Physical exercise in liver diseases.

Liver diseases contribute to ~2 million deaths each year and account for 4% of all deaths globally. Despite various treatment options, the management of liver diseases remains challenging. Physical exercise is a promising nonpharmacological approach to maintain and restore homeostasis and effectively prevent and mitigate liver diseases. In this review, we delve into the mechanisms of physical exercise in preventing and treating liver diseases, highlighting its effects on improving insulin sensitivity, regulating lipid homeostasis, and modulating immune function. In addition, we evaluate the impact of physical exercise on various liver diseases, including liver ischemia/reperfusion injury, cardiogenic liver disease, metabolic dysfunction-associated steatotic liver disease, portal hypertension, cirrhosis, and liver cancer. In conclusion, the review underscores the effectiveness of physical exercise as a beneficial intervention in combating liver diseases.

Neutrophil extracellular traps promote MASH fibrosis by metabolic reprogramming of HSC.

BACKGROUND AND AIMS: Metabolic dysfunction-associated steatohepatitis (MASH) fibrosis is a reversible stage of liver disease accompanied by inflammatory cell infiltration. Neutrophils extrude a meshwork of chromatin fibers to establish neutrophil extracellular traps (NETs), which play important roles in inflammatory response regulation. Our previous work demonstrated that NETs promote HCC in MASH. However, it is still unknown if NETs play a role in the molecular mechanisms of liver fibrosis. APPROACH AND RESULTS: Following 12 weeks of Western diet/carbon tetrachloride, MASH fibrosis was identified in C57BL/6 mice with increased NET formation. However, NET depletion using DNase I treatment or mice knocked out for peptidyl arginine deaminase type IV significantly attenuated the development of MASH fibrosis. NETs were demonstrated to induce HSCs activation, proliferation, and migration through augmented mitochondrial and aerobic glycolysis to provide additional bioenergetic and biosynthetic supplies. Metabolomic analysis revealed markedly an altered metabolic profile upon NET stimulation of HSCs that were dependent on arachidonic acid metabolism. Mechanistically, NET stimulation of toll-like receptor 3 induced cyclooxygenase-2 activation and prostaglandin E2 production with subsequent HSC activation and liver fibrosis. Inhibiting cyclooxygenase-2 with celecoxib reduced fibrosis in our MASH model. CONCLUSIONS: Our findings implicate NETs playing a critical role in the development of MASH hepatic fibrosis by inducing metabolic reprogramming of HSCs through the toll-like receptor 3/cyclooxygenase-2/cyclooxygenase-2 pathway. Therefore, NET inhibition may represent an attractive treatment target for MASH liver fibrosis.

Recommendations on Robotic Hepato-Pancreato-Biliary Surgery. The Paris Jury-Based Consensus Conference.

OBJECTIVE: To establish the first consensus guidelines on the safety and indications of robotics in Hepato-Pancreatic-Biliary (HPB) surgery. The secondary aim was to identify priorities for future research. SUMMARY BACKGROUND DATA: HPB robotic surgery is reaching the IDEAL 2b exploration phase for innovative technology. An objective assessment endorsed by the HPB community is timely and needed. METHODS: The ROBOT4HPB conference developed consensus guidelines using the Zurich-Danish model. An impartial and multidisciplinary jury produced unbiased guidelines based on the work of ten expert panels answering predefined key questions and considering the best-quality evidence retrieved after a systematic review. The recommendations conformed with the GRADE and SIGN50 methodologies. RESULTS: Fifty-four experts from 20 countries considered 285 studies, and the conference included an audience of 220 attendees. The jury (n=10) produced recommendations or statements covering five sections of robotic HPB surgery: technology, training and expertise, outcome assessment, and liver and pancreatic procedures. The recommendations supported the feasibility of robotics for most HPB procedures and its potential value in extending minimally invasive indications, emphasizing however the importance of expertise to ensure safety. The concept of expertise was defined broadly, encompassing requirements for credentialing HPB robotics at a given center. The jury prioritized relevant questions for future trials and emphasized the need for prospective registries, including validated outcome metrics for the forthcoming assessment of HPB robotics. CONCLUSION: The ROBOT4HPB consensus represents a collaborative and multidisciplinary initiative, defining state-of-the-art expertise in HPB robotics procedures. It produced the first guidelines to encourage their safe use and promotion.

