Thrombosis Rates and Genetic Thrombophilia Risk Among Patients With Advanced Germ Cell Tumors Treated With Chemotherapy.

INTRODUCTION: Men with advanced germ cell tumors (GCT) treated with chemotherapy are at high risk of venous thromboembolism (VTE). Predictors of VTE may identify patients who would benefit from prophylactic anticoagulation. PATIENTS AND METHODS: Men with advanced GCT (Stage IS, II, III) treated with chemotherapy were identified at 2 centers. High genomic risk was defined from a 5 single nucleotide polymorphism (SNP) germline panel. Logistic regression was used to evaluate the impact of genomic risk on VTE within 6 months of chemotherapy initiation. Orthogonal Projection to Latent Structures Discriminant Analysis (OPLS-DA) was used to build models to predict VTE based on clinical variables and an 86 SNP panel. RESULTS: This 123-patient cohort experienced a VTE rate of 26% with an incidence of high genomic risk of 21%. Men with high genomic risk did not have a significantly higher VTE rate (31%, 8/26) than men with low genomic risk (25%, 24/97), unadjusted OR 1.4 (95% CI 0.5-3.5, P = .54). Incorporation of clinical variables (Khorana score, N3 status and elevated LDH) resulted in adjusted OR 2.1 (95% CI 0.7-6.5, P = .18). A combined model using clinical variables and 86 SNPs performed similarly (AUC 0.77) compared to clinical variables alone (AUC 0.72). CONCLUSIONS: A previously established 5-SNP panel was not associated with VTE among patients with GCT receiving chemotherapy. However, multivariable models based on clinical variables alone warrant further validation to inform prophylactic anticoagulation strategies.

Hematocrit control and thrombotic risk in patients with polycythemia vera treated with ruxolitinib in clinical practice.

Polycythemia vera (PV) is a myeloproliferative neoplasm characterized by unregulated red blood cell production resulting in elevated hemoglobin and/or hematocrit levels. Patients often have symptoms such as fatigue, pruritus, and painful splenomegaly, but are also at risk of thrombosis, both venous and arterial. Ruxolitinib, a selective Janus kinase inhibitor, is approved by the US Food and Drug Administration as second-line cytoreductive treatment after intolerance or inadequate response to hydroxyurea. Although ruxolitinib has been widely used in this setting, limited data exist in the literature on ruxolitinib treatment patterns and outcomes among patients with PV in routine clinical practice. We report a retrospective, observational, cohort study of patients treated for PV with ruxolitinib across three US centers (academic and regional practice) from December 2014-December 2019. The study included 69 patients, with a median follow-up duration of 3.7 years (95% CI, 2.9-4.4). Our data demonstrate very high rates of hematocrit control (88% of patients by three months and 89% by six months); few patients required dose adjustments or suspension. No arterial thromboses were observed; however, the follow-up duration does not allow for the generation of meaningful conclusions from this. Three patients had thrombotic events; one was in the setting of a second malignancy, one post-operative, and a third related to prolonged immobility. We also found that 28% of patients initiated ruxolitinib as a result of poorly controlled platelet counts, second only to hydroxyurea intolerance (46%) as a reason to start therapy. In clinical practice, ruxolitinib continues to be effective in controlling hematocrit levels after three and six months of treatment in patients and is associated with low thrombotic risk.

Low co-expression of PD-L1 and oncogenic receptor tyrosine kinases HER2 and cMET in urothelial carcinoma is associated with discordant expression between primary and metastatic sites.

