Desmoglein 2 Functions as a Receptor for Fatty Acid Binding Protein 4 in Breast Cancer Epithelial Cells.

Fatty acid binding protein 4 (FABP4) is a secreted adipokine linked to obesity and progression of a variety of cancers. Obesity increases extracellular FABP4 (eFABP4) levels in animal models and in obese breast cancer patients compared with lean healthy controls. Using MCF-7 and T47D breast cancer epithelial cells, we show herein that eFABP4 stimulates cellular proliferation in a time and concentration dependent manner while the non-fatty acid-binding mutant, R126Q, failed to potentiate growth. When E0771 murine breast cancer cells were injected into mice, FABP4 null animals exhibited delayed tumor growth and enhanced survival compared with injections into control C57Bl/6J animals. eFABP4 treatment of MCF-7 cells resulted in a significant increase in phosphorylation of extracellular signal-regulated kinase 1/2 (pERK), transcriptional activation of nuclear factor E2-related factor 2 (NRF2) and corresponding gene targets ALDH1A1, CYP1A1, HMOX1, SOD1 and decreased oxidative stress, while R126Q treatment did not show any effects. Proximity-labeling employing an APEX2-FABP4 fusion protein revealed several proteins functioning in desmosomes as eFABP4 receptor candidates including desmoglein (DSG), desmocollin, junction plankoglobin, desomoplankin, and cytokeratins. AlphaFold modeling predicted an interaction between eFABP4, and the extracellular cadherin repeats of DSG2 and pull-down and immunoprecipitation assays confirmed complex formation that was potentiated by oleic acid. Silencing of DSG2 in MCF-7 cells attenuated eFABP4 effects on cellular proliferation, pERK levels, and ALDH1A1 expression compared with controls. IMPLICATIONS: These results suggest desmosomal proteins, and in particular desmoglein 2, may function as receptors of eFABP4 and provide new insight into the development and progression of obesity-associated cancers.

A nonhuman primate model of vertical sleeve gastrectomy facilitates mechanistic and translational research in human obesity.

The obesity epidemic significantly contributes to overall morbidity and mortality. Bariatric surgery is the gold standard treatment for obesity and metabolic dysfunction, yet the mechanisms by which it exerts metabolic benefit remain unclear. Here, we demonstrate a model of vertical sleeve gastrectomy (VSG) in nonhuman primates (NHP) that mimics the complexity and outcomes in humans. We also show that VSG confers weight loss and durable metabolic benefit, where equivalent caloric intake in shams resulted in significant weight gain following surgery. Furthermore, we show that VSG is associated with early, weight-independent increases in bile acids, short-chain fatty acids, and reduced visceral adipose tissue (VAT) inflammation with a polarization of VAT-resident immunocytes toward highly regulatory myeloid cells and Tregs. These data demonstrate that this strongly translational NHP model can be used to interrogate factors driving successful intervention to unravel the interplay between physiologic systems and improve therapies for obesity and metabolic syndrome.

Bariatric surgery outcomes in Medicare beneficiaries.