Survival benefit associated with screening of patients at elevated risk for pancreatic cancer.

BACKGROUND & OBJECTIVES: Screening for pancreatic cancer is recommended for individuals with a strong family history, certain genetic syndromes, or a neoplastic cyst of the pancreas. However, limited data supports a survival benefit attributable to screening these higher-risk individuals. METHODS: All patients enrolled in screening at a High-Risk Pancreatic Cancer Clinic (HRC) from July 2013 to June 2020 were identified from a prospectively maintained institutional database and compared to patients evaluated at a Surgical Oncology Clinic (SOC) at the same institution during the same period. Clinical outcomes of patients selected for surgical resection, particularly clinicopathologic stage and overall survival, were compared. RESULTS: Among 826 HRC patients followed for a median (IQR) of 2.3 (0.8-4.2) years, 128 were selected for surgical resection and compared to 402 SOC patients selected for resection. Overall survival was significantly longer among HRC patients (median survival: not reached vs. 2.6 years, p < 0.001). Among 31 HRC and 217 SOC patients with a diagnosis of pancreatic ductal adenocarcinoma (PDAC), the majority of HRC patients were diagnosed with stage 0 disease (carcinoma in situ), while the majority of SOC patients were diagnosed with stage II disease (p < 0.001). Overall survival after resection of invasive PDAC was also significantly longer among HRC patients compared to SOC patients (median survival 5.5 vs. 1.6 years, p = 0.002). CONCLUSION: Patients at increased risk for PDAC and followed with guideline-based screening exhibited downstaging of disease and improved survival from PDAC in comparison to patients who were not screened.

Surgery-mediated tumor-promoting effects on the immune microenvironment.

Surgical resection continues to be the mainstay treatment for solid cancers even though chemotherapy and immunotherapy have significantly improved patient overall survival and progression-free survival. Numerous studies have shown that surgery induces the dissemination of circulating tumor cells (CTCs) and that the resultant inflammatory response promotes occult tumor growth and the metastatic process by forming a supportive tumor microenvironment (TME). Surgery-induced platelet activation is one of the initial responses to a wound and the formation of fibrin clots can provide the scaffold for recruited inflammatory cells. Activated platelets can also shield CTCs to protect them from blood shear forces and promote CTCs evasion of immune destruction. Similarly, neutrophils are recruited to the fibrin clot and enhance cancer metastatic dissemination and progression by forming neutrophil extracellular traps (NETs). Activated macrophages are also recruited to surgical sites to facilitate the metastatic spread. More importantly, the body's response to surgical insult results in the recruitment and expansion of immunosuppressive cell populations (i.e. myeloid-derived suppressor cells and regulatory T cells) and in the suppression of natural killer (NK) cells that contribute to postoperative cancer recurrence and metastasis. In this review, we seek to provide an overview of the pro-tumorigenic mechanisms resulting from surgery's impact on these cells in the TME. Further understanding of these events will allow for the development of perioperative therapeutic strategies to prevent surgery-associated metastasis.

Disparities in Care Access to Liver-Directed Therapy Among Medicare Beneficiaries with Colorectal Cancer Liver Metastasis.

BACKGROUND: Liver-directed therapies (LDT) are important components of the multidisciplinary care of patients with colorectal cancer liver metastases (CRCLM) that contribute to improved long-term outcomes. Factors associated with receipt of LDT are poorly understood. PATIENTS AND METHODS: Patients > 65 years old diagnosed with CRCLM were identified within the Medicare Standard Analytic File (2013-2017). Patients with extrahepatic metastatic disease were excluded. Mixed-effects analyses were used to assess patient factors associated with the primary outcome of LDT, defined as hepatectomy, ablation, and/or hepatic artery infusion chemotherapy (HAIC), as well as the secondary outcome of hepatectomy. RESULTS: Among 23,484 patients with isolated CRCLM, only 2004 (8.5%) received LDT, although resectability status could not be determined for the entire cohort. Among patients who received LDT, 61.7% underwent hepatectomy alone, 28.1% received ablation alone, 8.5% underwent hepatectomy and ablation, and 1.8% received HAIC either alone (0.8%) or in combination with hepatectomy and/or ablation (0.9%). Patient factors independently associated with lower odds of LDT included older age, female sex, Black race, greater comorbidity burden, higher social vulnerability index, primary rectal cancer, synchronous liver metastasis, and further distance from a high-volume liver surgery center (p < 0.05). Results were similar for receipt of hepatectomy. CONCLUSIONS: Despite the well-accepted role of LDT for CRCLM, only a small proportion of Medicare beneficiaries with CRCLM receive LDT. Increasing access to specialized centers with expertise in LDT, particularly for Black patients, female patients, and those with higher levels of social vulnerability or long travel distances, may improve outcomes for patients with CRCLM.

