Surgical Resection Alone is Associated With Higher Long-Term Survival Than Multiagent Chemotherapy Alone for Patients With Localized Biliary Tract Cancers.

INTRODUCTION: We compared long-term survival of patients with localized biliary tract cancers (BTCs) treated with either surgical resection or multiagent chemotherapy. METHODS: Patients with localized BTC [gallbladder adenocarcinoma, extrahepatic cholangiocarcinoma, intrahepatic cholangiocarcinoma] were identified within the National Cancer Database (2010-2017). Piecewise-constant hazard modeling was used to estimate hazard ratios (HRs) at prespecified intervals: 0-30 d, 31-60 d, 61-90 d, and >90 d post-treatment. RESULTS: A total of 5988 patients with localized BTC were identified: 2697 (45.0%) received multiagent chemotherapy and 3291 (55.0%) underwent surgical resection. Patients with gallbladder adenocarcinoma or extrahepatic cholangiocarcinoma who were treated with surgical resection had an associated decline in overall survival (OS) as compared to those treated with multiagent chemotherapy within 0-30 d of treatment initiation (gallbladder adenocarcinoma [adjusted HR = 3.94, 95% confidence interval [CI]: 1.77-8.80]; extrahepatic cholangiocarcinoma [adjusted HR = 4.88, 95% CI: 2.76-8.61]). However, there was an associated improvement in OS for patients treated with surgical resection after 90 d from treatment initiation (gallbladder adenocarcinoma [adjusted HR = 0.36, 95% CI: 0.28-0.46]; extrahepatic cholangiocarcinoma [adjusted HR = 0.27, 95% CI: 0.24-0.32]). Among patients with intrahepatic cholangiocarcinoma, those who underwent surgical resection had an associated improvement in OS at 31-60 d (adjusted HR = 0.63, 95% CI: 0.40-0.99) and a further associated increase in OS at 61-90 d (adjusted HR = 0.34, 95% CI: 0.21-0.54) and after 90 d (HR = 0.23, 95% CI: 0.21-0.27) of treatment initiation. CONCLUSIONS: For patients with localized BTC, surgical resection alone is associated with improved long-term survival outcomes compared to multiagent chemotherapy alone.

American Radium Society Appropriate Use Criteria for the use of liver-directed therapies for nonsurgical management of liver metastases: Systematic review and guidelines.

The liver is a common site of cancer metastases. Systemic therapy is widely accepted as the standard treatment for liver metastases (LM), although select patients with liver oligometastases may be candidates for potentially curative liver resection. Recent data support the role of nonsurgical local therapies such as ablation, external beam radiotherapy, embolization, and hepatic artery infusion therapy for management of LM. Additionally, for patients with advanced, symptomatic LM, local therapies may provide palliative benefit. The American Radium Society gastrointestinal expert panel, including members representing radiation oncology, interventional radiology, surgical oncology, and medical oncology, performed a systemic review and developed Appropriate Use Criteria for the use of nonsurgical local therapies for LM. Preferred Reporting Items for Systematic reviews and Meta-Analyses methodology was used. These studies were used to inform the expert panel, which then rated the appropriateness of various treatments in seven representative clinical scenarios through a well-established consensus methodology (modified Delphi). A summary of recommendations is outlined to guide practitioners on the use of nonsurgical local therapies for patients with LM.

The Role of the Microbiome in Gastroentero-Pancreatic Neuroendocrine Neoplasms (GEP-NENs).

