Shiven B. Patel

Mitochondrial depolarization following hydrogen sulfide exposure in erythrocytes from a sulfide-tolerant marine invertebrate

SUMMARY Sulfide-tolerant marine invertebrates employ a variety of mechanisms to detoxify sulfide once it has entered their bodies, but their integumentary, respiratory epithelium and circulatory cells may still be exposed to toxic sulfide concentrations. To investigate whether sulfide exposure is toxic to mitochondria of a sulfide-tolerant invertebrate, we used the fluorescent dyes JC-1 and TMRM to determine the effect of sulfide exposure on mitochondrial depolarization in erythrocytes from the annelid Glycera dibranchiata. In erythrocytes exposed to 0.11-1.9 mmol l-1 sulfide for 1 h, the dyes showed fluorescence changes consistent with sulfide-induced mitochondrial depolarization. At the highest sulfide concentration, the extent of depolarization was equivalent to that caused by the mitochondrial uncoupler carbonyl cyanide m-chlorophenylhydrazone (CCCP). Even when induced by as little as 0.3 mmol l-1 sulfide, the depolarization was not reversible over a subsequent 5 h recovery period. The mechanism of toxicity was likely not via inhibition of cytochrome c oxidase (COX), since other COX inhibitors and other mitochondrial electron transport chain inhibitors did not produce similar effects. Furthermore, pharmacological inhibition of the mitochondrial permeability transition pore failed to prevent sulfide-induced depolarization. Finally, increased oxidation of the free radical indicators H2DCFDA and MitoSOX™ in erythrocytes exposed to sulfide suggests that sulfide oxidation increased oxidative stress and superoxide production, respectively. Together, these results indicate that sulfide exposure causes mitochondrial depolarization in cells of a sulfide-tolerant annelid, and that this effect, which differs from the actions of other COX inhibitors, may be via increased free radical damage.

Subdural hematomas in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy

Imatinib mesylate and other tyrosine kinase inhibitors (TKIs) that inhibit BCR–ABL have had a favorable impact on the treatment of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). TKIs are generally well tolerated, but they can induce platelet dysfunction, which is of particular concern in the setting of thrombocytopenia in patients with acute leukemia. We present three patients with Ph+ ALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy who developed subdural hematomas (SDHs). All three were thrombocytopenic and had undergone repeated lumbar punctures for prophylactic intrathecal chemotherapy, but they were not coagulopathic and did not have meningeal leukemia. SDHs occurred in three of a total of 10 adult patients with Ph+ ALL receiving imatinib mesylate in conjunction with systemic and intrathecal chemotherapy at our institution from 2007 to 2010, but in none of 22 adult patients with Ph− ALL receiving the same therapy without imatinib mesylate (p < 0.05). Patients with Ph+ ALL receiving imatinib mesylate, and likely also dasatinib, in conjunction with systemic and intrathecal chemotherapy may be at increased risk of SDH, and should be closely monitored for subtle manifestations of this complication.

Neutrophil-lymphocyte ratio as a predictive biomarker for response to high dose interleukin-2 in patients with renal cell carcinoma

BackgroundImmunotherapy with high-dose interleukin-2 (HD-IL2) results in long-term survival in some metastatic renal cell carcinoma (mRCC) patients but has significant acute toxicities. Biomarkers predicting response to therapy are needed to better select patients most likely to benefit. NLR (absolute neutrophil count (ANC)/absolute lymphocyte count (ALC)) is a prognostic and predicative biomarker in various malignancies. The goal was to determine whether NLR can predict response to HD-IL2 in this setting.MethodsPatients with clear cell mRCC treated with HD-IL2 were identified from an institutional database from 2003–2012. Baseline variables for the assessment of IMDC risk criteria, and neutrophil and lymphocyte count, were collected. Best response criteria were based on RECIST 1.0. Wilcoxon rank-sum test was used to evaluate the association of continuous baseline variables with disease control. NLR was stratified by ≤4 or >4. Progression free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier method and Cox proportional hazard models assessed associations of NLR with survival.ResultsIn 71 eligible patients, median NLR in those with an objective response (n = 14, 20%) was 2.3 vs 3.4 in those without (n = 57, 80%, p = 0.02). NLR ≤4 was associated with improved progression free and overall survival. After adjustment for IMDC risk criteria, NLR remained a significant predictor of OS (ANC/ALC ≤4 vs >4, HR 0.41, 95% CI 1.09-5.46, p = 0.03; ANC/ALC continuous variable per unit change in NLR, HR 1.08, 95% CI 1.01-1.14, p = 0.03).ConclusionsIn this discovery set, NLR predicts overall survival in patients treated with HD-IL2 in mRCC, and may allow better patient selection in this setting. Data needs validation in an independent cohort.