OBJECTIVES: Novel regimens targeting immune checkpoints and the cMET or HER2 pathways are under investigation in metastatic urothelial carcinoma (mUC) though co-expression of these molecular targets has not been defined. We sought to characterize the protein co-expression rates of PD-L1, cMET and HER2 in primary and metastatic mUC lesions and agreement rates in paired biopsies. MATERIALS AND METHODS: We assessed PD-L1, cMET and HER2 protein expression by immunohistochemistry (IHC) in archival mUC samples identified from an institutional database (n = 143). Correlation of expression between primary and metastatic biopsies was performed in patients with available paired biopsies (n = 79). Protein expression levels by predefined thresholds were measured, and Cohen's kappa statistics (κ) were utilized to assess the agreement in expression between paired primary and metastatic samples. RESULTS: In primary tumors (n = 85), high expression of PD-L1, cMET, and HER2 was observed in 14.1%, 34.1%, and 12.9%, respectively. In metastatic samples (n = 143), high expression of PD-L1, cMET and HER2 was detected in 9.8%, 41.3%, and 9.8%, respectively. Expression agreement rates between paired specimens (n = 79) were PD-L1: 79.7% (κ = 0.09), cMET: 69.6% (κ = 0.35), HER2: 84.8% (κ = 0.17). High PD-L1/cMET co-expression was observed in only 5.1% (n = 4) of primary and 4.9% (n = 7) of metastatic specimens. High co-expression of PD-L1/HER2 occurred in 3.8% (n = 3) of primary samples and no metastatic samples. The overall co-expression agreement between paired samples was 55.7% (κ = 0.22) for PD-L1/cMET and 67.1% (κ = 0.06) for PD-L1/HER2, but agreement for high co-expression between paired samples was very low (2.5% for PD-L1/cMET and 0% for PD-L1/HER2). CONCLUSIONS: Tumor co-expression of high cMET or HER2 and PD-L1 is low in this cohort. Agreement of high co-expression between primary and metastatic sites is rare. Biomarker-based strategies used in selection of patients for contemporary trials testing combinations of immune checkpoint inhibitors with either cMET or HER2-targeted agents should account for discordant biomarker expression between primary and metastatic sites.

A Clinical and Correlative Study of Elotuzumab, Carfilzomib, Lenalidomide, and Dexamethasone (Elo-KRd) for Lenalidomide Refractory Multiple Myeloma in First Relapse.

INTRODUCTION: Treatment of patients with multiple myeloma (MM) in first relapse remains a challenge. This phase II study combined elotuzumab (Elo) with carfilzomib, lenalidomide, and dexamethasone (KRd) for treatment of MM in first relapse with the aim of improving efficacy. METHODS: Enrolled patients received Elo-KRd induction for 4 cycles, and Elo-lenalidomide maintenance until progression. The primary endpoint was VGPR or better (≥VGPR) postinduction. Secondary endpoints were MRD by flow cytometry, OS, PFS, and safety. Correlatives included characterization of the impact of Elo-KRd on NK and T cell subsets via flow cytometry. Target accrual of 40 patients was not met due to COVID-19 pandemic. RESULTS: Of 15 patients enrolled, 10 (67%) had high-risk features (del17p, t[4;14], t[14;16], 1q gain/amplification, plasma cell leukemia, extramedullary MM, or functional high risk), 12 (80%) were lenalidomide-refractory, and 5 (33.3%) bortezomib-refractory. Postinduction ≥VGPR was 7/15 (46.7%) and MRD-negative (10-5) rate 20%. Overall response during study was 80%, including ≥VGPR as best response of 53.3%. At median follow-up of 28.2 (range, 3.8 to 44.2) months, the median PFS was 11.5 months (95% CI 1.9, 18), and median OS not reached (95% CI 10.1, NA). No new safety concerns were reported. Elo-KRd treatment did not augment NK cell distribution or activity in blood or bone marrow. Effector CD4+ and CD8+ T cells significantly decreased postinduction, with concomitant acquisition of T central memory phenotype, particularly at a high rate in ≥VGPR group. CONCLUSION: A short course of Elo-KRd induction followed by Elo-lenalidomide maintenance demonstrated activity in predominantly lenalidomide-refractory and / or high-risk MM. The results with this well-tolerated combination are comparable to other contemporary approved triplet combinations.

Phase III Study of Pemetrexed in Combination With Cisplatin Versus Cisplatin Alone in Patients With Malignant Pleural Mesothelioma.

PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P = .020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P = .001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P < .0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.

Prognostic value of galectin-1 and galectin-3 expression in localized urothelial bladder cancer.