Gut microbiome balance plays a key role in human health and maintains gut barrier integrity. Dysbiosis, referring to impaired gut microbiome, is linked to a variety of diseases, including cancers, through modulation of the inflammatory process. Most studies concentrated on adenocarcinoma of different sites with very limited information on gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs). In this study, we have analyzed the gut microbiome (both fungal and bacterial communities) in patients with metastatic GEP-NENs. Fecal samples were collected and compared with matched healthy control samples using logistic regression distances utilizing R package MatchIt (version 4.2.0, Daniel E. Ho, Stanford, CA, USA). We examined differences in microbiome profiles between GEP-NENs and control samples using small subunit (SSU) rRNA (16S), ITS1, ITS4 genomic regions for their ability to accurately characterize bacterial and fungal communities. We correlated the results with different behavioral and dietary habits, and tumor features including differentiation, grade, primary site, and therapeutic response. All tests are two-sided and p-values ≤ 0.05 were considered statistically significant. Gut samples of 34 patients (12 males, 22 females, median age 64 years) with metastatic GEP-NENs (22 small bowel, 10 pancreatic, 1 gall bladder, and 1 unknown primary) were analyzed. Twenty-nine patients had well differentiated GEP-neuroendocrine tumors (GEP-NETs), (G1 = 14, G2 = 12, G3 = 3) and five patients had poorly differentiated GEP-neuroendocrine carcinomas (GEP-NECs). Patients with GEP-NENs had significantly decreased bacterial species and increased fungi (notably Candida species, Ascomycota, and species belonging to saccharomycetes) compared to controls. Patients with GEP-NECs had significantly enriched populations of specific bacteria and fungi (such as Enterobacter hormaechei, Bacteroides fragilis and Trichosporon asahii) compared to those with GEP-NETs (p = 0.048, 0.0022 and 0.034, respectively). In addition, higher grade GEP-NETs were associated with significantly higher Bacteroides fragilis (p = 0.022), and Eggerthella lenta (p = 0.00018) species compared to lower grade tumors. There were substantial differences associated with dietary habits and therapeutic responses. This is the first study to analyze the role of the microbiome environment in patients with GEP-NENs. There were significant differences between GEP-NETs and GEP-NECs, supporting the role of the gut microbiome in the pathogenesis of these two distinct entities.

Altering O-linked ß-N-acetylglucosamine cycling disrupts mitochondrial function.

Mitochondrial impairment is commonly found in many diseases such as diabetes, cancer, and Alzheimer disease. We demonstrate that the enzymes responsible for the addition or removal of the O-GlcNAc modification, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively, are critical regulators of mitochondrial function. Using a SILAC (stable isotope labeling of amino acids in cell culture)-based proteomics screen, we quantified the changes in mitochondrial protein expression in OGT- and OGA-overexpressing cells. Strikingly, overexpression of OGT or OGA showed significant decreases in mitochondria-localized proteins involved in the respiratory chain and the tricarboxylic acid cycle. Furthermore, mitochondrial morphology was altered in these cells. Both cellular respiration and glycolysis were reduced in OGT/OGA-overexpressing cells. These data demonstrate that alterations in O-GlcNAc cycling profoundly affect energy and metabolite production.

Bioenergetic flux, mitochondrial mass and mitochondrial morphology dynamics in AD and MCI cybrid cell lines.

Bioenergetic dysfunction occurs in Alzheimer's disease (AD) and mild cognitive impairment (MCI), a clinical syndrome that frequently precedes symptomatic AD. In this study, we modeled AD and MCI bioenergetic dysfunction by transferring mitochondria from MCI, AD and control subject platelets to mtDNA-depleted SH-SY5Y cells. Bioenergetic fluxes and bioenergetics-related infrastructures were characterized in the resulting cytoplasmic hybrid (cybrid) cell lines. Relative to control cybrids, AD and MCI cybrids showed changes in oxygen consumption, respiratory coupling and glucose utilization. AD and MCI cybrids had higher ADP/ATP and lower NAD+/NADH ratios. AD and MCI cybrids exhibited differences in proteins that monitor, respond to or regulate cell bioenergetic fluxes including HIF1α, PGC1α, SIRT1, AMPK, p38 MAPK and mTOR. Several endpoints suggested mitochondrial mass increased in the AD cybrid group and probably to a lesser extent in the MCI cybrid group, and that the mitochondrial fission-fusion balance shifted towards increased fission in the AD and MCI cybrids. As many of the changes we observed in AD and MCI cybrid models are also seen in AD subject brains, we conclude reduced bioenergetic function is present during very early AD, is not brain-limited and induces protean retrograde responses that likely have both adaptive and mal-adaptive consequences.

Effect of one month duration ketogenic and non-ketogenic high fat diets on mouse brain bioenergetic infrastructure.