BACKGROUND: The Medicare population is increasing while the prevalence of obesity remains high. Bariatric surgery is the most efficacious treatment of obesity and its comorbidities. The objective of this investigation was to assess trends in utilization, readmission, mortality, and cost of bariatric surgery in the Medicare population. METHODS: Utilizing the Medicare Provider Analysis and Review database, patients with clinically severe obesity undergoing laparoscopic Roux-en-Y gastric bypass (RYGB), laparoscopic sleeve gastrectomy (SG), and laparoscopic adjustable gastric banding (LAGB) from 2011-2015 were identified. Trends in procedure selection, readmissions, mortality, and cost were examined. A multivariable logistic regression analysis to evaluate factors associated with readmission and mortality was performed. RESULTS: Of the 73,718 patients identified, 53,949 (73%) of patients were enrolled in Medicare due to disability, 19,191 (26%) due to age, and 578 (<1%) due to end stage renal disease (ESRD). Utilization of SG increased (1% in 2011 to 61% in 2015), while utilization of RYGB (68% to 32%) and LAGB (31% to 1%) decreased. Length of stay (LOS) was highest after RYGB (2.54 days), and lowest after LAGB (1.32 days). LOS decreased from 2.23 days in 2011 to 2.12 days in 2015. Thirty-day readmissions were 8.24% for the disabled, 5.5% for the elderly, 12.8% with ESRD. Odds of readmission increased with black race, higher body mass index (BMI), and RYGB. Readmission decreased from 8% in 2011 to 7% in 2015. Thirty-day mortality was 0.22% in the disabled, and 0.28% in the elderly. Odds of 30-day mortality increased among men, those with higher BMI, some comorbidities, and those who underwent RYGB. Cost of SG decreased while cost of RYGB increased. CONCLUSIONS: Among the Medicare population, an increase in SG while a decrease in RYGB and LAGB utilization was noted from 2011-2015. Readmissions and cost have decreased, while mortality has remained low.

Adjuvant chemotherapy for intrahepatic cholangiocarcinoma: approaching clinical practice consensus?

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is rare with limited evidence-based guidelines. This retrospective study evaluates the use of chemotherapy in patients with resected ICC. METHODS: The Surveillance Epidemiology and End Results (SEER) program database was used to identify patients with resected ICC. Patients were stratified by date of diagnosis (2000-2004, 2005-2009, 2010-2014), T, and N stage. Multivariable logistic regression models identified predictors of chemotherapy use. Kaplan-Meier and Cox proportional hazard models were used to identify survival trends. RESULTS: One thousand and two hundred twenty-three patients met inclusion criteria. Chemotherapy utilization increased over time (33% to 41%, P≤0.05). Chemotherapy use increased in lymph node (LN) positive patients [32% to 60% in 2010-2014; (P≤0.05) and T3/T4 disease (40% to 60% in 2010-2014; P≤0.01], but not in patients with LN negative or T1/T2 disease. LN positivity was associated with utilization of chemotherapy in 2005-2009 and 2010-2014. Overall survival increased from 32 to 41 months (P≤0.05). In LN positive patients, chemotherapy was associated with a decreased hazard ratio of death (P≤0.05) and T3/T4 disease was associated with an increased hazard ratio of death (P≤0.05). CONCLUSIONS: Adjuvant chemotherapy use in ICC has increased. More LN positive or patients with T3/T4 tumors are receiving chemotherapy, which may explain the improvement in overall survival.

Peri-operative antibiotics acutely and significantly impact intestinal microbiota following bariatric surgery.

Bariatric surgery is the most effective treatment for weight loss. Vertical sleeve gastrectomy (VSG) involves the resection of ~ 80% of the stomach and was conceived to purely restrict oral intake. However, evidence suggests more complex mechanisms, particularly postoperative changes in gut microbiota, in facilitating weight loss and resolving associated comorbidities. VSG in humans is a complex procedure and includes peri-operative antibiotics and caloric restriction in addition to the altered anatomy. The impact of each of these factors on the intestinal microbiota have not been evaluated. The aim of this study was to determine the relative contributions of each of these factors on intestinal microbiota composition following VSG prior to substantial weight loss. Thirty-two obese patients underwent one of three treatments: (1) VSG plus routine intravenous peri-operative antibiotics (n = 12), (2) VSG with intravenous vancomycin chosen for its low intestinal penetrance (n = 12), and (3) caloric restriction (n = 8). Fecal samples were evaluated for bacterial composition prior to and 7 days following each intervention. Only patients undergoing VSG with routine peri-operative antibiotics showed a significant shift in community composition. Our data support the single dose of routine peri-operative antibiotics as the most influential factor of intestinal microbial composition acutely following VSG.

Systemic therapy without radiation may be appropriate as neoadjuvant therapy for localized pancreas cancer.