Background: Galectin-1 (Gal-1) and Galectin-3 (Gal-3) are carbohydrate binding proteins with a wide range of biological activity, including regulation of cellular adhesion, proliferation, and apoptosis in solid tumors. Prior small studies have reported that Gal-3 expression is associated with progression of disease in urothelial carcinoma (UC), from non-muscle invasive UC progression to muscle invasive UC. We assessed Gal-1 and Gal-3 protein expression H-score utilizing a tissue microarray (TMA) created from 301 cystectomy specimens. Methods: Immunohistochemistry for Gal-1 and Gal-3 was performed on TMA generated from tumor blocks from chemotherapy naïve cystectomy specimens. The variable of interest, H-score, was defined as the product of the percentage of cells staining positive (0-100) and intensity score (0-3) scored by a single pathologist. Survival end points were analyzed using Kaplan-Meier and Cox Proportional Hazards methods. Clinical data including Charlson Comorbidity Index (CCI), pathologic tumor (T) stage, tumor size, node stage, and surgical margins, were included in multivariable analysis. Results: We found that Gal-1 and Gal-3 expression correlated with intratumoral T stage (median Gal-1 H-score was 0 across non-invasive tissue types and 200 in invasive, P<0.01 and median Gal-3 score was 270 across non-invasive tissue types and 70 in invasive, P<0.01). However, the highest intratumoral H-score per cystectomy core did not independently predict for recurrence-free survival (RFS) (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.65) or OS (Gal-1: HR =1.02, P=0.44, Gal-3: HR =1.01, P=0.72) in this cohort. Significant intratumoral heterogeneity was present for both Gal-1 and Gal-3, with an average difference between the highest and lowest H score was 95 for Gal-1 and 109 for Gal-3 for cystectomy specimens with more than one biopsy. Conclusions: Gal-1 and Gal-3 H-score per bladder did not independently predict for RFS or OS. Intra-tumoral Gal-1/Gal-3 heterogeneity complicates the use of Gal-1 and Gal-3 expression as a prognostic biomarker. Future studies should consider the evaluation of serum and urinary galectins as an approach to mitigate tumor heterogeneity.

Sickle Cell Trevor Thompson Transition Project (ST3P-UP) protocol for managing care transitions: Methods and rationale.

BACKGROUND: Emerging adults with sickle cell disease (EASCD) experience significant challenges transitioning from pediatric to adult care. Acute care utilization increases, quality of life (QOL) declines, with an increased risk of mortality. Currently, there are no practice standards to guide emerging adults through the transition process. We are creating a structured transition education (STE) based program for EASCD by customizing the Six Core Elements (6 CE) of Health Care Transition model and are evaluating the effectiveness of adding peer mentoring (PM). METHODS: The Sickle Cell Trevor Thompson Transition Project (ST3P-UP) is an ongoing multi-site, cluster randomized clinical trial with a target enrollment of 537 EASCD aged 16 to 25 years in pediatric care. Each site (n = 14) comprises a pediatric clinic, adult clinic, and a sickle cell disease (SCD) community-based organization (CBO). Sites are randomized 1:1 to either STE or STE + PM. EASCDs are followed prospectively for 24 months. Rapid cycle plan-do-study-act quality improvement (QI) methods are used to implement the STE. The primary objective is to compare the effectiveness of STE + PM versus STE only at decreasing the number of acute care visits per year over 24 months. The secondary objectives are to compare overall healthcare utilization and patient-reported QOL outcomes at 24 months. CONCLUSION: We aim to demonstrate the feasibility of using a QI approach to implement 6 CE-based practice standards at 14 disparate SCD clinical programs to guide EASCD through the transition process. We hypothesize that adding PM to the STE program will improve acute care reliance, QOL, and satisfaction with transition outcomes.

Genomic alterations and clinical outcomes in patients with dedifferentiated liposarcoma.