Diet composition may affect energy metabolism in a tissue-specific manner. Using C57Bl/6J mice, we tested the effect of ketosis-inducing and non-inducing high fat diets on genes relevant to brain bioenergetic infrastructures, and on proteins that constitute and regulate that infrastructure. At the end of a one-month study period the two high fat diets appeared to differentially affect peripheral insulin signaling, but brain insulin signaling was not obviously altered. Some bioenergetic infrastructure parameters were similarly impacted by both high fat diets, while other parameters were only impacted by the ketogenic diet. For both diets, mRNA levels for CREB, PGC1α, and NRF2 increased while NRF1, TFAM, and COX4I1 mRNA levels decreased. PGC1ß mRNA increased and TNFα mRNA decreased only with the ketogenic diet. Brain mtDNA levels fell in both the ketogenic and non-ketogenic high fat diet groups, although TOMM20 and COX4I1 protein levels were maintained, and mRNA and protein levels of the mtDNA-encoded COX2 subunit were also preserved. Overall, the pattern of changes observed in mice fed ketogenic and non-ketogenic high fat diets over a one month time period suggests these interventions enhance some aspects of the brain's aerobic infrastructure, and may enhance mtDNA transcription efficiency. Further studies to determine which diet effects are due to changes in brain ketone body levels, fatty acid levels, glucose levels, altered brain insulin signaling, or other factors such as adipose tissue-associated hormones are indicated.

Executive Summary of the American Radium Society on Appropriate Use Criteria for Nonoperative Management of Rectal Adenocarcinoma: Systematic Review and Guidelines.

For patients with rectal cancer, the standard approach of chemotherapy, radiation therapy, and surgery (trimodality therapy) is associated with significant long-term toxicity and/or colostomy for most patients. Patient options focused on quality of life (QOL) have dramatically improved, but there remains limited guidance regarding comparative effectiveness. This systematic review and associated guidelines evaluate how various treatment strategies compare to each other in terms of oncologic outcomes and QOL. Cochrane and Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) methodology were used to search for prospective and retrospective trials and meta-analyses of adequate quality within the Ovid Medline database between January 1, 2012, and June 15, 2023. These studies informed the expert panel, which rated the appropriateness of various treatments in 6 clinical scenarios through a well-established consensus methodology (modified Delphi). The search process yielded 197 articles that advised voting. Increasing data have shown that nonoperative management (NOM) and primary surgery result in QOL benefits noted over trimodality therapy without detriment to oncologic outcomes. For patients with rectal cancer for whom total mesorectal excision would result in permanent colostomy or inadequate bowel continence, NOM was strongly recommended as usually appropriate. Restaging with tumor response assessment approximately 8 to 12 weeks after completion of radiation therapy/chemoradiation therapy was deemed a necessary component of NOM. The panel recommended active surveillance in the setting of a near-complete or complete response. In the setting of NOM, 54 to 56 Gy in 27 to 31 fractions concurrent with chemotherapy and followed by consolidation chemotherapy was recommended. The panel strongly recommends primary surgery as usually appropriate for a T3N0 high rectal tumor for which low anterior resection and adequate bowel function is possible, with adjuvant chemotherapy considered if N+. Recent data support NOM and primary surgery as important options that should be offered to eligible patients. Considering the complexity of multidisciplinary management, patients should be discussed in a multidisciplinary setting, and therapy should be tailored to individual patient goals/values.

Neutrophil extracellular traps induced by chemotherapy inhibit tumor growth in murine models of colorectal cancer.

Neutrophil extracellular traps (NETs), a web-like structure of cytosolic and granule proteins assembled on decondensed chromatin, kill pathogens and cause tissue damage in diseases. Whether NETs can kill cancer cells is unexplored. Here, we report that a combination of glutaminase inhibitor CB-839 and 5-FU inhibited the growth of PIK3CA-mutant colorectal cancers (CRCs) in xenograft, syngeneic, and genetically engineered mouse models in part through NETs. Disruption of NETs by either DNase I treatment or depletion of neutrophils in CRCs attenuated the efficacy of the drug combination. Moreover, NETs were present in tumor biopsies from patients treated with the drug combination in a phase II clinical trial. Increased NET levels in tumors were associated with longer progression-free survival. Mechanistically, the drug combination induced the expression of IL-8 preferentially in PIK3CA-mutant CRCs to attract neutrophils into the tumors. Further, the drug combination increased the levels of ROS in neutrophils, thereby inducing NETs. Cathepsin G (CTSG), a serine protease localized in NETs, entered CRC cells through the RAGE cell surface protein. The internalized CTSG cleaved 14-3-3 proteins, released BAX, and triggered apoptosis in CRC cells. Thus, our studies illuminate a previously unrecognized mechanism by which chemotherapy-induced NETs kill cancer cells.