Modified Radical Mastectomy in De Novo Stage IV Inflammatory Breast Cancer.

BACKGROUND: There are few studies on surgical management in patients with de novo metastatic inflammatory breast cancer (IBC). The objective of this study is to examine the association between modified radical mastectomy (MRM) and disease-specific survival (DSS) in patients with de novo stage IV IBC. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Result Program was queried for patients ≥18 years old with cT4d/pT4d pathology, histology type 8530 and 8533 with distant disease between 2010 and 2016. The sample was divided into two groups: (1) the MRM group, defined as MRM or mastectomy with at least ten lymph nodes removed, and (2) the no-surgery group. Sociodemographic and clinical variables were compared between the groups on bivariable analysis. After propensity score matching, Kaplan-Meier curves and a Cox proportional-hazards model examined DSS. RESULTS: 1293 patients were included in the study, of whom 240 underwent MRM. A higher percentage in the MRM group had only one metastatic site (69.8% versus 52.2%), received chemotherapy (88.3% versus 66.1%) and radiation (58.8% versus 26.0%) compared with the no-MRM group. MRM was associated with an increase in DSS compared with no MRM [HR 0.63 (95% CI 0.50-0.80), p < 0.001]. Patients with MRM had a 5-year DSS rate of 31.4% compared with 17.7% for patients not undergoing surgery (p = 0.001). Survival time was 38 months (range 27-45 months) for the MRM group versus 27 months (22-29 months) for the no-MRM group. CONCLUSION: MRM in patients with de novo metastatic IBC may improve DSS in a subset of patients.

Surgery Refusal Among Black and Hispanic Women with Non-Metastatic Breast Cancer.

BACKGROUND: Studies have shown a lower receipt of treatment among minority women with non-metastatic breast cancer. Those who refuse surgery have increased disease-specific mortality, contributing to disproportionately higher breast cancer mortality in non-Hispanic black (NHB) and Hispanic women. This study aimed to assess surgery refusal in these groups, identify factors associated with surgery refusal, and characterize the association between surgery refusal and survival. METHODS: Surveillance, Epidemiology, and End Results (SEER) Program data from 2005 to 2015 for NHB and Hispanic women with a diagnosis of non-metastatic breast cancer (n = 113,987) was divided into data of those who underwent surgery and data of those who refused surgery. Sociodemographic and tumor clinical/pathologic differences were analyzed by multivariate logistic regression of predictors of surgery refusal and Cox-proportional hazard model of disease-specific mortality. RESULTS: Of 799 patients who refused surgery, 562 were NHB and 237 were Hispanic. The percentage of patients refusing surgery increased from 0.6% in 2005 to 0.9% in 2015. The women who refused surgery were more likely to be older than 81 years, less likely to be married, and more likely to be uninsured or have Medicaid. The refusers presented with more advanced disease and more frequent estrogen receptor-positivity (ER+) and progesterone receptor-positivity (PR+) subtype on histology. Breast cancer-specific mortality increased significantly with surgery omission. Surgery refusal was independently associated with NHB race. CONCLUSION: Surgery refusal among NHB and Hispanic women with potentially curable non-metastatic breast cancer is rising, especially among NHB women, women older than 60 years, single women, and women with a later stage of disease at diagnosis. Additional studies are needed to analyze qualitative data in these populations and their underlying health beliefs, communication needs, and possible use of alternative medicine.