PURPOSE: Patients with unresectable dedifferentiated liposarcoma (DDLPS) have poor overall outcomes. Few genomic alterations have been identified with limited therapeutic options. EXPERIMENTAL DESIGN: Patients treated at Levine Cancer Institute with DDLPS were identified. Next generation sequencing (NGS), immunohistochemistry (IHC), and fluorescence in situ hybridization (FISH) testing were performed on tumor tissue collected at diagnosis or recurrence/progression. Confirmation of genomic alterations was performed by orthologous methods and correlated with clinical outcomes. Univariate Cox regression was used to identify genomic alterations associated with clinical outcomes. RESULTS: Thirty-eight DDLPS patients with adequate tissue for genomic profiling and clinical data were identified. Patient characteristics included: median age at diagnosis (66 years), race (84.2% Caucasian), and median follow-up time for the entire cohort was 12.1 years with a range from approximately 3.5 months to 14.1 years. Genes involved in cell cycle regulation, including MDM2 (74%) CDK4 (65%), and CDKN2A (23%), were amplified along with WNT/Notch pathway markers: HMGA2, LGR5, MCL1, and CALR (19%-29%). While common gene mutations were identified, PDE4DIP and FOXO3 were also mutated in 47% and 34% of patients, respectively, neither of which have been previously reported. FOXO3 was associated with improved overall survival (OS) (HR 0.37; p = 0.043) along with MAML2 (HR 0.30; p = 0.040). Mutations that portended worse prognosis included RECQL4 (disease-specific survival HR 4.67; p = 0.007), MN1 (OS HR = 3.38; p = 0.013), NOTCH1 (OS HR 2.28, p = 0.086), and CNTRL (OS HR 2.42; p = 0.090). CONCLUSIONS: This is one of the largest retrospective reports analyzing genomic aberrations in relation to clinical outcomes for patients with DDLPS. Our results suggest therapies targeting abnormalities should be explored and confirmation of prognostic markers is needed. Dedifferentiated liposarcoma is one of the most common subtypes of soft tissue sarcoma yet little is known of its molecular aberrations and possible impact on outcomes. The work presented here is an evaluation of genetic abnormalities among a population of patients with dedifferentiated liposarcoma and how they corresponded with survival and risk of metastases. There were notable gene mutations and amplifications commonly found, some of which had interesting prognostic implications.

Risk factors associated with palbociclib-induced neutropenia in patients with metastatic breast cancer.

BACKGROUND: Neutropenia is the most common adverse event with palbociclib, an oral cyclin-dependent kinase 4/6 inhibitor, with grade 3/4 neutropenia occurring in up to 67% of patients in phase III trials evaluating this agent in metastatic breast cancer. This retrospective chart review assessed characteristics of patients on palbociclib to evaluate for risk factors in the development of grade 3/4 neutropenia. PATIENTS AND METHODS: Patients with metastatic breast cancer who received palbociclib were included. Patient demographics collected included age, gender, race, body mass index, breast cancer treatment history, palbociclib starting dose, baseline absolute neutrophil count, baseline platelet count, concomitant hormonal therapy, concomitant use of denosumab, and use of concomitant strong CYP3A4 inhibitors/inducers. Events of interest occurring within 30 days of initiation of palbociclib were also noted including antibiotic and corticosteroid use, mucosal conditions, open wounds, or surgery. The incidence and potential risk factors for grade 3/4 neutropenia in the first 6 months of treatment were analyzed. RESULTS: A total of 257 patients were included in the analysis with 206 patients (80.2%) and 139 patients (54.1%) experiencing all-grade neutropenia and grade 3/4 neutropenia, respectively. Multivariate analysis found baseline myelosuppression and recent antibiotic use to be independent predictors of grade 3/4 neutropenia. Normal weight patients had an increased risk for grade 3/4 neutropenia compared to obese patients by multivariate analysis. CONCLUSION: The results of this study showed baseline myelosuppression and recent antibiotic use within 30 days of palbociclib initiation were predictive of a higher incidence of grade 3/4 neutropenia. Obese patients were less likely to develop grade 3/4 neutropenia compared to normal weight patients.

Impact of a Clinical Genomics Program on Trial Accrual for Targeted Treatments: Practical Approach Overcoming Barriers to Accrual for Underserved Patients.

PURPOSE: Clinical trials of novel and targeted agents increasingly require biomarkers for eligibility. Precision oncology continues to evolve, but challenges hamper broad use of molecular profiling (MP) that could increase the number of patients benefiting from targeted therapy. We implemented an integrated clinical genomics program (CGP), including a virtual Molecular Tumor Board (MTB), and examined its impact on MP use and impact on clinical trial accrual in a multisite regional-based cancer system with an emphasis on effects for isolated clinicians. METHODS: We assessed MP and MTB use from 2010 to 2020 by practice location, physician experience, and patient characteristics. Use of MTB-recommended treatments was assessed. Clinical trial enrollment was evaluated for patients with MP versus MP and MTB review. RESULTS: After CGP implementation, the number of physicians using MP and the number of MP tests increased ≥ 10-fold. The proportion of Hispanic patients with MP was the same as that in the system (both 2%) with marginal differences observed in the proportion of African Americans tested compared with the system population (16% v 19%). Physicians followed MTB treatment recommendations in 74% of cases. Rapid clinical decline was the most common reason why physicians did not follow MTB recommendations. Clinical trial accrual was 15% (669 of 4,459) for patients with MP alone and 28% (94 of 334) with both MP and MTB review. Clinical trial availability and patient out-of-pocket costs affected MP use. CONCLUSION: Integrating CGP into clinical workflow with decision support tools, trial matching, and management of patient costs led to increased use of MP by physicians with all levels of experience, enhanced clinical trial accrual, and has the potential to reduce disparities in MP.