Lactate administration reproduces specific brain and liver exercise-related changes.

The effects of exercise are not limited to muscle, and its ability to mitigate some chronic diseases is under study. A more complete understanding of how exercise impacts non-muscle tissues might facilitate design of clinical trials and exercise mimetics. Here, we focused on lactate's ability to mediate changes in liver and brain bioenergetic-associated parameters. In one group of experiments, C57BL/6 mice underwent 7 weeks of treadmill exercise sessions at intensities intended to exceed the lactate threshold. Over time, the mice dramatically increased their lactate threshold. To ensure that plasma lactate accumulated during the final week, the mice were run to exhaustion. In the liver, mRNA levels of gluconeogenesis-promoting genes increased. While peroxisome proliferator-activated receptor-gamma co-activator 1 alpha (PGC-1α) expression increased, there was a decrease in PGC-1ß expression, and overall gene expression changes favored respiratory chain down-regulation. In the brain, PGC-1α and PGC-1ß were unchanged, but PGC-1-related co-activator expression and mitochondrial DNA copy number increased. Brain tumor necrosis factor alpha expression fell, whereas vascular endothelial growth factor A expression rose. In another group of experiments, exogenously administered lactate was found to reproduce some but not all of these observed liver and brain changes. Our data suggest that lactate, an exercise byproduct, could mediate some of the effects exercise has on the liver and the brain, and that lactate itself can act as a partial exercise mimetic.

Role of mitochondrial homeostasis and dynamics in Alzheimer's disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disease that affects a staggering percentage of the aging population and causes memory loss and cognitive decline. Mitochondrial abnormalities can be observed systemically and in brains of patients suffering from AD, and may account for part of the disease phenotype. In this review, we summarize some of the key findings that indicate mitochondrial dysfunction is present in AD-affected subjects, including cytochrome oxidase deficiency, endophenotype data, and altered mitochondrial morphology. Special attention is given to recently described perturbations in mitochondrial autophagy, fission-fusion dynamics, and biogenesis. We also briefly discuss how mitochondrial dysfunction may influence amyloidosis in Alzheimer's disease, why mitochondria are a valid therapeutic target, and strategies for addressing AD-specific mitochondrial dysfunction.

Receipt of Targeted Therapy and Survival Outcomes in Patients With Metastatic Colorectal Cancer.

Importance: Professional society guidelines recommend treating patients with metastatic colorectal cancer with targeted therapies, including epithelial growth factor receptor (EGFR) inhibitors and vascular endothelial growth factor (VEGF) inhibitors, depending on the presence or absence of certain mutations. Since most studies of first-line targeted therapies have been limited by sample size, there is a need for larger studies using data from routine clinical care. Objectives: To identify factors associated with receipt of first-line targeted therapies among patients with metastatic colorectal cancer for whom RAS or BRAF mutation data in the tumor were available and investigate whether targeted therapy is associated with survival. Design, Setting, and Participants: This cohort study used deidentified data from an electronic health record-derived database to include patients from 800 sites of patient care across the US who were diagnosed with de novo metastatic colorectal cancer between January 1, 2013, and March 31, 2020 (n = 9134). Main Outcomes and Measures: Receipt of first-line targeted therapy, categorized as ever having received EGFR inhibitors, VEGF inhibitors, or neither. The secondary outcome was overall survival. Results: The study population included 9134 patients. The median age at diagnosis was 62 years (IQR, 53-71 years), 5019 (54.9%) were male, and 5692 (62.3%) were White. The median follow-up period was 15 months. Overall, 713 patients (7.8%) received EGFR inhibitors and 5081 patients (55.6%) received VEGF inhibitors as part of their first-line treatment. Among patients with RAS wild-type (RAS-WT) tumors, 625 patients (15.5%) received EGFR inhibitors and 2053 patients (50.9%) received VEGF inhibitors. In patients with RAS mutant (RAS-Mut) tumors, 50 patients (1.1%) received EGFR inhibitors and 2682 patients (59.7%) received VEGF inhibitors; among those with BRAF-mutant (BRAF-Mut) tumors, 38 patients (6.3%) received EGFR inhibitors and 346 patients (57.2%) received VEGF inhibitors. More than one-third of the patients (36.6%) received neither EGFR inhibitors nor VEGF inhibitors. Compared with patients younger than age 40 years, those aged 80 years or older had significantly lower odds to receive targeted therapies (EGFR or VEGF inhibitors in patients with RAS-WT tumors: adjusted odds ratio [aOR], 0.53; 95% CI, 0.36-0.79; and VEGF inhibitors in patients with RAS-Mut tumors: aOR, 0.62; 95% CI, 0.42-0.90). Improved survival was associated with EGFR inhibitor therapy in patients with RAS-WT tumors (adjusted hazard ratio [aHR], 0.85; 95% CI, 0.74-0.98). Unlike in clinical trials, however, no survival benefit was noted with use of VEGF inhibitors among patients with RAS-WT (aHR, 1.00; 95% CI, 0.91-1.11) or RAS-Mut (aHR, 1.01; 95% CI, 0.93-1.10) tumors. Conclusions and Relevance: The findings of this study showed mixed results on survival benefits associated with targeted therapy. In addition, given that some of the results differed from those of randomized clinical trials, this study highlights the importance of using data originating from routine clinical care.

