Prevalence of TP-53/Rb-1 Co-Mutation in Large Cell Neuroendocrine Carcinoma.

INTRODUCTION: Large cell neuroendocrine carcinoma (LCNEC) is a rare and highly aggressive high-grade neuroendocrine neoplasm, which can arise from anywhere in the body. Due to its rarity there is a lacuna in our understanding of LCNEC's molecular biology. In 2016, Rekhtman and colleagues presented one of the largest molecular sequencing series of pulmonary LCNEC. They differentiated genomic profiles of LCNEC into two major subsets: small cell lung cancer (SCLC)-like, characterized by TP53 + RB1 co-mutation/loss, and non-small cell lung cancer (NSCLC)-like, characterized by the lack of co-altered TP53 + RB1. This finding is of significance because at present LCNEC patients are often treated like SCLC. However, the universal genomic SCLC biomarker of TP53 and RB1 co-mutation was only found in 40% of their cohort. Since then various other scientists have looked into molecular profiling of LCNEC with markedly discordant results. The objective of this study was to conduct a systematic review of publicly available next generation sequencing (NGS) data to evaluate the prevalence of TP53 + RB1 co-mutation in LCNEC. METHOD: We conducted a literature search using PubMed. Seven studies including 302 patients with pulmonary LCNEC and four studies including 20 patients with extra-pulmonary LCNEC underwent final analysis. RESULTS: The prevalence of TP53 + RB1 co-mutation was 36% (109/302) among pulmonary LCNEC patients and 35% (7/20) among the extra-thoracic LCNEC cohort. This finding is in stark contrast to >90% TP53 + RB1 co-mutation in SCLC. CONCLUSION: It is now well established that LCNEC is molecularly distinct from SCLC. LCNEC seems to have two molecularly defined sub-cohort based on TP53 + RB1 co-mutation status. Future studies should look into prognostic and predictive implication of TP53 + RB1 co-mutation status in LCNEC. Prospective studies should be designed to characterize molecular subtypes and direct treatment accordingly. We are currently conducting a prospective pilot clinical trial wherein LCNEC patients are treated based on TP53 + RB1 co-mutation status. The study is currently enrolling. "Next Generation Sequencing-Based Stratification of Front Line Treatment of Neuroendocrine Carcinoma (PRECISION-NEC). SYSTEMATIC REVIEW: ClinicalTrials.gov, identifier NCT04452292.

A retrospective review of fall risk factors in the bone marrow transplant inpatient service.

Purpose The purpose of this study was to compare medications and potential risk factors between patients who experienced a fall during hospitalization compared to those who did not fall while admitted to the Blood and Marrow Transplant inpatient setting at The James Cancer Hospital. Secondary objectives included evaluation of transplant-related disease states and medications in the post-transplant setting that may lead to an increased risk of falls, post-fall variables, and number of tests ordered after a fall. Methods This retrospective, case-control study matched patients in a 2:1 ratio of nonfallers to fallers. Data from The Ohio State University Wexner Medical Center (OSUWMC) reported fall events and patient electronic medical records were utilized. A total of 168 adult Blood and Marrow Transplant inpatients with a hematological malignancy diagnosis were evaluated from 1 January 2010 to 30 September 2012. Results Univariable and multivariable conditional logistic regression models were used to assess the relationship between potential predictor variables of interest and falls. Variables that were found to be significant predictors of falls from the univariable models include age group, incontinence, benzodiazepines, corticosteroids, anticonvulsants and antidepressants, and number of days status-post transplant. When considered for a multivariable model age group, corticosteroids, and a cancer diagnosis of leukemia were significant in the final model. Conclusion Recent medication utilization such as benzodiazepines, anticonvulsants, corticosteroids, and antidepressants placed patients at a higher risk of experiencing a fall. Other significant factors identified from a multivariable analysis found were patients older than age 65, patients with recent corticosteroid administration and a cancer diagnosis of leukemia.

Quantitation of Targetable Somatic Mutations Among Patients Evaluated by a Personalized Medicine Clinical Service: Considerations for Off-Label Drug Use.

INTRODUCTION: Moffitt Cancer Center's Personalized Medicine Clinical Service (PMCS) reviews somatic next-generation sequencing (NGS) assay results, provides interpretations, and identifies potential therapeutic options. The number of individuals reviewed by our clinical service who are eligible for on-label or off-label drug therapy based on genetic test results has previously not been quantitated. We determined the number of patients harboring an actionable mutation that would qualify a patient for an on-label drug or consideration for off-label drug treatment. METHODS: The Food and Drug Administration (FDA) Table of Pharmacogenomic Biomarkers in Drug Labeling was utilized to identify anticancer agents containing genomic markers in the Indications and Usage section of the drug label. A database containing discrete NGS patient data was queried retrospectively for those drugs and associated genomic mutations included in this study. On-label was defined as those patients who were eligible for a drug based on harboring a targetable mutation in the FDA-approved cancer type. Off-label was defined as those patients who may be considered for a drug based on harboring a targetable mutation in a non-FDA-approved cancer type. RESULTS: A total of 1072 patients and 1131 NGS results were eligible for study inclusion. Fifty-two patients (4.9%) had results for more than one NGS assay. Seventeen drugs targeting ALK, BRAF, BRCA1/BRCA2, EGFR, or ERBB2 mutations met the study inclusion criteria. Of the entire patient population, 92 (8.6%) unique patients were eligible for at least one on-label drug; off-label use of at least one drug could be considered in 103 (9.6%) unique patients. CONCLUSION: Combining both on-label and off-label opportunities, 175 (16.3%) unique patients had actionable mutations in six genes. Because most patients reviewed by our PMCS have previously treated advanced disease with limited treatment options, identifying additional lines of therapy is of clinical utility.