Identification of potential biomarkers and novel therapeutic targets through genomic analysis of small cell bladder carcinoma and associated clinical outcomes.

OBJECTIVES: Small cell bladder carcinoma (SCBC) represents a rare histologic variant with a poor prognosis and for which no routine biomarkers exist. Limited reports of genomic sequencing in SCBC have demonstrated a high prevalence of TP53 and RB1 gene mutations, though the prognostic value of these and other gene variants in SCBC remains undefined. In this study, we performed targeted genomic sequencing on a cohort of SCBC patients and correlated genomic findings with clinical outcomes to identify potential novel biomarkers. MATERIALS AND METHODS: Thirty-one patients with SCBC and available treatment-naïve tumor specimens were identified from an institutional database (23 limited stage [LS], 8 extensive stage [ES]). Small cell carcinoma specimens were microdissected and subjected to tumor next-generation whole-exon sequencing with a 592 gene panel. Kaplan-Meier techniques and Cox proportional hazards models were used to evaluate genomic aberration association with relapse-free survival (RFS) and overall survival (OS) in the limited stage cohort. RESULTS: The most common pathogenic gene variants included ARID1A (48%), TP53 (48%) and RB1 (48%). Mutations in genes with potential therapeutic targets not routinely evaluated in SCBC included BRCA1/2 (16%), POLE (13%), JAK2 (13%), PDGFB (13%) and FGFR3 (3%). Multiple novel biomarker candidates showed trends for improvements in OS in the LS subset including ERCC2 (HR 0.322, P = 0.122) and RB1 (HR 0.481, P = 0.182), while LS patients with TP53 mutations (HR 2.730, P = 0.056), and MCL1 gene amplification (HR 4.183, P = 0.018) suggested inferior OS. Additionally, gene or copy number variants with potential prognostic benefit included UBR5 and DAXX (P = 0.02, [hazard ratios nonestimable due to zero events in biomarker positive groups]). CONCLUSIONS: These results support the role for tumor genomic profiling in SCBC and identify multiple potential novel biomarkers and therapeutic targets in this rare disease. Efforts to validate these findings should lead to improved decision-making and treatment outcomes in SCBC.

Financial Toxicity Intervention Improves Outcomes in Patients With Hematologic Malignancy.

PURPOSE: Patients with hematologic malignancies are extremely vulnerable to financial toxicity (FT) because of the high costs of treatment and health care utilization. This pilot study identified patients at high risk because of FT and attempted to improve clinical outcomes with comprehensive intervention. METHODS: All patients who presented to the Levine Cancer Institute's Leukemia Clinic between May 26, 2019, and March 10, 2020, were screened for inclusion by standardized two question previsit survey. Patients screening positive were enrolled in the comprehensive intervention that used nurse navigators, clinical pharmacists, and community pro bono financial planners. Primary outcomes were defined as improvement in mental and physical quality of life in all patients and improvement in overall survival in the high-risk disease group. RESULTS: One hundred seven patients completed comprehensive intervention. Patients experiencing FT had increased rates of noncompliance including to prescription (16.8%) and over-the-counter medications (15.9%). The intervention resulted in statistically significantly higher quality of life when measured by using Patient-Reported Outcomes Measurement Information System physical (12.5 ± 2.2 v 13.7 ± 1.8) and mental health scores (11.4 ± 2.2 v 12.4 ± 2.2; all P < .001). In patients with high-risk disease (as determined by using disease-specific scoring systems), risk of death in those receiving the intervention was 0.44 times the risk of death in those without the intervention after adjusting for race, and treatment with stem-cell transplant, oral chemotherapy, or immunotherapy (95% CI, 0.21 to 0.94; P = .034). CONCLUSION: Screening and intervention on FT for patients with hematologic malignancies is associated with increased quality of life and survival.