BACKGROUND: The utility of neoadjuvant treatment for resectable pancreas cancer is yet to be determined, but has commonly included chemoradiation. We evaluated outcomes in patients with radiographically resectable pancreatic adenocarcinoma treated with neoadjuvant chemotherapy without chemoradiation. METHODS: A retrospective review of patients in our institutional pancreatic cancer registry was performed, which identified 36 patients who received neoadjuvant chemotherapy alone for resectable pancreatic adenocarcinoma between 2012 and 2016. RESULTS: Median age at diagnosis was 66.3 years. Chemotherapy regimens included gemcitabine (n=17), gemcitabine/nab-paclitaxel (n=8), or 5-FU/leucovorin/irinotecan/oxaliplatin (FOLFIRINOX) (n=11). Surgical resection was performed in 69% of patients (n=25), with an R0 resection rate of 92% (n=23 patients). During chemotherapy, distant disease became apparent in 19% of patients (n=7), while no patients had evidence of local progression. Resection rates were similar between chemotherapy regimens (single agent =59%, multiple agent =79%). Median overall survival for all patients who received neoadjuvant chemotherapy was 30.3 and 34.4 months for those who underwent surgical resection. There was no difference in median survival for patients treated with gemcitabine (31.3 months) or multi-agent chemotherapy (29.7 months). CONCLUSIONS: A short course of neoadjuvant chemotherapy without chemoradiation may improve patient selection prior to surgical resection for pancreas cancer. Further, local disease progression did not limit surgical resection in this small series.

Bariatric Surgery is Associated With Decreased Progression of Nonalcoholic Fatty Liver Disease to Cirrhosis: A Retrospective Cohort Analysis.

OBJECTIVE: This study sought to compare trends in the development of cirrhosis between patients with NAFLD who underwent bariatric surgery and a well-matched group of nonsurgical controls. SUMMARY OF BACKGROUND DATA: Patients with NAFLD who undergo bariatric surgery generally have improvements in liver histology. However, the long-term effect of bariatric surgery on clinically relevant liver outcomes has not been investigated. METHODS: From a large insurance database, patients with a new NAFLD diagnosis and at least 2 years of continuous enrollment before and after diagnosis were identified. Patients with traditional contraindications to bariatric surgery were excluded. Patients who underwent bariatric surgery were identified and matched 1:2 with patients who did not undergo bariatric surgery based on age, sex, and comorbid conditions. Kaplan-Meier analysis and Cox proportional hazards modeling were used to evaluate differences in progression from NAFLD to cirrhosis. RESULTS: A total of 2942 NAFLD patients who underwent bariatric surgery were identified and matched with 5884 NAFLD patients who did not undergo surgery. Cox proportional hazards modeling found that bariatric surgery was independently associated with a decreased risk of developing cirrhosis (hazard ratio 0.31, 95% confidence interval 0.19-0.52). Male gender was associated with an increased risk of cirrhosis (hazard ratio 2.07, 95% confidence interval 1.31-3.27). CONCLUSIONS: Patients with NAFLD who undergo bariatric surgery are at a decreased risk for progression to cirrhosis compared to well-matched controls. Bariatric surgery should be considered as a treatment strategy for otherwise eligible patients with NAFLD. Future bariatric surgery guidelines should include NAFLD as a comorbid indication when determining eligibility.

Incidence and predictors of incisional hernia after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Background and objectives: The incidence of incisional hernia (IH) after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is largely unknown. Methods: We conducted a retrospective study to identify patients who underwent CRS/HIPEC from 2001 to 2016. Patients were followed postoperatively for a minimum of two years. The primary outcome was the occurrence of an IH identified either on CT scan or physical examination. Univariate and multivariable logistic regression models were used to test associations with IH. Results: We identified 155 patients who underwent CRS/HIPEC; 26 patients (17%) were diagnosed with an IH at a median time of 245 days (Interquartile range [IQR] 175 - 331 days). On multivariable analysis, older age [50-64 vs. 18-49 years: hazard ratio (HR) = 0.08; 95% confidence interval (CI), 0.01 to 0.64)], female gender (HR = 0.09; 95% CI, 0.01 to 0.75), and increased BMI (>30 vs. <25; HR = 0.03; 95% CI, 0.01 to 0.37) were significant independent predictors of IH. Conclusions: The incidence of IH in this high-risk patient population treated with CRS/HIPEC is similar to that after other abdominal cancer operations. Nevertheless, the occurrence of IH is an important patient outcome, so alternative closure techniques for reducing IH should be studied in this patient population. Synopsis In a single-institutional study, the incidence of incisional hernia was 17% after cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy. Independent risk factors of incisional hernia were older age, female gender and obesity.

