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AbstractPurpose/Objective(s)Bladder and prostate are unfavorable sites for rhabdomyosarcoma (B/P‐RMS), and represent a challenging location for radiotherapy.Materials/MethodsNineteen patients with B/P‐RMS were enrolled on a prospective registry protocol (2008‐2017) and treated with chemotherapy, proton beam therapy (PBT), and surgical resection (n = 8; 42%). Emphasis was given to treatment technique, disease‐related outcomes, and toxicity associated with PBT.ResultsThe majority of patients had bladder RMS (74%) of embryonal histology (95%), Group III (68%), and intermediate‐risk disease by Children's Oncology Group (COG) risk stratification (89%). Seven patients (37%) had primary tumors >5 cm in size. All patients were treated according to COG protocols. With a median follow‐up of 66.2 months, 5‐year overall survival (OS) and progression‐free survival (PFS) were 76%. Four patients (21%) experienced disease relapse, all presenting with local failure. The 5‐year local control (LC) rate was 76%. Tumor size predicted LC, with 5‐year LC for patients with >5 cm tumors being 43% versus 100% for those with ≤5 cm tumors (P = .006). Univariate analysis demonstrated an effect of tumor size on OS (tumor >5 cm, hazard ratio [HR] 17.7, P = .049) and PFS (HR 17.7, P = .049). Acute grade 2 toxicity was observed in two patients (11%, transient proctitis). Late grade 2+ toxicity was observed in three patients (16%; n = 1 grade 2 skeletal deformity; n = 3 transient grade 2 urinary incontinence; one patient experienced both).ConclusionsPBT for B/P‐RMS affords promising disease‐related outcomes with an acceptable toxicity profile. Higher local failure rates were observed for larger tumors, supporting dose‐escalation components of ongoing RMS clinical trials.

Epithelial ovarian cancer is the leading cause of death from gynecologic cancer in the United States, with less than half of patients living >5 years from diagnosis. A major challenge in treating ovarian cancer is that most patients have advanced disease at initial diagnosis. The best outcomes are observed in patients whose primary treatment includes complete resection of all visible disease plus combination platinum-based chemotherapy. Research efforts are focused on primary neoadjuvant treatments that may improve resectability, as well as systemic therapies providing improved long-term survival. These NCCN Guidelines Insights focus on recent updates to neoadjuvant chemotherapy recommendations, including the addition of hyperthermic intraperitoneal chemotherapy, and the role of PARP inhibitors and bevacizumab as maintenance therapy options in select patients who have completed primary chemotherapy.

Background Pituitary carcinoma (PC) is an aggressive neuroendocrine tumor diagnosed when a pituitary adenoma (PA) becomes metastatic. PCs are typically resistant to therapy and develop multiple recurrences despite surgery, radiotherapy and chemotherapy. Recently, treatment with temozolomide (TMZ) has shown promising results, although the lack of prospective trials limits assessment of benefit. Methods We describe a single-center multidisciplinary experience in managing PC patients over a 22-year period and review previously published PC series. Results Seventeen patients were identified. Median age at PC diagnosis was 44 years (range 16–82 years), and the median time from PA to PC transformation was 5 years (range 1–29 years). Median follow-up time was 28 months. Most PCs were hormone-positive (n = 12): ACTH (n = 5), PRL (n = 4), LH/FSH (n = 2) and GH (n = 1). All patients underwent at least one resection and at least one course of radiation after PC diagnosis. Immunohistochemistry showed high Ki-67 labeling index (>3%) in 10/15 cases. Eight patients (47%) had only central nervous system (CNS) metastases; six (35%) had combined CNS and systemic metastases. The most commonly used chemotherapy was TMZ, and TMZ-based therapy was associated with the longest PFS in 12 (71%) cases, as well as the longest period from PC diagnosis to first progression (median 30 months). The 2, 3 and 5-year survival rate of the entire cohort was 71, 59 and 35%, respectively. All patients surviving >5 years had been treated with TMZ-based therapy. Conclusions PC management benefits from multidisciplinary care and multimodality therapy. TMZ-based regimens were associated with high survival rates and long disease control.