Malnutrition risk at solid tumor diagnosis: the malnutrition screening tool in a large US cancer institute.

BACKGROUND: In cancer, malnutrition is common and negatively impacts tolerance and outcomes of anti-tumor therapies. The aim of this study was to evaluate the prevalence of malnutrition risk and compare the clinicodemographic features between those with high malnutrition screening tool (MST) scores (i.e., ≥ 2 of 5 = high risk for malnutrition, H-MST) to low scores (L-MST). METHODS: A cohort of 3585 patients (May 2017 through December 2018), who completed the MST at least once at the time of diagnosis of any stage solid tumor, were analyzed. Logistic regression tested for associations between clinicodemographic factors, symptom scores, and H-MST prevalence. RESULTS: The median age was 64 years (25-75 IQR, 55-72), with 62% females and 81% White. Most common tumor primary sites were breast (28%), gastrointestinal (GI) (21%), and thoracic (13%). Most had non-metastatic disease (80%). H-MST was found in 28%-most commonly in upper (58%) and lower GI (42%), and thoracic (42%) tumors. L-MST was most common in breast (90%). Multivariable regression confirmed that Black race (OR 1.9, 95% CI 1.5-2.4, p = < 0.001), cancer primary site (OR 1.6-5.7, p = < 0.001), stage IV disease (OR 1.8, 95% CI 1.4-2.2, p = < 0.001), low BMI (OR 4.2, 95% CI 2.5-6.9 p = < 0.001), and higher symptom scores were all independently associated with H-MST. CONCLUSIONS: Twenty-eight percent of solid tumor oncology patients at diagnosis were at high risk of malnutrition. Patients with breast cancer rarely had malnutrition risk at diagnosis. Significant variation was found in malnutrition risk by cancer site, stage, race, and presence of depression, distress, fatigue, and trouble eating/swallowing.

Landscape and clinical impact of metabolic alterations in non-squamous non-small cell lung cancer.

Background: Metabolomics studies to date have described widespread metabolic reprogramming events during the development of non-squamous non-small cell lung cancer (NSCLC). Extending far beyond the Warburg effect, not only is carbohydrate metabolism affected, but also metabolism of amino acids, cofactors, lipids, and nucleotides. Methods: We evaluated the clinical impact of metabolic reprogramming. We performed comparative analysis of publicly available data on non-squamous NSCLC, to identify concensus altered metabolic pathways. We investigated whether alterations of metabolic genes controlling those consensus metabolic pathways impacted clinical outcome. Using the clinically annotated lung adenocarcinoma (LUAD) cohort from The Cancer Genome Atlas, we surveyed the distribution and frequency of function-altering mutations in metabolic genes and their impact on overall survival (OS). Results: We identified 42 metabolic genes of clinical significance, the majority of which (37 of 42) clustered across three metabolic superpathways (carbohydrates, amino acids, and nucleotides) and most functions (40 of 42) were associated with shorter OS. Multivariate analyses showed that dysfunction of carbohydrate metabolism had the most profound impact on OS [hazard ratio (HR) =5.208; 95% confidence interval (CI): 3.272 to 8.291], false discovery rate (FDR)-P≤0.0001, followed by amino acid metabolism (HR =3.346; 95% CI: 2.129 to 5.258), FDR-P≤0.0001 and nucleotide metabolism (HR =2.578; 95% CI: 1.598 to 4.159), FDR-P=0.0001. The deleterious effect of metabolic reprogramming on non-squamous NSCLC was observed independently of disease stage and across treatments groups. Conclusions: By providing a detailed landscape of metabolic alterations in non-squamous NSCLC, our findings offer new insights in the biology of the disease and metabolic adaptation mechanisms of clinical significance.

Evaluation of Intravenous Diphenhydramine Use in Patients with Sickle Cell Vaso-Occlusive Crisis.