Access Denied: Inequities in Clinical Trial Enrollment for Pancreatic Cancer.

BACKGROUND: The influence of social determinants of health (SDH) on participation in clinical trials for pancreatic cancer is not well understood. In this study, we describe trends and identify disparities in pancreatic cancer clinical trial enrollment. PATIENTS AND METHODS: This is a retrospective study of stage I-IV pancreatic cancer patients in the 2004-2016 National Cancer Database. Cohort was stratified into those enrolled in clinical trials during first course of treatment versus not enrolled. Bivariate analysis and logistic regression were used to understand the relationship between SDH and clinical trial participation. RESULTS: A total of 1127 patients (0.4%) enrolled in clinical trials versus 301,340 (99.6%) did not enroll. Enrollment increased over the study period (p < 0.001), but not for Black patients or patients on Medicaid. The majority enrolled had metastatic disease (65.8%). On multivariate analysis, in addition to year of diagnosis (p < 0.001), stage (p < 0.001), and Charlson score (p < 0.001), increasing age [odds ratio (OR) 0.96, 95% confidence interval (CI) 0.96-0.97], non-white race (OR 0.54, CI 0.44-0.66), living in the South (OR 0.42, CI 0.35-0.51), and Medicaid, lack of insurance, or unknown insurance (0.41, CI 0.31-0.53) were predictors of lack of participation. Conversely, treatment at an academic center (OR 6.36, CI 5.4-7.4) and higher neighborhood education predicted enrollment (OR 2.0, CI 1.55-2.67 for < 7% with no high school degree versus > 21%). DISCUSSION: Age, race, insurance, and geography are barriers to clinical trial enrollment for pancreatic cancer patients. While overall enrollment increased, Black patients and patients on Medicaid remain underrepresented. After adjusting for cancer-specific factors, SDH are still associated with clinical trial enrollment, suggesting need for targeted interventions.

Surgical resection rates after neoadjuvant therapy for localized pancreatic ductal adenocarcinoma: meta-analysis.

BACKGROUND: Neoadjuvant therapy is increasingly being used before surgery for localized pancreatic cancer. Given the importance of completing multimodal therapy, the aim of this study was to characterize surgical resection rates after neoadjuvant therapy as well as the reasons for, and long-term prognostic impact of, not undergoing resection. METHODS: A systematic review and meta-analysis of prospective trials and high-quality retrospective studies since 2010 was performed to calculate pooled resection rates using a generalized random-effects model for potentially resectable, borderline resectable, and locally advanced pancreatic cancer. Median survival times were calculated using random-effects models for patients who did and did not undergo resection. RESULTS: In 125 studies that met the inclusion criteria, neoadjuvant therapy consisted of chemotherapy (36.8 per cent), chemoradiation (15.2 per cent), or chemotherapy and radiation (48.0 per cent). Among 11 713 patients, the pooled resection rates were 77.4 (95 per cent c.i. 71.3 to 82.5), 60.6 (54.8 to 66.1), and 22.2 (16.7 to 29.0) per cent for potentially resectable, borderline resectable, and locally advanced pancreatic cancer respectively. The most common reasons for not undergoing resection were distant progression for resectable and borderline resectable cancers, and local unresectability for locally advanced disease. Among 42 studies with survival data available, achieving surgical resection after neoadjuvant therapy was associated with improved survival for patients with potentially resectable (median 38.5 versus 13.3 months), borderline resectable (32.3 versus 13.9 months), and locally advanced (30.0 versus 14.6 months) pancreatic cancer (P < 0.001 for all). CONCLUSION: Although rates of surgical resection after neoadjuvant therapy vary based on anatomical stage, surgery is associated with improved survival for all patients with localized pancreatic cancer. These pooled resection and survival rates may inform patient-provider decision-making and serve as important benchmarks for future prospective trials.

Proceedings From the Advances in Surgery Channel Diversity, Equity, and Inclusion Series: Lessons Learned From Asian Academic Surgeons.

