC specialties.

Efficacy of mitoxantrone-based salvage therapies in relapsed or refractory acute myeloid leukemia in the Mayo Clinic Cancer Center: Analysis of survival after 'CLAG-M' vs. 'MEC'.

Salvage therapy regimens for refractory and relapsed AML include mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M). We analyzed patients receiving either CLAG-M or MEC as salvage therapy for RR-AML between 09/01/2009-12/31/2017. Of 150 patients with RR-AML, 34 patients received CLAG-M and 116 MEC. CR/CRi rates for CLAG-M and MEC were 61.3 % (19/31) and 55.6 % (60/108). Median OS was 9.5 months for CLAG-M and 10.0 months for MEC (HR = 0.88,95 %CI = 0.54-1.41,p = 0.59). 76 patients proceeded to ASCT following salvage therapy. Median OS after ASCT was 13.0 months for CLAG-M and 31.0 months for MEC (HR = 1.76,95 %CI = 0.87-3.56,p = 0.12). Among those with late relapse and ASCT, median OS was 9.0 and 48.0 months for CLAG-M and MEC, respectively (HR = 17.6,95 %CI = 1.57-198,p < 0.001). There were no significant differences in outcome between CLAG-M vs. MEC regardless of transplant status. There was a significant improvement in survival in patients with late relapse treated with MEC who proceeded to ASCT.

Germ Cell Tumors with Malignant Somatic Transformation: A Mayo Clinic Experience.

BACKGROUND: Germ cell tumors (GCTs) with malignant somatic transformation (MST) represent an uncommon variant of what is typically a curable malignancy. There is a paucity of data on time of somatic transformation, response to conventional therapy, and survival outcomes of different somatic subtypes. METHODS: After obtaining institutional review board (IRB) approval, we searched our institutional database from 1982 to 2017 and identified patients with GCTs with MST. Patient characteristics, pathologic description, treatment, and clinical outcomes were extracted from the medical records. RESULTS: We identified 24 cases of GCTs with MST; the MST was adenocarcinoma in 50% and sarcoma in 50%. Median age at diagnosis was 27. Alpha-fetoprotein and beta-human chorionic gonadotropin were undetectable in 44%, both were elevated in 54%. The majority were advanced stage (71% stage III), and International Germ Cell Cancer Collaborative Group (IGCCCG) risk was classified as 'good' in 60%. Median follow-up was 41 months (range 10-346 months). Median progression-free survival was 84 months (95% confidence interval (CI) 56-232), and median overall survival was 219 months (95% CI 165-not reported). CONCLUSION: Patients with GCTs with an MST appear to have poor responses to cisplatin-based chemotherapy, suggesting that somatic component-driven therapies should be considered. Furthermore, resection of residual disease when feasible is an essential component of management.

Role of Debt and Loan Forgiveness/Repayment Programs in Osteopathic Medical Graduates' Plans to Enter Primary Care.

CONTEXT: Osteopathic medicine emphasizes partnering with patients to help them attain or maintain health. This philosophy encourages physicians to practice primary care and a mission of improving community health. However, there is currently a shortage of primary care physicians in many areas of the United States. OBJECTIVE: To determine whether intended practice patterns of recent graduates of colleges of osteopathic medicine favor primary care and whether practice patterns correlate with medical education debt. METHODS: Responses were analyzed from the American Association of Colleges of Osteopathic Medicine survey of pending medical school graduates from 2007 through 2016 regarding indebtedness and specialty selection. RESULTS: The percentage of graduating osteopathic medical students who chose a primary care specialty increased from 28.1% (676 students) in 2007 to 33.2% (1377 students) in 2016. Among graduates, those above the 75th percentile of debt had a general move toward more non-primary care positions, with a value of 74.4% in 2007 and 79.9% in 2016. Graduates below the 25th percentile had a gradual increase in primary care representation, moving from 24.6% in 2007 to 29.4% in 2016. In 2007, graduates with a loan forgiveness/repayment program were more likely to choose primary care over graduates without such a program (OR, 0.681 [95% CI, 0.505-0.920]; P=.02). Analysis of subsequent years showed a declining OR with increasing significance. CONCLUSIONS: Results of this analysis indicated that increased educational debt loan directly influenced physician practice choice. Graduates with high debt burden were more likely to enter primary care fields and use loan forgiveness/repayment programs. Graduates with high debt burden who did not use loan forgiveness/repayment programs were more likely to enter non-primary care specialty fields, with this trend increasing as mean medical school debt increased. This association has implications for policies that could affect choice of primary care. However, further research is needed to fully understand the primary care choice by graduates of colleges of osteopathic medicine.