Sociodemographic and clinical factors associated with receipt of biomarker testing in patients with metastatic colorectal cancer.

BACKGROUND: Standard clinical practice and national guidelines dictate somatic testing of metastatic colorectal cancer (mCRC) tumors to guide appropriate therapy; however, previous studies suggest that not all patients are tested. The objective of this study was to investigate potential differences in testing for mCRC by demographic and clinical factors. METHODS: We performed a retrospective review of de-identified patient data derived from electronic health records (EHRs) of 25,469 patients diagnosed with mCRC between the years 2013 and 2020. Our outcome was a receipt of the following tests: (a) biomarker testing (BRAF, KRAS, NRAS, MMR/MSI) and (b) next-generation sequencing (NGS). We interrogated our data using the machine-learning algorithm Classification and Regression Tree (CART), a unique approach to identifying combinations of, rather than individual demographic and clinical characteristics associated with receipt of testing. RESULTS: A total of 25,469 patients were identified with mCRC. Of these, 21,133 (83%) received either biomarker testing only (n = 12,485) or any testing (biomarker + NGS) (n = 8648). The proportion of patients who received any testing increased over calendar time for all age, race, and sex categories. Receipt of any testing was highest (90%) among younger and patients with better performance status, and there was no difference in receipt of any testing by race. The highest percentage of NGS testing was among those with better performance status, <70 years old, commercial or other governmental program payers, and low comorbidity burden; however, those who were Black or Hispanic had a lower prevalence of NGS testing than those who were White. CONCLUSIONS AND RELEVANCE: Considerable variations exist in somatic biomarker testing across subgroups of the population. Identification of genomic alterations can aid in determining targeted treatment and improving clinical outcomes; therefore, equitable use of these testing strategies, particularly NGS, is necessary.

Variation in KRAS/NRAS/BRAF-Mutation Status by Age, Sex, and Race/Ethnicity Among a Large Cohort of Patients with Metastatic Colorectal Cancer (mCRC).

