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Background Metastatic high-grade neuroendocrine neoplasms (G3NENs) have limited treatment options after progression on platinum-based therapy. We addressed the role of Pembrolizumab in patients with previously treated metastatic G3NENs. Methods Two open-label, phase 2 studies enrolled patients with G3NEN (Ki-67 > 20%) to receive Pembrolizumab at 200 mg I.V. every 3 weeks. Radiographic evaluation was conducted every 9 weeks with overall response rate as the primary endpoint. Results Between November 2016 and May 2018, 29 patients (13 males/16 females) with G3NENs were enrolled. One patient (3.4%) had an objective response and an additional six patients (20.7%) had stable disease, resulting in a disease control rate of 24.1%. Disease control rate (DCR) at 18 weeks was 10.3% (3/29). There was no difference in the DCR, PFS or OS between the PD-L1-negative and -positive groups ( p 0.56, 0.88 and 0.55, respectively). Pembrolizumab was well tolerated with only 9 grade 3, and no grade 4 events considered drug-related. Conclusions Pembrolizumab can be safely administered to patients with G3NENs but has limited activity as a single agent. Successful completion of our trials suggest studies in G3NENs are feasible and present an unmet need. Further research to identify active combination therapies should be considered. Clinical trial registration number NCT02939651 (10/20/2016).

Background Antibiotic therapy (ABT)-induced dysbiosis may affect the efficacy of immune checkpoint inhibitors (ICI) therapy. We investigated the association between ABT and real-world overall survival (rwOS) and progression-free survival (rwPFS) in patients with metastatic urothelial carcinoma (mUC) receiving ICI or cisplatin-based chemotherapy (CIS). Methods Three thousand, one hundred seventy-nine patients were included from a nationwide electronic health record-derived de-identified database. Three-month landmark Kaplan–Meier methods and log-rank tests were used to estimate rwOS/PFS between treatment modalities based on ABT groups (stratified by exposure, timing, excretion mode, and administration route). Cox proportional models with time-varying coefficients were used to investigate the associations between ABT, treatment modality, and rwOS/PFS. Results A total of 402 (27.1%) ICI and 655 (38.6%) CIS patients received ABT ( p  < 0.001). ICI receipt (OR 0.65, p  < 0.001) and advanced age (OR 0.98, p  < 0.001) were associated with lower ABT use. ICI exclusive findings included a negative correlation with rwOS in patients who received post-treatment initiated (ICI median: pre—13.2 vs post—7.9 vs none—13.3 months; p  = 0.009), oral (median oral—9.6 vs none—13.3 months, p  = 0.03), and renally cleared (median renal—9.9 vs none—13.3 months, p  = 0.04) ABT. ABT’s effect was negatively associated with rwOS in ICI patients within first 6 months (HR 1.36, 95% CI 1.107–1.74, p  = 0.01) but not thereafter ( p  = 0.7). Conclusions This study identified a potential ICI-specific negative correlation between ABT and rwOS in patients with mUC, specifically those exposed to ABT pills and receipt before treatment initiation. These results emphasize the importance of antibiotic stewardship and continued investigation of the role of gut microbiome in mUC treatment efficacy.

PurposePerceiving positive life changes (“benefit finding”) is thought to promote better adjustment after cancer, yet is poorly understood among colorectal cancer (CRC) patients. We characterized benefit finding and examined its relationship to demographic/medical factors, change over time, and association with distress.MethodsCRC outpatients (N = 133, 50% metastatic) completed self-report measures (demographic/medical factors, benefit finding, distress) at baseline and 6 months later. Wilcoxon rank-sum (Kruskal-Wallis) tests or Spearman correlations tested associations between benefit finding and demographic/medical factors. Linear regressions assessed (1) change in benefit finding over time and whether this differed by demographic/medical factors, and (2) association between benefit finding and distress and whether this changed over time.ResultsBenefit finding was common among patients with CRC, with highest rated items reflecting gratitude, acceptance, and stronger family relationships. Women and racial minorities reported greater benefit finding than men (p < 0.001) and White patients (p = 0.015), respectively. Medical factors (e.g., metastatic disease) were not associated with benefit finding. Benefit finding significantly increased over time (p = 0.03). While greater benefit finding trended towards an association with lower distress, results were not statistically significant and the relationship did not change over time.ConclusionBenefit finding was characterized largely by perceived psychological and social benefits, as opposed to pragmatic benefits. Individual differences and social determinants may be more informative than medical characteristics when it comes to benefit finding; although, cultural factors and mediators should be examined further. Benefit finding seems to evolve over time perhaps as a coping process; however, its association with psychological distress appears tenuous.