Myeloid growth factors, version 2.2017

Myeloid growth factors (MGFs) are given as supportive care to patients receiving myelosuppressive chemotherapy to reduce the incidence of neutropenia. This selection from the NCCN Guidelines for MGFs focuses on the evaluation of regimen- and patient-specific risk factors for the development of febrile neutropenia (FN), the prophylactic use of MGFs for the prevention of chemotherapy-induced FN, and assessing the risks and benefits of MGF use in clinical practice.

Everolimus Versus Temsirolimus in Metastatic Renal Cell Carcinoma After Progression With Previous Systemic Therapies

BACKGROUND Everolimus is an approved agent for use after disease progression with vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs) in patients with metastatic renal cell carcinoma. With recently published trials showing efficacy of nivolumab and cabozantinib in the second-line therapy setting, the use of everolimus will likely move to the third- or fourth-line therapy setting. Temsirolimus has occasionally been used instead of everolimus for many reasons, including financial considerations, assurance of patient compliance given its intravenous administration, its toxicity profile, patient performance status, and patient or physician preference. However, efficacy of everolimus and temsirolimus in this setting have not been compared in a randomized trial. The results from retrospective studies have been inconsistent. MATERIALS AND METHODS We identified patients treated with a first-line VEGFR-TKI for metastatic renal cell carcinoma and then treated with either everolimus or temsirolimus on progression from the databases of 2 large academic cancer centers. Progression-free survival (PFS) and overall survival (OS) were assessed from the initiation of second-line treatment using the Kaplan-Meier method. RESULTS A total of 90 patients received either everolimus (n = 59; 66%) or temsirolimus (n = 31; 34%) after progression during first-line VEGFR-TKI therapy. The patient and disease characteristics were similar in both groups. The median PFS was not different, but OS was superior with everolimus compared with temsirolimus (24.2 months vs. 12.1 months; hazard ratio, 0.58; P = .047). CONCLUSION Our results bolster existing guidelines supporting everolimus over temsirolimus as salvage therapy after previous systemic therapies.

Profile of panitumumab as first-line treatment in patients with wild-type KRAS metastatic colorectal cancer

Targeted therapies against EGFR, vascular endothelial growth factor, and vascular endothelial growth factor receptor have expanded treatment options for patients with metastatic colorectal cancer (mCRC). Unfortunately, biomarkers to identify patients that are most likely to derive benefit from targeted therapies in this disease are still needed. Indeed, only RAS mutations have been identified as predictive of lack of benefit from monoclonal antibodies against EGFR in patients with mCRC. Panitumumab is a fully humanized monoclonal antibody against EGFR. In this study, we review data to support the use of panitumumab in combination with a chemotherapy backbone, in the first line setting in patients with RAS wild-type mCRC. Ongoing efforts are aimed at identifying smaller subsets of patients within the RAS wild-type group that will derive the largest benefit from anti-EGFR therapy. In the meantime, treatment with anti-EGFR therapy should be reserved for patients with RAS wild-type mCRC.