In this series of talks and the accompanying panel session, leaders from the Society of Asian Academic Surgeons discuss issues faced by Asian Americans and the importance of the role of mentors and allyship in professional development in the advancement of Asian Americans in leadership roles. Barriers, including the model minority myth, are addressed. The heterogeneity of the Asian American population and disparities in healthcare and in research, specifically as relates to Asian Americans, also are examined.

Neighborhood socioeconomic status and low-value breast cancer care.

BACKGROUND: The objective of this study is to examine the association between neighborhood socioeconomic status (nSES) and receipt of low-value breast cancer procedures. METHODS: Patients with breast cancer diagnosed between 2010 and 2016 were identified in the Surveillance, Epidemiology, and End Results (SEER) Program. Low value procedures included: (1) axillary lymph node dissection (ALND) for patients with limited nodal disease receiving breast conservation therapy (BCT); (2) contralateral prophylactic mastectomies (CPM); and (3) sentinel lymph node biopsies (SLNB) in patients ≥70 years old with clinically node negative early-stage hormone-positive breast cancer. The cohort was divided by nSES. Univariable and multivariable logistic regression analysis compared the groups. RESULTS: The study included 412 959 patients. Compared to patients in high nSES areas, residing in neighborhoods with low nSES (odd ratio [OR] 2.20, 95% confidence interval [CI] 2.0-2.42) and middle nSES (OR 1.42, 95% CI 1.20-1.56) was associated with a higher probability of undergoing low value ALND. Conversely, patients in low SES neighborhoods were less likely to receive low value SLNB (OR 0.89, 95% CI 0.85-0.94) or CPM than (low nSES OR 0.75, 95% CI 0.73-0.77); middle nSES OR 0.91 (0.89-0.92) those in high SES neighborhoods. CONCLUSION: In the SEER Program, low nSES was associated with a lower probability of low value procedures except for ALND utilization.

Constitutively Active Androgen Receptor in Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the predominant type of liver cancer and a leading cause of cancer-related death globally. It is also a sexually dimorphic disease with a male predominance both in HCC and in its precursors, non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH). The role of the androgen receptor (AR) in HCC has been well documented; however, AR-targeted therapies have failed to demonstrate efficacy in HCC. Building upon understandings of AR in prostate cancer (PCa), this review examines the role of AR in HCC, non-androgen-mediated mechanisms of induced AR expression, the existence of AR splice variants (AR-SV) in HCC and concludes by surveying current AR-targeted therapeutic approaches in PCa that show potential for efficacy in HCC in light of AR-SV expression.

Multi-specialty physician perspectives on barriers and facilitators to the use of neoadjuvant therapy for pancreatic ductal adenocarcinoma.

BACKGROUND: Neoadjuvant therapy (NT) is increasingly utilized for patients with localized pancreatic ductal adenocarcinoma (PDAC). Given the importance of completing multimodality therapy, the purpose of this qualitative study was to characterize physician perspectives on barriers and facilitators to delivering NT. METHODS: A purposive sample of surgical, medical, and radiation oncologists participated in semi-structured interviews. Interviews were transcribed and coded by 3 independent researchers, iteratively identifying themes until saturation was achieved. RESULTS: Participants (n = 27) were heterogeneous in specialty, years of experience, practice setting, gender, and geography. The most commonly cited advantage of NT was the ability to downstage patients. The most commonly cited barriers included lack of access and limited evidence. Patient preference for immediate surgery was frequently cited as a barrier, but most participants felt that patients eventually understood the treatment recommendation after informed discussion. Recommendations to enhance the delivery of NT included improved patient education, communication, and better evidence. CONCLUSION: In this qualitative study, indications for, barriers to, and opportunities to improve the delivery of NT for localized PDAC were identified. These results highlight the need for better evidence and protocol standardization for NT as well as methods of improving care coordination, communication, and education to improve patient-centered outcomes.

Variation in outcomes across surgeons meeting the Leapfrog volume standard for complex oncologic surgery.