IntroductionMany patients seek breast reconstruction following mastectomy. Debate exists regarding the best reconstructive option. The authors evaluate outcomes comparing implant, free flap, and pedicled flap reconstruction.MethodsPatients undergoing implant, pedicled flap, and free flap reconstruction were identified in the 2011–2016 NSQIP database. Demographics were analyzed and covariates were balanced using overlap propensity score. Logistic regression was used for binary outcomes and Gamma GLM for length of stay (LOS).ResultsOf 23,834 patients, 87.7% underwent implant, 8.1% free flap, and 4.2% pedicled flap reconstruction. The implant group had the lowest mean operative time (206 min, SD 85.6). Implant patients had less pneumonia (OR 0.09, CI 0.02–0.36, p < 0.01), return to operating room (OR 0.62, CI 0.50–0.75, p < 0.01), venous thromboembolism (VTE) (OR 0.33, CI 0.14–0.79, p = 0.01), postoperative bleeding (OR 0.10, CI 0.06–0.15, p < 0.01), and urinary tract infections (UTI) (OR 0.21, CI 0.07–0.58, p < 0.01) than free flap patients. Pedicled flap patients had less postoperative bleeding (OR 0.69, CI 0.49–0.96, p = 0.03) than free flap patients. Pedicled flap patients had more superficial surgical site infections (p = 0.03), pneumonia (p = 0.02), postoperative bleeding (p < 0.01), VTE (p = 0.04), sepsis (p = 0.05), and unplanned reintubation (p = 0.01) than implant patients. Implant patients had the lowest LOS (1.6 days, p < 0.01).ConclusionImplant reconstruction has less short-term postoperative complications than free flaps and pedicled flap reconstructions. The overall complication rate among all reconstructive modalities remains acceptably low and patients should be informed of all surgical options.

BackgroundThe literature lacks large-scale population studies comparing survival outcomes between signet-ring cell gastric carcinoma (SRGC) and non-SRGC (NSRGC) when treatment is delivered at academic versus community cancer centers.MethodsThe National Cancer Database (NCDB) from 2004 to 2016 was queried to examine the association between treatment facility category and overall survival of patients who underwent gastrectomy for resectable gastric adenocarcinoma (GAC).ResultsThe study investigated 22,871 patients. Upstaging of resectable GAC to pathologic stage 4 was more evident at community centers (3.5%) than at academic centers (2.8%) for the NSRGC variant (p = 0.211), whereas it was comparable between the two facility categories for the SRGC variant (5.9% vs 6%, respectively). Patients with pathologic stage 1 or 3 NSRGC who underwent gastrectomy at academic programs had better overall survival (OS) (hazard ratio [HR], 0.68; p < 0.0001) than those who underwent gastrectomy at community centers (HR, 0.79; p < 0.0065). Similarly, patients with stage 2 SRGC had better OS when treated at academic versus community centers (HR, 0.54; p = 0.0019). No statistically significant improvement in OS was observed between patients with stage 2 NSRGC (HR, 0.84; p = 0.083) and those with stage 3 SRGC (HR, 0.78; p = 0.054) who were treated at academic centers. No survival benefit was demonstrated for stage 1 SRGC when academic and community centers were compared (p = 0.56).ConclusionsThis is the first study based on a large-scale database in the Western population that addressed the overall survival-by-stage of two distinct GAC histologic variants. Treatment at academic centers was associated with significant improvements in OS.

Red fluorescent proteins are useful as morphological markers in neurons, often complementing green fluorescent protein-based probes of neuronal activity. However, commonly used red fluorescent proteins show aggregation and toxicity in neurons or are dim. We report the engineering of a bright red fluorescent protein, Crimson, that enables long-term morphological labeling of neurons without aggregation or toxicity. Crimson is similar to mCherry and mKate2 in fluorescence spectra but is 100 and 28% greater in molecular brightness, respectively. We used a membrane-localized Crimson-CAAX to label thin neurites, dendritic spines and filopodia, enhancing detection of these small structures compared to cytosolic markers.

Summary The destructive bacterial pathogen Ralstonia solanacearum delivers effector proteins via a type‐III secretion system for its pathogenesis of plant hosts. However, the biochemical functions of most of these effectors remain unclear. RipAK of R. solanacearum GMI1000 is a type‐III effector with unknown functions. Functional analysis demonstrated that in tobacco leaves, ripAK knockout bacteria produced an obvious hypersensitive response; also, infected tissues accumulated reactive oxygen species in a shorter period postinfection, compared with wild type. This strongly indicates that RipAK can inhibit hypersensitive response during infection. Further analysis showed that RipAK localizes to peroxisomes and interacts with host catalases (CATs) in plant cells. Truncation of 2 putative domains of RipAK caused it to fail to target the peroxisome and fail to interact with AtCATs, suggesting that RipAK localization depends on its interaction with CATs. Furthermore, heterologous expression of RipAK inhibited CAT activity in vivo and in vitro. Finally, compared with the ripAK mutant, infection with a bacterial strain overexpressing RipAK inhibited the transcription of many immunity‐associated genes in infected tobacco leaves at 2‐ and 4‐hr postinfection, although mRNA levels of NtCAT1 were upregulated. These data indicate that GMI1000 suppresses hypersensitive response by inhibiting host CATs through RipAK at early stages of infection.