Genomic analysis of adult B-ALL identifies potential markers of shorter survival

B lymphoblastic leukemia (B-ALL) in adults has a higher risk of relapse and lower long-term survival than pediatric B-ALL, but data regarding genetic prognostic biomarkers are much more limited for adult patients. We identified 70 adult B-ALL patients from three institutions and performed genome-wide analysis via single nucleotide polymorphism (SNP) arrays on DNA isolated from their initial diagnostic sample and, when available, relapse bone marrow specimens to identify recurring copy number alterations (CNA). As B-cell developmental genes play a crucial role in this leukemia, we assessed such for recurrent deletions in diagnostic and relapse samples. We confirmed previous findings that the most prevalent deletions of these genes occur in CDKN2A, IKZF1, and PAX5, with several others at lower frequencies. Of the 16 samples having paired diagnostic and relapse samples, 5 showed new deletions in these recurrent B-cell related genes and 8 showed abolishment. Deletion of EBF1 heralded a significant negative prognostic impact on relapse free survival in univariate and multivariate analyses. The combination of both a CDKN2A/B deletion and an IKZF1 alteration (26% of cases) also showed a trend toward predicting worse overall survival compared to having only one or neither of these deletions. These findings add to the understanding of genomic influences on this comparably understudied disease cohort that upon further validation may help identify patients who would benefit from upfront treatment intensification.

Inherited Variants in SULT1E1 and Response to Abiraterone Acetate by Men with Metastatic Castration Refractory Prostate Cancer

PURPOSE Germline variations in genes involved in androgen biosynthesis and metabolic pathways may predict the response to abiraterone acetate in men with metastatic, castration refractory prostate cancer. The variations may serve as prognostic and predictive biomarkers to allow for more individualized therapy. MATERIALS AND METHODS We evaluated 832 single nucleotide polymorphisms from the OmniExpress genotyping platform (Illumina®) in the boundaries of 61 candidate genes reported to be involved in the androgen metabolic pathway. The purpose was to investigate them for an association with time to treatment failure in 68 white men with metastatic, castration refractory prostate cancer undergoing treatment with abiraterone acetate. Cox proportional hazard analysis was used with Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation as covariates. Each single nucleotide polymorphism was assessed using an allele carriage genetic model in which carriage of 1 or more minor alleles contributes to increased risk. Subset analyses were done to determine whether metastasis site, or prior treatment with ketoconazole or docetaxel would interact with the single nucleotide polymorphisms investigated. RESULTS Six single nucleotide polymorphisms in the estrogen sulfotransferase gene SULT1E1 were associated with time to treatment failure on abiraterone acetate therapy after false discovery rate (q value) correction for multiple testing while controlling for Gleason score, age, level of alkaline phosphatase and prostate specific antigen at treatment initiation (q <0.05). CONCLUSIONS Single nucleotide polymorphisms in SULT1E1 were significantly associated with time to treatment failure in men on abiraterone acetate therapy. The single nucleotide polymorphisms may serve as predictive markers for treatment with abiraterone acetate.

Survival Outcomes and Tumor IMP3 Expression in Patients with Sarcomatoid Metastatic Renal Cell Carcinoma.

Metastatic renal cell carcinoma with sarcomatoid histology (SmRCC) is associated with poor survival. No data is available from randomized trials on the efficacy of vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) inhibitors in SmRCC. We identified SmRCC patients from a single institutional database. To identify predictive and prognostic biomarkers, immunohistochemistry (IHC) analysis was performed on the tumor samples for downstream targets of VEGF and mTOR pathways. Survival outcomes were stratified by IHC analysis, extent of sarcomatoid component, Memorial Sloan-Kettering Cancer Center (MSKCC), and Heng risk criteria. Twenty-seven patients with SmRCC were included. First line therapy included targeted therapy (n = 19), immunotherapy (n = 4), cytotoxic chemotherapy (n = 1), and no treatment (n = 3). Median OS was 8.2 months (95% CI 3.8–14.2 months). Median survival in months, based on MSKCC and Heng risk groups, was favorable 89.3 versus 84.5, intermediate 9.5 versus 12.7, and poor 3.9 versus 5.1. None of the IHC markers predicted outcomes of treatment with VEGF or mTOR inhibitors. Only tumor IMP3 expression was associated with inferior OS, although not statistically significant (IMP3 negative 14.2 versus IMP3 positive 4.9 months; HR 0.46, 95% CI 0.16–1.21; P = 0.12). The study was limited by small sample size.

Immunotherapy after chemoradiotherapy in stage III non-small cell lung cancer: a new standard of care?

Stage III non-small cell lung cancer (NSCLC) remains a clinical challenge with only modest improvements in treatment over two decades and a plateau in survival.