ABSTRACTBackground and objectiveIncreases in Cheyne–Stokes respiration (CSR) cycle length (CL), lung‐to‐periphery circulation time (LPCT) and time to peak flow (TTPF) may reflect impaired cardiac function. This retrospective analysis used an automatic algorithm to evaluate baseline CSR‐related features and then determined whether these could be used to identify patients with systolic heart failure (HF) who experienced serious adverse events in the Treatment of Sleep‐Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE‐HF) substudy.MethodsA total of 280 patients had overnight diagnostic polysomnography data available; an automated algorithm was applied to quantify CSR‐related features.ResultsMedian baseline CL, LPCT and TTPF were similar in the control (n = 152) and adaptive servo‐ventilation (ASV, n = 156) groups. In both groups, CSR‐related features were significantly longer in patients who did (n = 129) versus did not (n = 140) experience a primary endpoint event (all‐cause death, life‐saving cardiovascular intervention or unplanned hospitalization for worsening HF): CL, 61.1 versus 55.1 s (P = 0.002); LPCT, 36.5 versus 31.5 s (P < 0.001); TTPF, 15.20 versus 13.35 s (P < 0.001), respectively. This finding was independent of treatment allocation.ConclusionPatients with systolic HF and central sleep apnoea who experienced serious adverse events had longer CSR CL, LPCT and TTPF. Future studies should examine an independent role for CSR‐related features to enable risk stratification in systolic HF.

Background:Carfilzomib (CFZ) combined with dexamethasone is approved to treat patients (pts) with relapsed and/or refractory multiple myeloma (RRMM), with CFZ given once‐weekly at 70 mg/m2 (Kd70 QW) or twice‐weekly at 56 mg/m2 (Kd56 BIW). No randomized trials have directly compared Kd70 QW with Kd56 BIW.Aims:We performed a post hoc comparison between pts who received Kd56 BIW in the ENDEAVOR trial and pts who received Kd70 QW in the A.R.R.O.W. or CHAMPION‐1 trials.Methods:Data were analyzed from 3 trials of CFZ in RRMM: A.R.R.O.W. (240 pts in Kd70 QW arm; 2–3 prior therapies and refractory to most recent therapy), CHAMPION‐1 (104 pts received Kd70 QW; 1–3 prior therapies), and ENDEAVOR (464 pts in Kd56 BIW arm; 1–3 prior therapies). Pts who received Kd70 QW in A.R.R.O.W. and CHAMPION‐1 were pooled and compared with pts who received Kd56 BIW in ENDEAVOR. As study populations slightly varied among the 3 trials, an analysis of safety and efficacy was performed in a subgroup of pts who received 2–3 prior therapy lines and were not refractory to bortezomib (BTZ). Also, we performed regression analyses (controlling for age, ISS stage, BTZ and lenalidomide refractory status, and number of prior regimens) among all pts in the trials who received Kd70 QW or Kd56 BIW.Results:Among BTZ non‐refractory pts with 2–3 lines of prior therapy, median progression‐free survival (PFS) was 12.1 months (95% CI 8.4–14.3) for Kd70 QW (n = 146) and 14.5 months (95% CI 10.2–NE) for Kd56 BIW (n = 217), and the overall response rate (ORR) was 69.9% (95% CI 61.7–77.2) for Kd70 QW and 72.4% (95% CI 65.9–78.2) for Kd56 BIW. The rate of grade ≥3 adverse events (Kd70 QW vs Kd56 BIW) was 67.6% and 85.3%; among adverse events of interest, the grade ≥3 rate was 1.4% and 5.1% for cardiac failure, 3.4% and 6.0% for renal failure, and 5.5% and 15.7% for hypertension. Kd70 QW represents a convenient and well‐tolerated treatment modality for pts with RRMM. In a Cox proportional hazards model, the hazard ratio for PFS (Kd70 QW vs Kd56 BIW) was 0.91 (95% CI 0.69–1.19), and in a logistic regression model the odds ratio for ORR (Kd70 QW vs Kd56 BIW) was 1.12 (95% CI 0.74–1.69).Summary/Conclusion:This post hoc analysis suggests that once‐weekly Kd70 has a comparable benefit‐risk profile to twice‐weekly Kd56.© 2019 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2019 ASCO Annual Meeting. All rights reserved.