Antibiotic-induced Disruption of Intestinal Microbiota Contributes to Failure of Vertical Sleeve Gastrectomy.

OBJECTIVE: The aim of this study was to test whether the perioperative composition of intestinal microbiota can contribute to variable outcomes following vertical sleeve gastrectomy (VSG). SUMMARY OF BACKGROUND DATA: Although bariatric surgery is the most effective treatment for obesity, metabolic outcomes are variable. METHODS: Diet-induced obese mice were randomized to VSG or sham surgery, with or without exposure to antibiotics that selectively suppress mainly gram-positive (fidaxomicin, streptomycin) or gram-negative (ceftriaxone) bacteria on postoperative days (POD) 1-4. Fecal microbiota was characterized before surgery and on POD 7 and 28. Mice were metabolically characterized on POD 30-32 and euthanized on POD 35. RESULTS: VSG resulted in weight loss and shifts in the intestinal microbiota composition relative to sham-operated mice. Antibiotic exposure resulted in sustained reductions in alpha (within-sample) diversity of microbiota and shifts in its composition. All antibiotic treatments proved to be detrimental to metabolic VSG outcomes, regardless of antimicrobial specificity of antibiotics. These effects involved functionally distinct pathways. Specifically, fidaxomicin and streptomycin markedly altered hepatic bile acid signaling and lipid metabolism, while ceftriaxone resulted in greater reduction of key antimicrobial peptides. However, VSG mice exposed to antibiotics, regardless of their specificity, had significantly increased subcutaneous adiposity and impaired glucose homeostasis without changes in food intake relative to control VSG mice. CONCLUSION: Dysbiosis induced by brief perioperative antibiotic exposure attenuates weight loss and metabolic improvement following VSG. Potential mechanisms include disruption of bile acid homeostasis and reduction in the production of gut antimicrobial peptides. Results of this study implicate the intestinal microbiota as an important contributor to metabolic homeostasis and a potentially modifiable target influencing clinical outcomes following VSG.

Racial disparities in perioperative outcomes after bariatric surgery.

BACKGROUND: NonHispanic black patients bear a disproportionate burden of the obesity epidemic and its related medical co-morbidities. While bariatric surgery is the most effective treatment for morbid obesity, black patients access bariatric surgery at lower rates than nonHispanic white patients. OBJECTIVES: To examine racial differences before bariatric surgery and in short-term perioperative outcomes and complications, and the extent to which race is independently associated with perioperative morbidity and mortality. SETTING: Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program national database. METHODS: Data were extracted from the 2015 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program Participant Use File. Multivariate analysis was used to identify differences in mortality, length of stay, readmission, and reintervention by race in patients undergoing laparoscopic Roux-en-Y gastric bypass or laparoscopic sleeve gastrectomy (SG). RESULTS: A total of 108,198 patients were included in the analysis. There were significant differences in perioperative disease burden. Black patients had a higher body mass index at the time they underwent surgery (laparoscopic Roux-en-Y gastric bypass: 48.0 versus 45.7 kg/m2; SG: 46.8 versus 44.9 kg/m2; P < .001). Black patients had significantly longer length of stay and higher rates of readmission in both the laparoscopic Roux-en-Y gastric bypass and SG groups. In the SG group, black patients had significantly higher 30-day mortality (.2% versus .1%, odds ratio = 3.613, 95% confidence interval 1.990-6.558, P < .001) and higher rates of reoperation or reintervention. CONCLUSIONS: We found significant racial disparities in bariatric surgery outcomes, including higher mortality in black patients undergoing SG. The specific causes of these disparities remain unclear and must be the subject of future research.

