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Resection of the primary (RP) in metastatic neuroendocrine tumor (NET) is controversial. The aim was to evaluate survival outcomes for RP in metastatic NET patients.Data were obtained from US hospitals at the National Cancer Database between 2004 and 2014. χ2, analysis of variance tests, univariate, and multivariate cox proportional hazards models were evaluated. Kaplan-Meier curves and log-rank tests conducted to compare the survival difference of patient characteristics.A total of 2361 patients were identified. The mean age was 62.1 years (standard deviation, 13 years), male-to-female ratio 1:1; 33% were small intestine, 26.3% pancreas, and 24.4% lung; 69.6% were well-differentiated; and 42.5% underwent RP. The 5-year overall survival (OS) was significantly improved for patients who underwent RP in small intestine (5-year OS, 63.9% vs 44.2%), lung (5-year OS, 65.4% vs 20.2%), and pancreas tumors (5-year OS, 75.6% vs 30.6%). On multivariate analysis, RP (hazard ratio, 0.46; 95% confidence interval, 0.29-0.73; P0.001), female, year of diagnosis 2010-2014, margin, Charlson-Deyo score less than 2, and age less than 51 years, were associated with better OS.Resection of the primary in metastatic well-differentiated NET is associated with improved OS compared with no RP.

INTRODUCTION AND OBJECTIVE: Androgen deprivation therapy (ADT) can help maintain remission in advanced prostate cancer (PCa) patients with bone metastases, however, growth and metastatic spread often recur. To address the need for more predictive pre-clinical research platforms and to identify new targets and therapies for bone metastatic castration-resistant prostate cancer (CRPC). METHODS: We used patient-derived xenograft (PDX) tumors from bone metastatic prostate cancer patients to establish threedimensional (3D) organoids and investigated their response to ADT by either withholding di-hydro-testosterone (no DHT) or treating with enzalutamide. Cyst/spheroid quantitation, immunohistopathology, cell viability assay, qRT-PCR, RNA sequencing, gene set enrichment analysis (GSEA) and live cell cycle tracking using Fucci2BL were performed in PDXs: PCSD1, PCSD13 and PCSD25 and compared to PCa Cell lines: P, DU145 and LNCaP. RESULTS: ADT resulted in CRPC spheroids with CK5D CK8D cells, up-regulated stem-cell transcription factors, steroidogenic and neurogenic pathways and down-regulated AR-target genes, interferon, cell cycle, cell division and circadian pacemaker pathways. Enzalutamide-treated spheroids transitioned to G0 and AR protein was decreased but not AR mRNA. Moreover, ADT decreased both ACE2 and TMPRSS2, host cell viral entry factors for the severe acute respiratory syndrome (SARS) SARS-CoV-2. CONCLUSIONS: In organoids, or mini-tumors, established from prostate cancer bone metastasis PDXs, a novel type of dormant ADT-resistant cell with specific gene changes emerged which may be targeted in order to eradicate dormant metastases before they can progress. This study identified a new dormant CRPC basal-luminal hybrid prostate cancer cell and gene signature which may be therapeutically targeted to eradicate dormant CRPC bone metastases in order to prevent disease recurrence. ADT also reduced the cell factors required for SARS-CoV-2 or its variants to infect its host cells and thus may reduce COVID-19 disease severity. The PDX organoid models can be used to screen for therapies that target the dormant CRPC cells and that reduce ACE2 and TMPRSS2 expression to suppress viral load of SARS-CoV-2 and its variants.

OBJECTIVES Surgical resection for locally advanced rectal adenocarcinoma commonly occurs 6 to 10 weeks after completion of neoadjuvant chemoradiation (nCRT). We sought to determine the optimal timing of surgery related to the pathologic complete response rate and survival endpoints. METHODS The study is a retrospective analysis of 92 patients treated with nCRT followed by surgery from 2004 to 2011 at our institution. Univariate and multivariate analyses were performed to assess the impact of timing of surgery on locoregional control, distant failure (DF), disease-free survival, and overall survival (OS). RESULTS Time-to-surgery was ≤8 weeks (group A) in 72% (median 6.1 wk) and >8 weeks (group B) in 28% (median 8.9 wk) of patients. No significant differences in patient characteristics, locoregional control, or pathologic complete response rates were noted between the groups. Univariate analysis revealed that group B had significantly shorter time to DF (group B, median 33 mo; group A, median not reached, P=0.047) and shorter OS compared with group A (group B, median 52 mo; group A, median not reached, P=0.03). Multivariate analysis revealed that increased time-to-surgery showed a significant increase in DF (HR=2.96, P=0.02) and trends toward worse OS (HR=2.81, P=0.108) and disease-free survival (HR=2.08, P=0.098). CONCLUSIONS We found that delaying surgical resection longer than 8 weeks after nCRT was associated with an increased risk of DF. This study, in combination with a recent larger study, questions the recent trend in promoting surgical delay beyond the traditional 6 to 10 weeks. Larger, prospective databases or randomized studies may better clarify surgical timing following nCRT in rectal adenocarcinoma.