BACKGROUND: A large body of evidence supports regionalization of complex oncologic surgery to high-volume surgeons at high-volume hospitals. However, whether there is heterogeneity of outcomes among high-volume surgeons at high-volume hospitals remains unknown. METHODS: Patients who underwent esophagectomy, lung resection, pancreatectomy, or proctectomy for primary cancer were identified within the Medicare 100% Standard Analytic File (2013-2017). Mixed-effects analyses assessed the association between Leapfrog annual volume standards for surgeons (esophagectomy ≥7, lung resection ≥15, pancreatectomy ≥10, proctectomy ≥6) and hospitals (esophagectomy ≥20, lung resection ≥40, pancreatectomy ≥20, proctectomy ≥16) relative to postoperative complications and 90-day mortality. Additional analyses using New York's all-payer Statewide Planning and Research Cooperative System (2004-2015) were performed. RESULTS: Among 112,154 Medicare beneficiaries, high-volume surgeons at high-volume hospitals were associated with lower adjusted odds of complications (esophagectomy: odds ratio [OR], 0.73 [95% CI, 0.61-0.86]; lung resection: OR, 0.88 [95% CI, 0.82-0.94]; pancreatectomy: OR, 0.73 [95% CI, 0.66-0.80]; proctectomy: OR, 0.92 [95% CI, 0.85-0.99]) and 90-day mortality (esophagectomy: OR, 0.60 [95% CI, 0.44-0.76]; lung resection: OR, 0.82 [95% CI, 0.73-0.93]; pancreatectomy: OR, 0.66 [95% CI, 0.56-0.76]; proctectomy: OR, 0.74 [95% CI, 0.65-0.85]). For the average patient at the average high-volume hospital, there was a 2-fold difference in the adjusted complication rate between the best-performing and worst-performing high-volume surgeon for all operations (esophagectomy, 28%-55%; lung resection, 7%-21%; pancreatectomy, 16%-35%; proctectomy, 16%-28%). Wide variation was also present in adjusted 90-day mortality for esophagectomy (3.5%-9.3%). Results from New York's all-payer database were similar. CONCLUSIONS: Even among high-volume surgeons meeting the Leapfrog volume standards, wide variation in postoperative outcomes exists. These findings suggest that volume alone should not be used as a quality indicator, and quality metrics should be continuously evaluated across all surgeons and hospital systems. LAY SUMMARY: Previous studies have demonstrated a surgical volume-outcome relationship for high-risk operations-that is high-volume surgeons and hospitals that perform a specific surgical procedure more frequently have better outcomes for that operation. Although most high-volume surgeons had better outcomes, this study demonstrated that some high-volume surgeons did not have better outcomes. Therefore, volume is an important factor but should not be the only factor considered when assessing the quality of a surgeon and a hospital for cancer surgery.

Regulatory T-cell and neutrophil extracellular trap interaction contributes to carcinogenesis in non-alcoholic steatohepatitis.

BACKGROUND & AIMS: Regulatory T-cells (Tregs) impair cancer immunosurveillance by creating an immunosuppressive environment that fosters tumor cell survival. Our previous findings demonstrated that neutrophil extracellular traps (NETs), which are involved both in innate and adaptive immunity, are abundant in livers affected by non-alcoholic steatohepatitis (NASH). However, how NETs interact with Tregs in the development of NASH-associated hepatocellular carcinoma (NASH-HCC) is not known. METHODS: A choline-deficient, high-fat diet+diethylnitrosamine mouse model and the stelic animal model were utilized for NASH-HCC and a western diet mouse model was used for NASH development. Treg depletion was achieved using FoxP3-DTR mice. RNA sequencing was used to explore the mechanism by which NETs could regulate Treg differentiation. Bioenergetic analyses of naïve CD4+ T-cells were assessed by Seahorse. RESULTS: Although the absolute number of CD4+ T-cells is lower in NASH livers, the Treg subpopulation is selectively increased. Depleting Tregs dramatically inhibits HCC initiation and progression in NASH. There is a positive correlation between increased NET and hepatic Treg levels. RNA sequencing data reveals that NETs impact gene expression profiles in naïve CD4+ T-cells, with the most differentially expressed genes being those involved in mitochondrial oxidative phosphorylation. By facilitating mitochondrial respiration, NETs can promote Treg differentiation. Metabolic reprogramming of naïve CD4+ T-cells by NETs requires toll-like receptor 4. Blockade of NETs in vivo using Pad4-/- mice or DNase I treatment reduces the activity of Tregs. CONCLUSIONS: Tregs can suppress immunosurveillance in the premalignant stages of NASH. NETs facilitate the crosstalk between innate and adaptive immunity in NASH by promoting Treg activity through metabolic reprogramming. Therapies targeting NETs and Treg interactions could offer a potential strategy for preventing HCC in patients with NASH. LAY SUMMARY: Regulatory T-cells (Tregs) can promote tumor development by suppressing cancer immunosurveillance, but their role in carcinogenesis during non-alcoholic steatohepatitis (NASH) progression is unknown. Herein, we discovered that selectively increased intrahepatic Tregs can promote an immunosuppressive environment in NASH livers. Neutrophil extracellular traps (NETs) link innate and adaptive immunity by promoting Treg differentiation via metabolic reprogramming of naïve CD4+ T-cells. This mechanism could be targeted to prevent liver cancer in patients with NASH.