AbstractObjectiveOnset of multiple sclerosis (MS) occurs in childhood for approximately 5% of cases (pediatricMS, or ped‐MS). Epigenetic influences are strongly implicated inMSpathogenesis in adults, including the contribution from microRNAs (miRNAs), small noncodingRNAs that affect gene expression by binding target genemRNAs. Few studies have specifically examined miRNAs in ped‐MS, but individuals developingMSat an early age may carry a relatively high burden of genetic risk factors, and miRNAdysregulation may therefore play a larger role in the development of ped‐MSthan in adult‐onsetMS. This study aimed to look for evidence of miRNAinvolvement in ped‐MSpathogenesis.MethodsGWASresults from 486 ped‐MScases and 1362 controls from the U.S. PediatricMSNetwork and Kaiser Permanente Northern California membership were investigated for miRNA‐specific signals. First, enrichment of miRNA‐target gene network signals was evaluated usingMIGWASsoftware. Second,SNPs in miRNAgenes and in target gene binding sites (miR−SNPs) were tested for association with ped‐MS, and pathway analysis was performed on associated target genes.ResultsMIGWASanalysis showed that miRNA‐target gene signals were enriched inGWAS(P = 0.038) and identified 39 candidate biomarker miRNA‐target gene pairs, including immune and neuronal signaling genes. The miR‐SNPanalysis implicated dysregulation of miRNAbinding to target genes in five pathways, mainly involved in immune signaling.InterpretationEvidence fromGWASsuggests that miRNAs play a role in ped‐MSpathogenesis by affecting immune signaling and other pathways. Candidate biomarker miRNA‐target gene pairs should be further studied for diagnostic, prognostic, and/or therapeutic utility.

Objective: The aim of this study was to determine whether a vitamin D genetic risk score (vitDGRS) is associated with 25-hydroxyvitamin D (25(OH)D) level and multiple sclerosis (MS) relapses in children. Methods: DNA samples were typed for single nucleotide polymorphisms (SNPs) from four genes previously identified to be associated with 25(OH)D levels. SNPs with strong associations with 25(OH)D after multiple comparison correction were used to create a genetic risk score (vitDGRS). Cox regression models tested associations of vitDGRS with relapse hazard. Results: Two independent SNPs within or near GC and NADSYN1/DHCR7 genes were strongly associated with 25(OH)D levels in the discovery cohort ( n = 182) after Bonferroni correction. The vitDGRS of these SNPs explained 4.5% of the variance of 25(OH)D level after adjustment for genetic ancestry. Having the highest versus lowest vitDGRS was associated with 11 ng/mL lower 25(OH)D level (95% confidence interval (CI) = −17.5, −4.5, p = 0.001) in the discovery cohort. Adjusting for ancestry, sex, disease-modifying therapy (DMT), and HLA-DRB1*15 carrier status, the highest versus lowest vitDGRS was associated with 2.6-fold (95% CI = 1.37, 5.03, p = 0.004) and 2.0-fold (95% CI = 0.75, 5.20, p = 0.16) higher relapse hazard in the discovery and replication cohorts, respectively. Conclusion: The vitDGRS identifies children at greater risk of relapse. These findings support a causal role for vitamin D in MS course.

Abstract Purpose Proton therapy is currently used in the management of pediatric tumors to decrease late toxicities. However, one of the criticisms of proton therapy is the limited data regarding efficacy on disease control. The purpose of this study was to examine local and distant control rates after proton therapy for neuroblastoma. Methods and materials Eighteen patients with high‐risk ( n = 16) and locally recurrent neuroblastoma ( n = 2) were treated with curative intent and received proton therapy to the primary site and up to three post‐induction MIBG‐avid metastatic sites. Primary sites ( n = 18) were treated to 21–36 Gy (relative biological effectiveness [RBE]), and metastatic sites ( n = 16) were treated to 21–24 Gy (RBE). Local control and survival rates were calculated using the Kaplan–Meier method. Results With a median follow‐up of 60.2 months, two‐ and five‐year local control rates at the irradiated primary site were 94% and 87%, respectively. No failures at irradiated distant metastatic sites were observed. The five‐year progression‐free survival (PFS) was 64%, and the five‐year overall survival (OS) was 94%. The extent of surgical resection was not associated with local control, PFS, or OS. No radiation‐related nephropathy or hepatopathy was reported. Conclusions Excellent local control was achieved using proton therapy to the primary and post‐induction MIBG‐positive distant sites. The predominant site of failure is progression in post‐induction non‐MIBG‐avid distant sites. Although proton therapy provides high rates of local control with acceptable toxicity for neuroblastoma, further advances in systemic therapy are needed for the improved control of systemic disease.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Cutaneous melanoma have been significantly revised over the past few years in response to emerging data on immune checkpoint inhibitor therapies and BRAF-targeted therapy. This article summarizes the data and rationale supporting extensive changes to the recommendations for systemic therapy as adjuvant treatment of resected disease and as treatment of unresectable or distant metastatic disease.