The benefit of adjuvant chemotherapy in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and surgery is controversial. We examined the association of perineural invasion (PNI) with outcomes to determine whether PNI could be used to risk-stratify patients. We performed a retrospective study of 110 patients treated with nCRT and surgery for LARC at our institution from 2004 to 2011. Eighty-seven patients were identified in our final analysis. We evaluated the association of PNI with locoregional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival, using log-rank and Cox proportional hazard modeling. Fourteen patients (16%) were PNI+ and 73 patients (84%) were PNI−. The median follow-up was 27 months (range, 0.9 to 84 mo). The median DMFS was 13.5 months for PNI+ and median not reached (>40 mo) for PNI− (P

Background— Skeletal muscle dysfunction and exercise intolerance are clinical hallmarks of patients with heart failure. These have been linked to a progressive catabolic state, skeletal muscle inflammation, and impaired oxidative metabolism. Previous studies suggest beneficial effects of ω-3 polyunsaturated fatty acids and glutamine on exercise performance and muscle protein balance. Methods and Results— In a randomized double-blind, placebo-controlled trial, 31 patients with heart failure were randomized to either l -alanyl- l -glutamine (8 g/d) and polyunsaturated fatty acid (6.5 g/d) or placebo (safflower oil and milk powder) for 3 months. Cardiopulmonary exercise testing, dual-energy x-ray absorptiometry, 6-minute walk test, hand grip strength, functional muscle testing, echocardiography, and quality of life and lateral quadriceps muscle biopsy were performed at baseline and at follow-up. Oxidative capacity and metabolic gene expression were analyzed on muscle biopsies. No differences in muscle function, echocardiography, 6-minute walk test, or hand grip strength and a nonsignificant increase in peak V O 2 in the treatment group were found. Lean body mass increased and quality of life improved in the active treatment group. Molecular analysis revealed no differences in muscle fiber composition, fiber cross-sectional area, gene expression of metabolic marker genes (PGC1α, CPT1, PDK4, and GLUT4), and skeletal muscle oxidative capacity. Conclusions— The combined supplementation of l -alanyl- l -glutamine and polyunsaturated fatty acid did not improve exercise performance or muscle function but increased lean body mass and quality of life in patients with chronic stable heart failure. These findings suggest potentially beneficial effects of high-dose nutritional polyunsaturated fatty acids and amino acid supplementations in patients with chronic stable heart failure. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01534663.

Etanercept blocks tumor necrosis factor α (TNF-α), a proinflammatory cytokine that plays a role in cancer-related cachexia and tumor growth. A phase I/II study was conducted to assess the tolerability and efficacy of gemcitabine and etanercept in advanced pancreatic cancer.Twenty-five patients received etanercept 25 mg subcutaneously twice weekly with gemcitabine. A control cohort of 8 patients received gemcitabine alone. The primary end point was progression-free survival at 6 months. Blood specimens were analyzed for TNF-α, IL-1β, IL-6, interferon-γ, IL-10, and NF-κβ activation. The trial is registered with ClinicalTrials.gov, number NCT00201838.Thirty-eight patients participated in this study. In the gemcitabine-etanercept cohort, grade 3/4 drug-related toxicities included leucopenia (3) and neutropenia (6). There were 3 (12%) patients with partial response and 8 (32%) patients with stable disease. The rate of progression-free survival at 6 months was 28% [n = 7; 95% confidence interval (CI), 20%-36%]. Median time to progression was 2.23 months (95% CI, 1.86-4.36 months) and median overall survival was 5.43 months (95% CI, 3.30-10.23 months). Clinical benefit rate was 33% of the evaluable patients. A correlation was seen between IL-10 levels and clinical benefit.Etanercept added to gemcitabine is safe but did not show significant enhancement of gemcitabine in patients with advanced pancreatic cancer.

Background: Heart failure (HF) is a multi-organ, pro-inflammatory syndrome that impairs bone metabolism. Proinflammatory cytokines and bone catabolism enhance periodontal disease, a local inflammatory, bacteria-induced disease that causes bone loss and periodontal soft tissue destruction. Hypothesis: Patients with advanced HF before and after heart transplantation (HTx) have more severe periodontal disease as compared to age and smoking-matched controls. Further, local inflammatory markers in the saliva and gingival crevicular fluid (GCF) can be used as markers of the local inflammatory periodontal burden in patients with HF. Methods: Medical and dental examinations were performed on patients with HF (n=41), following heart transplantation (post-HTx, n=40) and controls (n=32). Blood, saliva and GCF samples were taken to investigate markers of bone metabolism and inflammation. Results: Average New York Heart Association classification for HF was class III. Average time since HTx was 33.14 months. Overall periodontal diagnosis was more severe in patients with advanced HF and post-HTx versus controls (p Conclusion: Patients with advanced HF exhibit more severe periodontal disease associated with increased bone turnover markers when compared to control patients. Further, periodontal disease severity was detectable in saliva and GCF making it a potential useful tool for identifying the need for periodontal treatment in patients with advanced HF.

We thank Haufe et al for their insightful comments on our study of adipose tissue inflammation and adiponectin resistance in patients with advanced heart failure (HF) and the impact of mechanical unloading.1 We appreciate the observation that incorrect homeostasis model of insulin resistance (HOMA-IR) values were listed in Table 3. Upon recalculation using the HOMA-IR formula, the correct values were found to be 1.0±0.6 for controls, 7.6±7.7 in advanced HF ( P =0.02 versus controls) and 4.5±3.6 after left ventricular assist device (LVAD) support ( P =0.01 versus HF). This supports the conclusion …