Purpose: To compare the incidence of oversedation between oral and parenteral diphenhydramine therapy for treatment of opioid-induced pruritus in patients with sickle cell disease vaso-occlusive crisis (SCD VOC). Methods: This retrospective, single-center, cohort study included patients greater than or equal to 18 years old with sickle cell disease admitted for vaso-occlusive crisis who received either intravenous or oral diphenhydramine for opioid-induced pruritus. Patients were identified through ICD-9 and ICD-10 codes from June 1, 2016 through July 1, 2017. Rates of oversedation were compared between the 2 formulations. Secondary endpoints included length of stay, amount and duration of diphenhydramine, rate of acute chest and indication for IV therapy. Results: Fifty unique patients were included in the analysis representing 121 admissions. Seven patients received both formulations on separate admissions and were included in both groups. Twenty-nine percent of patients in the IV diphenhydramine group experienced oversedation (12/42) versus 13% in the oral diphenhydramine group (2/15, P = .312). The average number of admissions was significantly higher in the IV versus oral group (2.45 vs 1.20; P = .005) with average and median length of stay also significantly higher in the IV versus oral group (30.57, 16.0 vs 10.67, 10.0; P = .003). Conclusion: While there was no statistically significant difference in the rates of oversedation with use of IV versus oral diphenhydramine formulations, patients with SCD VOC who received IV diphenhydramine had more frequent admissions and a longer length of stay. Clinicians may consider oral diphenhydramine preferentially in appropriate patients over IV administration.

Phase II Study of Pembrolizumab in Combination with Doxorubicin in Metastatic and Unresectable Soft-Tissue Sarcoma.

PURPOSE: Doxorubicin is standard therapy for advanced soft-tissue sarcoma (STS) with minimal improvement in efficacy and increased toxicity with addition of other cytotoxic agents. Pembrolizumab monotherapy has demonstrated modest activity and tolerability in previous advanced STS studies. This study combined pembrolizumab with doxorubicin to assess safety and efficacy in frontline and relapsed settings of advanced STS. PATIENTS AND METHODS: This single-center, single-arm, phase II trial enrolled patients with unresectable or metastatic STS with no prior anthracycline therapy. Patients received pembrolizumab 200 mg i.v. and doxorubicin (60 mg/m2 cycle 1 with subsequent escalation to 75 mg/m2 as tolerated). The primary endpoint was safety. Secondary endpoints included overall survival (OS), objective response rate (ORR), and progression-free survival (PFS) based on RECIST v1.1 guidelines. RESULTS: Thirty patients were enrolled (53.3% female; median age 61.5 years; 87% previously untreated) with 4 (13.3%) patients continuing treatment. The study met its primary safety endpoint by prespecified Bayesian stopping rules. The majority of grade 3+ treatment-emergent adverse events were hematologic (36.7% 3+ neutropenia). ORR was 36.7% [95% confidence interval (CI), 19.9-56.1%], with documented disease control in 80.0% (95% CI, 61.4-92.3%) of patients. Ten (33.3%) patients achieved partial response, 1 (3.3%) patient achieved complete response, and 13 (43.3%) patients had stable disease. Median PFS and OS were 5.7 months (6-month PFS rate: 44%) and 17 months (12-month OS rate: 62%), respectively. Programmed cell death ligand-1 (PD-L1) expression was associated with improved ORR, but not OS or PFS. CONCLUSIONS: Combination pembrolizumab and doxorubicin has manageable toxicity and preliminary promising activity in treatment of patients with anthracycline-naive advanced STS.

Pilot study of multi-gene pharmacogenetic testing for pain management in oncology palliative medicine.

Aim: We evaluated the application and clinical impact of multi-gene pharmacogenetic testing in oncology palliative medicine. Patients & methods: In a single-arm pilot trial, cancer patients with uncontrolled pain were assessed in a palliative medicine clinic at baseline and received pharmacogenetic testing. Results were used as applicable up to the final visit (day 30). Pain scores, opioid prescribing, and use of pharmacogenetic test results were collected. Results: In 75 patients, the median baseline pain score was 7/10. Of 54 evaluable at the final visit, 28 required opioid modifications and 19 had actionable genotypes, mostly CYP2D6. Pain improvement (≥2-point reduction) was higher than historical data (56 vs 30%; p < 0.001). There were no differences in pain improvement between those with and without actionable genotypes (61 vs 53%). Conclusion: Multi-gene testing identified actionable genotypes and may improve cancer pain.