Time to Surgery and Colon Cancer Survival in the United States.

PURPOSE: Time to surgery (TTS) is of concern to patients diagnosed with cancer and their physicians. Controversy surrounds the impact of TTS on colon cancer survival. There are limited national data evaluating the association; thus, our aim was to estimate the overall survival (OS) impact from increasing TTS for patients with colon cancer. METHODS: Using the National Cancer Data Base (NCDB), we assessed OS as a function of time between diagnosis and surgery by evaluating intervals encompassing <7, 7 to 30, 31 to 60, 61 to 90, 91 to 120, and 121 to 180 days in length. All patients were diagnosed with nonmetastatic colon cancer and underwent surgery as initial treatment. Our main outcome was OS as a function of time between diagnosis and surgery, after adjusting for patient, demographic, and tumor-related factors using Cox regression models and propensity score-based weighting. RESULTS: A total of 514,103 patients diagnosed between 1998 and 2012 were included. Individuals having <7, 7 to 30, 31 to 60, 61 to 90, 91 to 120, and 121 to 180 days between diagnosis and surgery comprised 35.4%, 45%, 15.1%, 2.9%, 1%, and 0.6% of the patients, respectively. There was a steady increase in median TTS across the years. On multivariable analysis, TTS >30 days or within the first week independently increased mortality risk. There was a significant increase in mortality with TTS 31 to 60 [hazard ratio (HR) 1.13], 61 to 90 (HR 1.49), <7 (HR 1.56), 91 to 120 (HR 2.28), and 121 to 180 (HR 2.46) compared to surgery performed 7 to 30 days after diagnosis (P < 0.001). CONCLUSIONS: TTS is independently associated with OS and this represents a public health issue that should be addressed at a national level. Although time is required for evaluation before surgery, efforts to reduce TTS should be pursued.

Hormone receptor-positive breast cancer and black race: does sex matter?

PURPOSE: Black breast cancer patients have worse clinical outcomes than their White counterparts. There are few studies comparing clinical outcomes between Black male breast cancer (MBC) and female breast cancer (FBC) patients. The objective of this study is to examine differences in presentation, treatment, and mortality between Black MBC and FBC. METHODS: The National Cancer Database was queried for all Black MBC and FBC patients, ages 18-90, with hormone receptor-positive breast cancer diagnosed between 2010 and 2016. Hormone receptor positivity was defined as estrogen receptor-positive, progesterone-positive and HER 2-negative cancer. Sociodemographic and clinical variables were compared between MBC and FBC patients on bivariable analysis. After propensity score matching, overall survival was evaluated using the log-rank test and Cox proportional hazards. RESULTS: Compared to FBC patients, MBC patients had higher rates of metastatic disease (stage 4, MBC 4.4% vs. FBC 2.6%, p < 0.001), larger tumors (tumor size < 2 cm, MBC 32.1 vs. FBC 49.1%, p < 0.001) and a higher percentage of poorly differentiated tumors (grade 3, MBC 28.5% vs. FBC 21.4%, p < 0.001). MBC patients had lower rates of hormone therapy (MBC 66.4% vs. FBC 80.7%, p < 0.001) and neoadjuvant chemotherapy (MBC 5.8% vs. FBC 7.5%, p = 0.05) than FBC. On propensity score matched analysis, Black MBC patients had a higher overall mortality (p25 of 60 months vs. 74 months) compared to FBC patients (p = 0.0260). CONCLUSION: Among hormone receptor-positive Black MBC and FBC patients, there are sex-based disparities in stage, hormone therapy use and overall survival.