Practice Area Intentions of Graduates of Colleges of Osteopathic Medicine: What Role Does Debt Play?

CONTEXT: Enrollment in colleges of osteopathic medicine continues to increase, as does the need for physicians practicing in underserved areas. The cost of osteopathic medical education is substantial, with students often incurring debt of $200,000 or more. It is unclear whether practice patterns of new graduates will be affected by debt-to-income ratios. OBJECTIVE: To determine whether the intended practice location of graduates of colleges of osteopathic medicine is associated with medical education debt. METHODS: Using data from the American Association of Colleges of Osteopathic Medicine's annual survey to graduates of colleges of osteopathic medicine, the authors focused on graduates' intention to practice in an underserved area, the amount of debt incurred, and plans to enter a loan-repayment program. Survey data from 2007, 2010, 2013, and 2016 were analyzed. RESULTS: From 2007 to 2016, the percentage of graduates who intended to practice in underserved areas increased (27.5% to 35.3%, respectively). Graduates with the most debt intended to practice in underserved areas at a higher percentage than those with the least amount of debt, and they also planned on using loan-repayment programs at a higher rate. CONCLUSION: There is a strong association among the intention to practice in an underserved area, high debt load, and intention to use a loan-repayment program. Therefore, the osteopathic medical community should support increased access to loan-repayment programs to help its graduates surmount economic and social barriers to providing care in underserved areas.

Evidence of selective reporting bias in hematology journals: A systematic review.

INTRODUCTION: Selective reporting bias occurs when chance or selective outcome reporting rather than the intervention contributes to group differences. The prevailing concern about selective reporting bias is the possibility of results being modified towards specific conclusions. In this study, we evaluate randomized controlled trials (RCTs) published in hematology journals, a group in which selective outcome reporting has not yet been explored. METHODS: Our primary goal was to examine discrepancies between the reported primary and secondary outcomes in registered and published RCTs concerning hematological malignancies reported in hematology journals with a high impact factor. The secondary goals were to address whether outcome reporting discrepancies favored statistically significant outcomes, whether a pattern existed between the funding source and likelihood of outcome reporting bias, and whether temporal trends were present in outcome reporting bias. For trials with major outcome discrepancies, we contacted trialists to determine reasons for these discrepancies. Trials published between January 1, 2010 and December 31, 2015 in Blood; British Journal of Haematology; American Journal of Hematology; Leukemia; and Haematologica were included. RESULTS: Of 499 RCTs screened, 109 RCTs were included. Our analysis revealed 118 major discrepancies and 629 total discrepancies. Among the 118 discrepancies, 30 (25.4%) primary outcomes were demoted, 47 (39.8%) primary outcomes were omitted, and 30 (25.4%) primary outcomes were added. Three (2.5%) secondary outcomes were upgraded to a primary outcome. The timing of assessment for a primary outcome changed eight (6.8%) times. Thirty-one major discrepancies were published with a P-value and twenty-five (80.6%) favored statistical significance. A majority of authors whom we contacted cited a pre-planned subgroup analysis as a reason for outcome changes. CONCLUSION: Our results suggest that outcome changes occur frequently in hematology trials. Because RCTs ultimately underpin clinical judgment and guide policy implementation, selective reporting could pose a threat to medical decision making.

Systematic review: Outcome reporting bias is a problem in high impact factor neurology journals.

BACKGROUND: Selective outcome reporting is a significant methodological concern. Comparisons between the outcomes reported in clinical trial registrations and those later published allow investigators to understand the extent of selection bias among trialists. We examined the possibility of selective outcome reporting in randomized controlled trials (RCTs) published in neurology journals. METHODS: We searched PubMed for randomized controlled trials from Jan 1, 2010 -Dec 31, 2015 published in the top 3 impact factor neurology journals. These articles were screened according to specific inclusion criteria. Each author individually extracted data from trials following a standardized protocol. A second author verified each extracted element and discrepancies were resolved. Consistency between registered and published outcomes was evaluated and correlations between discrepancies and funding, journal, and temporal trends were examined. RESULTS: 180 trials were included for analysis. 10 (6%) primary outcomes were demoted, 38 (21%) primary outcomes were omitted from the publication, and 61 (34%) unregistered primary outcomes were added to the published report. There were 18 (10%) cases of secondary outcomes being upgraded to primary outcomes in the publication, and there were 53 (29%) changes in timing of assessment. Of 82 (46%) major discrepancies with reported p-values, 54 (66.0%) favored publication of statistically significant results. CONCLUSION: Across trials, we found 180 major discrepancies. 66% of major discrepancies with a reported p-value (n = 82) favored statistically significant results. These results suggest a need within neurology to provide more consistent and timely registration of outcomes.