Pharmacists' roles in oncology pharmacy services: Results of a global survey.

Background Oncology pharmacists are capable of providing medication therapy management (MTM) because of their level of training, practice experiences, and responsibilities. Very little data exist about their current practice, including changing roles in the multidisciplinary team, overall impact, and effects in the education of patients and healthcare professionals. Methods A 70-item survey about oncology pharmacists' activities in oral chemotherapy programs, MTM, and collaborative practice agreements (CPAs) was deployed using a web survey tool (Qualtrics, Provo, UT, USA), targeting pharmacist members of American College of Clinical Pharmacy (ACCP) Hematology/Oncology Practice and Research Network (PRN). The objective of this study was to determine oncology pharmacists' activities in areas of oral chemotherapy programs, MTM, and CPAs. A cross-sectional survey was distributed to the ACCP Hematology/Oncology PRN membership. Investigational Review Board approval was obtained. Results Of the 795 members who were sent the survey, 81 members (10%) responded; 33 respondents (47%) are involved with an oral chemotherapy program; with 42% measuring outcomes of programs. Only six pharmacists (19%) have published or presented their data. A total of 28 (35%) respondents provide MTM services, with almost half (43%) of these MTM services being dictated by CPAs. A small fraction of these pharmacists (21.4%) reported conducting quality assurance evaluations of their MTM services and three pharmacists (10.7%) reported publishing their results. Those pharmacists practicing under CPAs ( n = 28) were surveyed as to activities included in their CPA. The most common activities included adjusting medication, ordering, interpreting, and monitoring lab tests, developing therapeutic plans and educating patients. Reimbursement for providing these services was uncommon: MTM (4%), oral chemotherapy program (6%), and CPA services (11%). Reported obstacles to reimbursement included lack of understanding, administrative assistance, or time with setting up reimbursement models within the institution. Conclusion Many oncology pharmacists are participating in oral chemotherapy programs, MTM, and/or CPAs and perceived barriers were identified. Increased efforts should be directed toward prospectively reporting and assessing the impact these services have on patient care.

Ibrutinib for treatment of chronic lymphocytic leukemia.

PURPOSE: The pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of ibrutinib are described. SUMMARY: Ibrutinib is a first-in-class oral inhibitor of Bruton tyrosine kinase (BTK) approved for treatment of relapsed chronic lymphocytic leukemia (CLL). Ibrutinib blocks downstream signaling of the B-cell receptor, disrupting stromal microenvironment interactions and B-cell cytokine signaling. BTK inhibition has been shown to be effective in relapsed or refractory CLL. A recent Phase III study evaluated ibrutinib (420 mg daily) versus ofatumumab (consistent with labeling) in relapsed or refractory CLL with a primary endpoint of progression free survival (PFS, n = 391). After a median follow-up period of 9.4 months, a PFS was not attained in ibrutinib-treated individuals with and without deletion 17p. In contrast, ofatumumab-treated individuals experienced a PFS of 8.1 months and those with deletion 17p experienced a PFS of 5.8 months. Major hemorrhage was reported in 2 (1%) patients treated with ibrutinib, and a total of 8 (4%) patients discontinued treatment due to toxicity or adverse reactions. Partial response or partial response with lymphocytosis was achieved in 63% of ibrutinib-treated individuals as determined by independent assessments. Overall, ibrutinib reduced the rate of mortality by 57%. CONCLUSION: Ibrutinib is a first-in-class, orally active, irreversible BTK inhibitor with a novel mechanism of action. This unique mechanism of action and high overall response rates observed in clinical trials make ibrutinib an attractive second-line option in patients who have disease progression while receiving monoclonal antibody therapy or chemoimmunotherapy.

Antileishmanial and Cytotoxic Activity of Some Highly Oxidized Abietane Diterpenoids from the Bald Cypress, Taxodium distichum.

Two new compounds, namely, a para-benzoquinone ring-containing abietane (1) and a para-benzoquinone ring-containing 7,8-seco-abietane (2), and 14 other known highly oxidized abietane diterpenoids (3-16) were isolated from an extract prepared from the cones of Taxodium distichum, collected in central Ohio. The active subfraction from which all compounds isolated in this study were purified was tested in vivo using Leishmania donovani-infected mice and was found to dose-dependently reduce the parasite burden in the murine livers after iv administration of this crude mixture at 5.6 and 11.1 mg/kg. The structures of 1 and 2 were established by detailed 1D- and 2D-NMR experiments, HRESIMS data, and electronic circular dichroism studies. Compounds 3 and 4 were each fully characterized spectroscopically and also isolated from a natural source for the first time. Compounds 2-16 were tested in vitro against L. donovani promastigotes and L. amazonensis intracellular amastigotes. Compound 2 was the most active against L. amazonensis amastigotes (IC50 = 1.4 µM), and 10 was the most potent against L. donovani promastigotes (IC50 = 1.6 µM). These compounds may be suggested for further studies such as in vivo experimentation either alone or in combination with other Taxodium isolates.