Western literature lacks large-scale population studies comparing the influence of academic and high-volume (HV) versus low-volume (LV) cancer centers on gastric cancer oncologic outcomes. The National Cancer Database from 2004 to 2016 was used. 22871 patients were studied. Patients with stage III signet-ring cell gastric carcinoma (SRGC) received neoadjuvant treatment (NAT) more frequently at academic and HV comprehensive cancer centers (OR: 4.27 and 2.42; p < 0.0001 and 0.009) compared to community centers. Patients with stage III non-SRGC (NSRGC) had a 2.4 times higher odds of receiving NAT at academic centers. The R1 resection rate for NSRGC was lower at academic centers (OR: 0.67; p = 0.0018). Lymph node harvest ≥15 nodes was 1.6 and 1.9 times higher at academic centers for NSRGC and SRGC, respectively. Patients treated at academic centers had a significantly improved overall survival (OS). Treatment at academic centers is associated with significant improvements in oncologic metrics and OS. [Display omitted] •Academic outperform community centers in management of resectable gastric cancer.•Despite delay in treatment initiation, survival is improved at academic centers.•Survival is greater in signet-ring cell gastric cancer treated at academic centers.

Introduction This investigation aims to assess the outcomes for second-line therapies to treat extrapulmonary neuroendocrine carcinoma (EP-NEC) after first-line platinum-based chemotherapy. Methods With IRB approval, we conducted a retrospective study of EP-NEC patients that progressed on first-line platinum chemotherapy from 2008 to 2018. Demographic data and treatment-related characteristics were collected and represented as descriptive statistics. The primary endpoints include overall survival (OS) and progression-free survival (PFS). OS and PFS were estimated and stratified by site of primary (gastroenteropancreatic [GEP] versus non-GEP) and type of second-line therapy (irino/topotecan versus others). Log-rank test and Kaplan–Meier curves were used to compare survival distributions between groups. Results Forty-seven patients met eligibility, with median age 65 (range 31–82), 62% male, and 83% White; 22 were GEP and 25 were non-GEP primary. Thirty patients (63.8%) received second-line therapy where 11 received irinotecan/topotecan (ir/to), while 19 received other agents (temozolomide, other platinum agents, gemcitabine, paclitaxel, pembrolizumab, and sunitinib). The median OS was 10.3 months in the ir/to group versus 13.4 months for other therapies, p  = 0.10. The median PFS for ir/to therapy compared to other therapies was 2.0 months versus 1.8 months, respectively, p  = 0.72. The OS and PFS with and without ir/to were not significantly different by the primary site ( p  = 0.61 and p  = 0.21). Discussion/Conclusion Many EP-NEC patients undergo second-line therapies. Interestingly, outcomes for ir/to-containing second-line therapies were not statistically different from other agents, regardless of the site of primary. With approval of new second-line therapies for small cell lung cancer, further research in therapeutic options is needed for this aggressive disease.

Background Despite national guideline recommendations for universal biomarker testing (KRAS, NRAS, BRAF, and mismatch repair and microsatellite instability [MMR/MSI]) in all patients with metastatic colorectal cancer (mCRC), little is known regarding adherence to these recommendations in routine practice. Methods We retrospectively reviewed patients with mCRC diagnosed between January 1, 2013, and December 27, 2018, from a de-identified electronic health record–derived database. We analyzed disparities in KRAS, NRAS, BRAF, and MMR/MSI testing by race, age, sex, and insurance status using χ2 tests and t tests. We evaluated changes in biomarker testing over time with attention to changes around dates of landmark publications and guideline updates using χ2 tests and Cochran-Armitage tests. Results A total of 20 333 patients were identified of which 66.6% had test results for any biomarker. Rates of test results for all 4 biomarkers statistically significantly increased over time (P < .001). However, as of June 30, 2018, the rate of test results was only 46% for NRAS, 56% for KRAS, and 46% for BRAF. As of December 31, 2017, the rate of MMR/MSI testing was 59%. Higher documented testing rates were associated with younger age, lower Eastern Cooperative Oncology Group performance status, and commercial insurance. There were no clinically meaningful and/or statistically significant differences in documented testing rates by tumor sidedness, race, sex, or initial stage. Conclusions Increased rates of documented testing for NRAS, BRAF, and MMR/MSI in mCRC was seen between 2013 and 2018 reflecting adoption of guideline recommendations. However, the rate of documented testing remains lower than expected and warrants additional research to understand the extent to which this may represent a clinical practice quality concern.