BACKGROUND: Racial/ethnic disparities in metastatic colorectal cancer (mCRC) survival are well documented as is the impact that tumor mutation of KRAS and BRAF has on prognosis. It has been suggested that frequency differences of KRAS- and BRAF-mutated tumors may partially explain this disparity. Demographic differences in mutation frequency are not well established nor whether mutation and microsatellite instability (MSI) differentially impact survival among groups. METHODS: Using data for 11,117 patients diagnosed with de-novo mCRC from an electronic health record-derived database we estimated adjusted odds ratios (aOR) to characterize the association between demographics and MSI and KRAS/NRAS/BRAF-mutation status. Stratified Cox models were used to identify differences in overall survival (OS), adjusting for treatment and demographics. RESULTS: Being female, compared to male, (aORKRAS:1.33 (1.23-1.44); aORBRAF:1.84 (1.56-2.16)), and non-Hispanic Black race (NHB), compared to non-Hispanic White (NHW) (aORKRAS:1.62 (1.42-1.85); aORBRAF: 0.55 (0.38-0.77)) were associated with KRAS- or BRAF-mutant tumors. MSI prevalence was similar across race/ethnicity but higher in women. BRAF-mutant tumors were associated with poorer prognosis overall, especially among non-white patients. Among patients who had KRAS/NRAS/BRAF-WT tumors we observed no difference in OS by race or MSI. Among patients with KRAS-mutant tumors, Hispanic patients had more favorable prognosis adjusted hazards ratio (aHR) = 0.76 (0.65-0.89)) than their NHW counterparts. Among those with BRAF-mutant tumors, NHB patients had poorer prognosis than NHW patients (aHR:1.78 (1.08-2.93)). CONCLUSION: MSI and frequency of KRAS and BRAF mutations differed by demographics. Racial/ethnic disparities in OS differed by mutation. Future studies should explore biological and/or social determinants underlying these differences.

Outcomes of Antineoplastic Immunotherapy at a Large Healthcare Organization: Impact of Provider, Race and Socioeconomic Status.

Purpose: Disparities in cancer care delivery remain a pressing health-care crisis within the United States (US). The use of immune checkpoint inhibitors (ICIs) and their management may be a disparity generator that impacts survival. This retrospective study assessed disparities in a cohort of patients with a variety of solid tumors treated with ICIs within a single health-care organization focusing on the impact of race, socioeconomic status (SES) and site of care delivery on survival and the development of severe immune-related adverse events (irAEs). Patients and Methods: Manual chart review was performed on all patients with solid tumors treated with ICIs within a health-care organization from 2012 to 2018. Care delivery was dichotomized as DOP (disease-oriented provider at academic center) and COP (community oncology provider). Primary and secondary outcomes were overall survival (OS) and rates of grade 3-4 irAEs, respectively. Relationships with covariates of interest, including race, socioeconomic status and type of care delivery, were assessed among both outcomes. Results: A total of 1070 eligible patients were identified. Of those, 11.4% were of Black race, 59.7% had either non-small cell lung cancer (NSCLC) or melanoma and 82.8% had stage IV disease. Patients of Black race and lower SES were more likely to be treated by DOPs (p<0.0001). A superior OS was associated with care delivered by DOPs when compared to COPs (HR 0.68; 95% CI 0.56-0.84; p=0.0002), which was durable after accounting for race, SES, histopathologic diagnosis and disease stage. Melanoma patients experienced higher rates of severe irAEs (HR 2.37; 95% CI 1.42-3.97; p=0.001). Race, SES and site of care delivery were not related to rates of severe irAEs. Conclusion: In a large health-care organization, patients treated with checkpoint inhibitors by DOPs benefited from a significant OS advantage that was durable after controlling for racial and socioeconomic factors, providing evidence that disease-oriented care has the potential to mitigate racial and socioeconomic disparities.

Average treatment effect of facility hepatopancreatobiliary malignancy case volume on survival of patients with nonoperatively managed hepatobiliary malignancies.

BACKGROUND: Surgical volume-outcome relationships have been described for a variety of procedures. There is scant literature on total institutional volume and outcomes in patients who are nonoperatively managed. We examined the average treatment effect of total hepatopancreatobiliary malignancy case volume on survival outcomes of patients with nonresected hepatobiliary malignancies. METHODS: We identified patients with hepatopancreatobiliary malignancies [pancreatic adenocarcinoma, pancreatic neuroendocrine neoplasms, hepatocellular carcinoma, biliary tract cancers] within the National Cancer Database (2004-2018). We determined percentile thresholds based on the total annual hepatopancreatobiliary malignancy case volume. We then identified nonoperatively managed patients with hepatocellular carcinoma or biliary tract cancers. We used inverse probability-weighted Cox regression to estimate the effect of facility volume on overall survival. RESULTS: We identified 710,988 patients with hepatopancreatobiliary malignancies. Total annual hepatopancreatobiliary malignancy case volume of 32, 71, and 177 cases/year corresponded to the 25th, 50th, and 75th percentiles. A total of 96,420 with hepatocellular carcinoma and 52,627 patients with biliary tract cancers were managed nonoperatively. In patients with hepatocellular carcinoma or biliary tract cancer, treatment at ≥25th, ≥50th, and ≥75th percentile facilities was associated with improved median, 1-, 2-, and 3-year overall survival compared with treatment at lower-percentile facilities. On inverse probability-weighted Cox analysis, treatment at higher-percentile facilities resulted in a lower hazard of death. Consistent findings were observed in patients with early or intermediate/advanced hepatocellular carcinoma or metastatic biliary tract cancers. CONCLUSION: Patients with nonoperatively managed hepatocellular carcinoma or biliary tract cancer who receive treatment at higher-volume facilities have improved survival outcomes. These data suggest regionalization of care for patients with hepatocellular carcinoma or biliary tract cancer to high-volume centers may improve survival.

