Purpose: Intrapatient heterogeneity of programmed death ligand 1 (PD-L1) expression and tumor mutational burden (TMB) in gastroesophageal adenocarcinoma (GEA) could influence their roles as predictive biomarkers for response to immune checkpoint inhibitors (ICIs). In this retrospective analysis, we evaluated the spatiotemporal heterogeneity and prognostic relevance of PD-L1 expression and TMB in GEA.Patients and methods: A cohort of 211 patients with stage II-IV GEA was retrospectively reviewed for a total of 407 tumor samples with PD-L1 expression data and 319 tumor samples with TMB data. PD-L1 status was defined as positive if combined positive score (CPS) ≥1 using the 22C3 pharmDx assay. TMB-levels were categorized as low, intermediate, or high (≤5, 5-15, or >15 mutations/Mb), or using a single threshold (<10 or ≥10 mutation/Mb), determined by next-generation sequencing using a targeted gene panel.Results: Of 407 tumors, 56% were PD-L1 negative and 44% PD-L1 positive. Of 319 tumors, 50% were TMB-low, 45% TMB-intermediate, and 5% TMB-high; 86% had <10 and 14% ≥10 mutations/Mb. TMB-level was significantly associated with MSI-status. PD-L1 expression and TMB exhibited marked spatial heterogeneity between baseline primary and metastatic tumors (61% and 69% concordance), and temporal heterogeneity between tumors before and after chemotherapy (57-63% and 73-75% concordance). PD-L1 expression and TMB were not significantly associated with overall survival.Conclusions: PD-L1 expression and TMB exhibit marked spatial and temporal heterogeneity in GEA. This heterogeneity should be considered when obtaining tumor samples for molecular testing and when deciding whether ICI therapy is appropriate.

The 1-year and median overall survivals (mOS) of advanced gastroesophageal adenocarcinomas (GEA) are ~50% and <12 months. Baseline spatial and temporal molecular heterogeneity of targetable alterations may be a cause of failure of targeted/immunooncologic therapies. This heterogeneity, coupled with infrequent incidence of some biomarkers, has resulted in stalled therapeutic progress. We hypothesized that a personalized treatment strategy, applied at first diagnosis then serially over up to three treatment lines using monoclonal antibodies combined with optimally-sequenced chemotherapy, could contend with these hurdles. This was tested using a novel clinical expansion platform type-II design with a survival primary endpoint. Of 68 patients by intention-to-treat, 1-year survival was 66% and mOS was 15.7 months, meeting the primary efficacy endpoint (one-sided p=0.0024). First-line response rate (74%), disease control rate (99%), and median progression free survival (8.2 months) were superior to historical controls. The PANGEA strategy led to improved outcomes warranting a larger randomized study. Significance This study highlights excellent outcomes achieved by individually optimizing chemotherapy, biomarker profiling, and matching of targeted therapies at baseline and over time for GEA. Testing a predefined treatment strategy resulted in improved outcomes versus historical controls. Therapeutic resistance observed in correlative analyses suggests that dual targeted inhibition may be beneficial. Research.

Therapy-related ALL is a distinct entity associated with poor-risk cytogenetics and inferior survival compared with de novo ALL.• Hematopoietic stem cell transplantation may improve outcomes and should be considered for all eligible patients with therapyrelated ALL.Patients with therapy-related acute lymphoblastic leukemia (t-ALL) represent a small subset of acute lymphoblastic leukemia (ALL) patients who received genotoxic therapy (ie, chemotherapy or radiation) for a prior malignancy. These patients should be distinguished from patients with de novo ALL (dn-ALL) and ALL patients who have a history of prior malignancy but have not received cytotoxic therapies in the past (acute lymphoblastic leukemia with prior malignancy [pm-ALL]). We report a retrospective multi-institutional study of patients with t-ALL (n 5 116), dn-ALL (n 5 100), and pm-ALL (n 5 20) to investigate the impact of prior cytotoxic therapies on clinical outcomes.Compared with patients with pm-ALL, t-ALL patients had a significantly shorter interval between the first malignancy and ALL diagnosis and a higher frequency of poor-risk cytogenetic features, including KMT2A rearrangements and myelodysplastic syndrome-like abnormalities (eg, monosomal karyotype). We observed a variety of mutations among t-ALL patients, with the majority of patients exhibiting mutations that were more common with myeloid malignancies (eg, DNMT3A, RUNX1, ASXL1), whereas others had ALL-type mutations (eg, CDKN2A, IKZF1). Median overall survival was significantly shorter in the t-ALL cohort compared with patients with dn-ALL or pm-ALL. Patients who were eligible for hematopoietic cell transplantation had improved long-term survival. Collectively, our results support t-ALL as a distinct entity based on its biologic and clinical features.

Purpose Although sleep disturbances are common in older adults, studies evaluating the prevalence of sleep disturbance and influence on functional outcomes in older adults with cancer are few. In this study, we examined the prevalence of sleep disturbance and its association with physical function and cognition in older adults with cancer. Methods Patients referred to the Specialized Oncology Care & Research in the Elderly clinics at the Universities of Rochester and Chicago from May 2011 to October 2015 who underwent a geriatric assessment (GA) and completed the sleep assessment were included. Presence of sleep disturbance was self-reported (yes/no). Physical function was assessed using Instrumental Activities of Daily Living (IADLs), physical activity (PA) survey, falls in the preceding six months, and Short Physical Performance Battery (SPPB). Bivariate and multivariable analyses were used to examine the associations between sleep disturbance with functional outcomes and cognition. Results We included 389 older patients. The prevalence of sleep disturbance was 40%. Sixty eight percent had ≥1 IADL impairment, 76% had PA limitation, 37% had ≥1 fall, 70% had impairment on SPPB, and 47% screened positive for cognitive impairment. On bivariate analyses, sleep disturbance was associated with IADL impairment (Odds ratio [OR] 1.96, 95% Confidence Interval [CI] 1.23-3.13, P=0.005) and PA limitation (OR 2.43, 95% CI 1.38-4.28, P=0.002). The associations remained significant on multivariable analyses. Sleep disturbance was not significantly associated with falls, impairment on SPPB and performance on the cognitive screen. Conclusion Sleep disturbance was associated with IADL impairment and PA limitation. It is important for oncologists to inquire about sleep problems, and these patients should also be screened for functional impairment if sleep disturbance was present.

The incidence of gastroesophageal junction (GEJ) adenocarcinomas has been rising over the past few decades, creating a need for effective therapeutic strategies. Treatment of locally advanced GEJ tumors, in particular, present a unique challenge because these tumors have generally been approached as either esophageal or gastric cancers, and thus optimal preoperative management remains uncertain. Both neoadjuvant chemoradiation and perioperative chemotherapy have been widely adopted in standard practice; however, it is unclear which approach offers the optimal outcome for the fit patient capable of receiving any planned strategy. In this review, we debate the management of locally advanced GEJ adenocarcinoma, and discuss areas of ongoing investigation which may provide more effective and individualized treatment of patients with GEJ cancers.