Trends in lobular carcinoma in situ management: endocrine therapy use in California and New Jersey.

PURPOSE: The diagnosis of lobular carcinoma in situ (LCIS) is a strong risk factor for breast cancer. Endocrine therapy (ET) for LCIS has been shown to decrease breast cancer risk substantially. The purpose of this study was to evaluate the trends of ET use for LCIS in two large geographic locations. PATIENTS AND METHODS: We identified women, ages 18 through 75, with a microscopic diagnosis of LCIS in California (CA) and New Jersey (NJ) from 2004 to 2014. We evaluated trends in unadjusted ET rates during the study period and used logistic regression to evaluate the relationship between patient, tumor, and treatment characteristics, and ET use. RESULTS: We identified 3,129 patients in CA and 2,965 patients in NJ. The overall use of ET during the study period was 14%. For the combined sample, women in NJ were significantly less likely to utilize ET then their counterparts in CA (OR 0.77, CI 0.66-0.90, NJ vs. CA). In addition, patients in the later year period (OR 1.27, CI 1.01-1.59, 2012-2014 vs. 2004-2005) and women who received an excisional biopsy (OR 2.35, CI 1.74-3.17), were more likely to utilize ET. Uninsured women were less likely to receive ET (OR 0.61, CI 0.44-0.84, non-insured vs. insured status). CONCLUSIONS: We observed that an increasing proportion of women are using ET for LCIS management, but geographical differences exist. Health insurance status played an important role in the underutilization of ET. Further research is needed to assess patient outcomes given the variations in management of LCIS.

The use of indocyanine green angiography in postmastectomy reconstruction: Do outcomes improve over time?

BACKGROUND: Indocyanine green angiography (ICGA) reduces ischemic complications by assessing mastectomy flap perfusion intraoperatively. However, outcomes of ICGA can be surgeon-dependent due to its relative novelty. We aimed to determine whether patient outcomes improved with the adoption of ICGA over time. METHODS: We conducted a single-institution retrospective study of mastectomy patients between March 2012 (date of ICGA introduction) and October 2016. We included patients who underwent immediate expander-based reconstruction with intraoperative ICGA, followed by second-stage permanent implant placement. Patients were chronologically sorted into 3 groups, of 45 patients each, based on the date of ICGA. Complications and reconstruction wait times (time between initial expander placement and subsequent final reconstruction) amongst the 3 groups were evaluated. Using the Cochran-Armitage test for trend, we tested the change in median adjusted expander fill volumes (expander fill volume in milliliter per gram of breast removed) over time. RESULTS: We identified 135 patients. Rates of ischemic complications significantly decreased (Group 1, 36%; Group 2, 22%; Group 3, 11%; p = 0.03), despite significantly increasing median adjusted expander fill volumes (Group 1, 0.46 mL/g; Group 2, 0.63 mL/g; Group 3, 0.76 mL/g; p = 0.003) over time. The rates of unexpected returns to the operating room across the 3 groups were not significantly different. The median reconstruction wait time was significantly reduced in the later groups (Group 1, 146 days; Group 2, 122 days; Group 3, 87 days; p = 0.01). CONCLUSIONS: Outcomes for mastectomy with immediate expander-based reconstruction were found to improve with increasing case volume after implementation of ICGA.

21-gene recurrence score testing in the older population with estrogen receptor-positive breast cancer.