Is Textbook Oncologic Outcome a Valid Hospital-Quality Metric after High-Risk Surgical Oncology Procedures?

BACKGROUND: "Textbook oncologic outcome" (TOO) is a composite quality measure representing the "ideal" outcome for patients undergoing cancer surgery. This study sought to assess the validity of TOO as a metric to evaluate hospital quality. METHODS: Patients who underwent curative-intent resection of gastric, pancreatic, colon, rectal, lung, esophageal, bladder, or ovarian cancer were identified in the National Cancer Database (2006-2017). Cancer site-specific TOO was defined as adequate lymph node yield, R0 resection, non-length-of-stay outlier, no hospital readmission, and receipt of guideline-concordant chemotherapy and/or radiation. Mixed-effects analyses estimated the adjusted TOO rate for each hospital stratified by cancer site. The association between hospital adjusted TOO rates and 5-year overall survival was assessed using mixed-effects Cox proportional hazards analyses. RESULTS: Among 852,988 cancer resections, the TOO rate varied across cancer sites as follows: stomach (31.8%), pancreas (25%), colon (66.9%), rectum (33.6%), lung (35.1%), esophagus (31.2%), bladder (43%), and ovary (44.7%). After characterization of adjusted hospital TOO rates into quintiles, an incremental improvement in overall survival was observed, with higher adjusted TOO rates. Similarly, with the adjusted hospital TOO rate treated as a continuous variable, there was a significant 4% to 12% improvement in overall survival for every 10% increase in the adjusted hospital TOO rate for gastric (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.85-0.91), pancreatic (HR, 0.90; 95% CI, 0.88-0.93), colon (0.93; 95% CI, 0.91-0.94), rectal (HR, 0.90; 95% CI, 0.87-0.93), lung (HR, 0.96; 95% CI, 0.95-0.97), esophageal (HR, 0.93; 95% CI, 0.90-0.95), bladder (HR, 0.94; 95% CI, 0.91-0.97), and ovarian (HR, 0.96; 95% CI, 0.94-0.98) cancer. CONCLUSIONS: A direct association exists between adjusted hospital TOO rates and survival after high-risk cancer procedures. As a valid hospital metric, TOO can be used to compare the overall quality of cancer care across hospitals.

Racial Differences in Response to Neoadjuvant Chemotherapy: Impact on Breast and Axillary Surgical Management.

BACKGROUND: Neoadjuvant chemotherapy (NAC), an increasingly used method for breast cancer patients, has the potential to downstage patient tumors and thereby have an impact on surgical options for treatment of the breast and axilla. Previous studies have identified racial disparities in tumor heterogeneity, nodal recurrence, and NAC completion. This report compares the effects of NAC response among non-Hispanic white women and black women in relation to surgical treatment of the breast and axilla. METHODS: A retrospective review of 85,303 women with stages 1 to 3 breast cancer in the National Cancer Database who received NAC between 1 January 2010 and 31 December 2016 was conducted. Differences in sociodemographic and clinical variables between black patients and white patients with breast cancer were tested. RESULTS: The study identified 68,880 non-Hispanic white and 16,423 non-Hispanic black women who received NAC. The average age at diagnosis was 54.8 years for the white women versus 52.5 years for the black women. A higher proportion of black women had stage 3 disease, more poorly differentiated tumors, and triple-negative subtype. The black women had lower rates of complete pathologic response, more breast-conservation surgery, and higher rates of axillary lymph node dissection, but fewer sentinel lymph node biopsies. Axillary management for the women who were downstaged showed more use of axillary lymph node dissection for black women compared with sentinel lymph node biopsy. CONCLUSIONS: The black patients were younger at diagnosis, had more advanced disease, and were more likely to have breast-conservation surgery. De-escalating axillary surgery is being adopted increasingly but used disproportionately for white women.