Impact of Sociodemographic Disparities and Insurance Status on Survival of Patients with Early-Onset Colorectal Cancer.

BACKGROUND: Low socioeconomic status (SES) has been linked to worse survival in patients with colorectal cancer (CRC); however, the impact of SES on early-onset CRC remains undescribed. MATERIALS AND METHODS: Retrospective analysis of data from the National Cancer Database (NCDB) between 2004 and 2016 was conducted. We combined income and education to form a composite measure of SES. Logistic regression and χ2 testing were used to examine early-onset CRC according to SES group. Survival rates and Cox proportional hazards models compared stage-specific overall survival (OS) between the SES groups. RESULTS: In total, 30,903 patients with early-onset CRC were identified, of whom 78.7% were White; 14.5% were Black. Low SES compared with high SES patients were more likely to be Black (26.3% vs. 6.1%) or Hispanic (25.3% vs. 10.5%), have T4 tumors (21.3% vs. 17.8%) and/or N2 disease (13% vs. 11.1%), and present with stage IV disease (32.8% vs. 27.7%) at diagnosis (p < .0001, all comparisons). OS gradually improved with increasing SES at all disease stages (p < .001). In stage IV, the 5-year survival rate was 13.9% vs. 21.7% for patients with low compared with high SES. In multivariable analysis, SES (low vs. high group; adjusted hazard ratio [HRadj ], 1.35; 95% confidence interval [CI], 1.26-1.46) was found to have a significant effect on survival (p < .0001) when all of the confounding variables were adjusted. Insurance (not private vs. private; HRadj , 1.38; 95% CI, 1.31-1.44) mediates 31% of the SES effect on survival. CONCLUSION: Patients with early-onset CRC with low SES had the worst outcomes. Our data suggest that SES should be considered when implementing programs to improve the early detection and treatment of patients with early-onset CRC. IMPLICATIONS FOR PRACTICE: Low socioeconomic status (SES) has been linked to worse survival in patients with colorectal cancer (CRC); however, the impact of SES on early-onset CRC remains undescribed. In this retrospective study of 30,903 patients with early-onset CRC in the National Cancer Database, a steady increase in the yearly rate of stage IV diagnosis at presentation was observed. The risk of death increased as socioeconomic status decreased. Race and insurance status were independent predictors for survival. Implementation of programs to improve access to care and early diagnostic strategies among younger adults, especially those with low SES, is warranted.

Equal access to care and nurse navigation leads to equitable outcomes for minorities with aggressive large B-cell lymphoma.

BACKGROUND: Aggressive large B-cell lymphomas (LBCLs) are curable, but previous studies have shown inferior outcomes in minorities. Nurse navigation programs can improve patient outcomes by providing patient support. This study presents the outcomes of White and minority patients with aggressive LBCL at an institution with an active nurse navigation program. METHODS: The authors prospectively collected baseline characteristics, treatment regimens, and outcome data for patients with aggressive LBCL. Navigation encounters were characterized as low or high intensity. Overall survival (OS) and progression-free survival (PFS) were calculated with Kaplan-Meier methods. Baseline characteristics were compared with Fisher exact tests. RESULTS: Two hundred four consecutive patients (47 minority patients and 157 White patients) were included. Results were presented as minorities versus Whites. There were no differences in prognostic scores (Revised International Prognostic Index score of 3-5, 43% vs 47%; P = .50), frontline chemotherapy (98% vs 96%; P = .68), or the incidence of relapsed/refractory disease (40% vs 38%; P = .74). For relapsed/refractory LBCL, similar proportions of patients underwent hematopoietic stem cell transplantation (32% vs 29%; P > .99) or chimeric antigen receptor T-cell therapy (16% vs 19%; P > .99). Enrollment in clinical trials was comparable (17% vs 14%; P = .64). More than 85% received nurse navigation, but minorities had higher intensity navigation encounters (42% vs 21%; P = .01). The 2-year OS rates were 81% and 76% for minorities and Whites, respectively (P = .27); the 2-year PFS rates were 62% and 65%, respectively (P = .78). CONCLUSIONS: This study shows similar survival between Whites and minorities with aggressive LBCL, which was likely due to equal access to guideline-concordant therapy. Minorities received higher intensity navigation encounters, which may have helped them to overcome socioeconomic disadvantages.