INTRODUCTION: The 21-gene recurrence score (RS) (Oncotype Dx, Genomic Health, Redwood City Ca) has not been validated in an older cohort with estrogen receptor (ER)-positive breast cancer. The objective of this study was to evaluate RS validity in a group of older women with ER-positive breast cancer. METHODS: Utilizing the Surveillance, Epidemiology, and End Results Program (SEER) database with available RS, we evaluated women with ER-positive breast cancer aged 18-69 and those 70 years of age and older from 2004 to 2014. We utilized multivariable logistic regression models to evaluate factors associated with RS testing as well as a high-risk categorization for those who underwent testing. Survival was analyzed using Kaplan Meier curves and Cox proportional hazard models. RESULTS: We identified 363,876 women aged 18-69 years and 147,107 women aged 70 years and older. A smaller proportion of patients in the older group (8%) underwent RS testing than in the younger group (18%). Of the patients who underwent testing, distribution of RS was similar between groups. High-risk categorization independently predicted a higher likelihood of death for older patients (hazard ratio 1.47, 95% confidence interval 1.15-1.90). Among patients with high-risk RS, chemotherapy was associated with a decreased risk of death in the younger group, but not in the older group. CONCLUSION: Older women are less likely to receive RS testing, but when tested, older patients have a similar distribution of RS as compared to younger patients. While high-risk categorization in the older cohort was prognostic, chemotherapy was not associated with improved survival.

Serum FABP4 concentrations decrease after Roux-en-Y gastric bypass but not after intensive medical management.

BACKGROUND: Serum concentrations of fatty acid binding protein 4, an adipose tissue fatty acid chaperone, have been correlated with insulin resistance and cardiovascular risk factors. The objective of this study were to assess relationships among Roux-en-Y gastric bypass, intensive lifestyle modification and medical management protocol, fatty acid binding protein 4, and metabolic parameters in obese patients with severe type 2 diabetes mellitus; and to evaluate the relative contribution of abdominal subcutaneous adipose and visceral adipose to the secretion of fatty acid binding protein 4. METHODS: Participants were randomly assigned to intensive lifestyle modification and medical management protocol (n = 29) or to intensive lifestyle modification and medical management protocol augmented with Roux-en-Y gastric bypass (n = 34). Relationships among fatty acid binding protein 4 and demographic characteristics, metabolic parameters, and 12-month changes in these values were examined. Visceral and subcutaneous adipose tissue explants from obese nondiabetic patients (n = 5) were obtained and treated with forskolin to evaluate relative secretion of fatty acid binding protein 4 in the different adipose tissue depots. RESULTS: The intensive lifestyle modification and medical management protocol and Roux-en-Y gastric bypass cohorts had similar fasting serum fatty acid binding protein 4 concentrations at baseline. At 1 year, mean serum fatty acid binding protein 4 decreased by 42% in Roux-en-Y gastric bypass participants (P = .002) but did not change significantly in the intensive lifestyle modification and medical management protocol cohort. Percentage of weight change was not a significant predictor of 12-month fatty acid binding protein 4 within treatment arm or in multivariate models adjusted for treatment arm. In adipose tissue explants, fatty acid binding protein 4 was secreted similarly between visceral and subcutaneous adipose tissue. CONCLUSION: After Roux-en-Y gastric bypass, fatty acid binding protein 4 is reduced 12 months after surgery but not after intensive lifestyle modification and medical management protocol in patients with type 2 diabetes mellitus. Fatty acid binding protein 4 was secreted similarly between subcutaneous and visceral adipose tissue explants.

Surgical resection of lymph node positive intrahepatic cholangiocarcinoma may not improve survival.

BACKGROUND: Nodal positivity is a predictor of poor survival following resection for intrahepatic cholangiocarcinoma (ICC). The aim of this study was to evaluate the impact of surgical resection on survival in patients with lymph node (LN) positive ICC. METHODS: An augmented version of the Surveillance, Epidemiology, and End Results program database was utilized to identify patients with LN-positive ICC without distant metastases from 2000 to 2014. Patients were stratified by treatment: chemotherapy alone or surgical resection with/without chemotherapy. Survival was evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: 169 patients who underwent treatment for LN-positive ICC were identified. 88% underwent surgical resection and 12% underwent chemotherapy alone. The median survival for patients who underwent surgical resection was not different from patients treated with chemotherapy alone (19 months 95% Confidence Interval (CI) 17-33 versus 20 months CI 10-27, p = 0.323). A cox-proportional hazard ratio model demonstrated that black race was associated with worse survival (p < 0.05), while surgical resection was not independently associated with survival. CONCLUSION: Surgical resection for patients with LN-positive ICC may not improve survival compared to chemotherapy alone. Pathologic LN evaluation should be performed prior to surgical resection, to improve patient selection and ensure receipt of optimal therapy.