Differences in the surgical management of early-stage hepatocellular carcinoma at minority versus non-minority-serving hospitals.

BACKGROUND: We examined differences in surgical intervention at minority-serving hospitals versus non-minority-serving hospitals among patients with early-stage hepatocellular carcinoma. We also investigated associations between surgical management and overall survival, stratified by minority-serving hospital status. METHODS: Patients with early-stage hepatocellular carcinoma, defined as cT1, were identified within the National Cancer Database (2004-2018). The primary outcome was surgical intervention (resection, ablation, or transplantation). The proportion of minority (non-Hispanic Black or Hispanic) patients treated at each facility was determined, and hospitals in the top decile were considered minority-serving hospitals. RESULTS: A total of 46,703 patients with early-stage hepatocellular carcinoma were identified, of whom 4,214 (9.0%) were treated at minority-serving hospitals. Patients treated at minority-serving hospitals were less likely to undergo surgical intervention than patients treated at non-minority-serving hospitals (odds ratio = 0.87, 95% confidence interval: 0.81-0.94). Minority patients treated at non-minority-serving hospitals were less likely to undergo surgical intervention than White patients (odds ratio = 0.86, 95% confidence interval: 0.82-0.90) and had a further associated decrease in the likelihood of surgical intervention when treated at minority-serving hospitals (odds ratio = 0.81, 95% confidence interval: 0.69-0.94). Regardless of minority-serving hospital status, surgery was associated with improved overall survival. There were no clinically meaningful differences in overall survival between White and minority patients who underwent surgery either at minority-serving hospitals or non-minority-serving hospitals. CONCLUSIONS: Patients with early-stage hepatocellular carcinoma had an associated decrease in the likelihood of surgical intervention when treated at minority-serving hospitals. Minority patients treated at minority-serving hospitals had an associated decrease in the likelihood of surgery, but to a lesser extent when treated at non-minority-serving hospitals. Surgery was associated with improved overall survival regardless of minority or minority-serving hospital status.

The predictive impact of dual somatostatin receptor/fluorodeoxyglucose (FDG) positron emission tomography (PET) in metastatic gastroenteropancreatic neuroendocrine tumors (GEP-NETs): review of literature and a single institution experience.

Treatment with radiolabelled somatostatin analogs, a form of peptide receptor radionuclide therapy (PRRT), has changed the management of patients with advanced gastroenteropancreatic neuroendocrine tumors (GEP-NETs). There is a subgroup of patients who have suboptimal benefit and rapidly progress on PRRT, indicating that accurate prognostic and predictive markers are urgently needed. Currently, most of the literature concentrate on the prognostic impact of the dual positron emission tomography (PET) scan with very few information regarding the predictive value. We report a case series and review the literature to summarizes the predictive value of combined somatostatin receptor (SSTR) and fluorodeoxyglucose (FDG) PET in metastatic GEP-NETs. We conducted a review of the literature for data published from 2010 to 2021 in MEDLINE, Embase, the National Institutes of Health trial registry, Cochrane CENTRAL, and published proceedings from major gastrointestinal and neuroendocrine cancer meetings. Our main criteria included all published prospective and retrospective data in which the predictive value of dual PET scans using SSTR and FDG was correlated with PRRT response in patients with metastatic GEP-NETs. We summarized clinical outcomes including progression-free survival (PFS), overall survival (OS), and post-therapy complications associated with PRRT according to FDG avidity. We excluded studies that did not include FDG PET scan, GEP patients, studies with no clear predictive value of the FDG PET scan, and studies that did not report a direct correlation between FDG avidity and primary outcome. Additionally, we summarized our institutional experience in eight patients who progressed during or within the first year of PRRT treatment. Our search identified 1306 articles; most of them showed only the prognostic value of Integrated SSTR/FDG PET imaging biomarker in GEP-NETs. Only three studies (n=75 patients) met our inclusion criteria and retrospectively investigated the predictive value of dual SSTR and FDG imaging in subjects being considered for PRRT. The results confirmed that FDG avidity correlates with advanced NET grades. Lesions that are both SSTR and FDG avid had early disease progression. In one study, at multivariate analysis, FDG PET results were independently predictive of lower PFS for PRRT. In our case series, there were eight patients with metastatic well-differentiated GEP-NETs (grades 2 and 3) who progressed within one year of PRRT. Seven of them had positive FDG PET scan at the time of progression. In conclusion, Dual SSTR/FDG PET imaging has a potential predictive impact for PRRT in GEP-NETs. It permits the capturing of the disease complexity and aggressiveness, which correlates with PRRT response. Therefore, prospective future trials should validate the predictive value of dual SSTRs/FDG PET for better PRRT stratification.

Thymoquinone Plus Immunotherapy in Extra-Pulmonary Neuroendocrine Carcinoma: Case Series for a Novel Combination.

BACKGROUND: Neuroendocrine neoplasms (NENs) are a heterogeneous group of cancers that had a significant increase in annual incidence in the last decade. They can be divided into well-differentiated neuroendocrine tumors (NETs) and poorly differentiated neuroendocrine carcinomas (NECs). Poorly differentiated NECs are aggressive forms of cancers with limited therapeutic options. The first line treatment of metastatic poorly differentiated NECs is similar to small cell lung cancer, with cytotoxic chemotherapy (etoposide plus platinum). Patients who progress have limited therapeutic options and poor overall survival, calling for other novel agents to combat this deadly disease. Therefore, in this article, we summarized the effects of a novel component, Thymoquinone (TQ, C10H12O2), which is the main bioactive component of the black seed (Nigella sativa, Ranunculaceae family), plus immunotherapy in case series of patients with refractory metastatic extra-pulmonary NEC (EP-NEC) and one case of mixed neuroendocrine-non-neuroendocrine neoplasm (MiNEN). METHODS: We report the effect of TQ plus dual immune checkpoint inhibitors (nivolumab plus ipilimumab) in four patients with poorly differentiated gastrointestinal Ep-NEC and MiNEN who progressed on cytotoxic chemotherapy. RESULTS: This is the first case series to report the clinical activity of TQ plus dual immune checkpoint inhibitors (nivolumab plus ipilimumab) in patients with refractory metastatic EP-NEC. The four patients showed benefits with the combined regimen TQ plus dual ICPIs with durable response and exceeded the two years of progression-free survival. None of the four patients experienced significant toxicity, and all of them showed improvement in quality of life. CONCLUSION: The reported clinical courses suggest that combined TQ plus ICPIs is a potential promising regimen for refractory EP-NEC and MiNEN that deserves further prospective investigation.

Management of Appendix Neuroendocrine Neoplasms: Insights on the Current Guidelines.

Appendiceal neuroendocrine neoplasms (ANENs) usually present as incidental findings at the time of appendectomy for acute appendicitis. They are rare, accounting for only 0.5-1% of intestinal neoplasms; they are found in 0.3-0.9% of all appendectomy specimens. They are usually sporadic tumors. There are several histological types including well-differentiated neuroendocrine tumors (NETs), poorly differentiated neuroendocrine carcinomas (NECs), and mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs). Histologic differentiation and the grade of well-differentiated NETs correlate with clinical behavior and prognosis. Management varies based on differentiation, aggressiveness, and metastatic potential. There is debate about the optimal surgical management for localized appendiceal NETs that are impacted by many factors including the tumor size, the extent of mesoappendiceal spread, lymphovascular invasion and perineural involvement. In addition, the data to guide therapy in metastatic disease are limited due to the paucity of these tumors. Here, we review the current advances in the management of ANENs within the context of a multidisciplinary approach to these tumors.