Current survival and treatment trends for surgically resected intrahepatic cholangiocarcinoma in the United States.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is a rare and aggressive disease with an increasing incidence in the United States, and there is no level 1 evidence to help guide treatment decisions. We sought to determine national trends in surgical and medical management of patients with resected ICC, and more specifically, the role of lymphadenectomy (LAD) and utilization of chemotherapy. METHODS: An augmented version of the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) cancer database registry was used to identify all surgically resected ICC patients from 2000 to 2014. We evaluated the incidence and adequacy of LAD, and receipt of chemotherapy over time. Next, multivariable logistic regressions were performed to determine the predictors of LAD and receipt of chemotherapy. Overall survival (OS) was evaluated using Kaplan-Meier and Cox proportional hazard models. RESULTS: We identified 1,263 patients who underwent resection for ICC. Lymph nodes (LNs) were removed in 49% of patients, however, only 10% of patients received adequate LAD by the American Joint Committee on Cancer (AJCC) criteria (≥6 nodes). LN metastases were found in 29% of patients who underwent nodal evaluation. Chemotherapy was administered to 40% of patients, was utilized more frequently over time (P<0.05), and was associated with improved survival in node positive patients (P<0.05). Patients who did not have LNs evaluated were significantly less likely to receive chemotherapy than those who did. Lastly, OS for the entire cohort improved over time (P<0.05). CONCLUSIONS: After analyzing the treatment and outcomes of resectable ICC, we concluded: (I) LN evaluation at the time of surgical resection remains inadequate; (II) utilization of chemotherapy has increased over time; (III) the lack of LAD likely results in under-staging and underutilization of chemotherapy; and (IV) despite less than ideal surgical and medical therapy median OS continues to improve.

Tumor grade and progesterone receptor status predict 21-gene recurrence score in early stage invasive breast carcinoma.

PURPOSE: The 21-gene recurrence score (RS) assay is increasingly utilized to predict the risk of recurrence in early stage estrogen receptor (ER)-positive breast cancer. We hypothesize that tumor grade and progesterone receptor (PR) status predict RS categorization. METHODS: We identified women between the ages of 18 and 74 years with stage I or II, ER-positive, invasive carcinoma of the breast from the Surveillance Epidemiology End-Results database from 2010 to 2013. Multivariable logistic regression was performed to determine factors associated with high-risk RS. RESULTS: We identified 42,530 patients that met inclusion criteria. Multivariable logistic regression demonstrated that grade I tumors [OR (odds ratio) 0.33, 95% CI (confidence interval) 0.31-0.37] and PR positive (PR+) status (OR 0.16, 95% CI 0.15-0.17) were significantly less likely to be associated with high-risk RS. Of patients with grade I PR+ tumors, 1% was in the high-risk group by the traditional cutoffs and 4% was in the high-risk group by the TAILORx cutoffs. The percentage of patients with high-risk RS remained low for grade I PR+ tumors regardless of age, race, tumor size, and lymph node status. CONCLUSIONS: We found that grade I PR+ tumors are associated a < 5% probability of having high-risk RS regardless of other patient demographic or pathologic factors. This suggests that the histologic factors of grade and PR status should be taken into consideration before ordering the 21-gene recurrence score assay.

Distribution of 21-Gene Recurrence Scores in Male Breast Cancer in the United States.

BACKGROUND: The 21-gene recurrence score (RS) is a RT-PCR assay estimating risk of distant recurrence in estrogen receptor positive (ER+), human epidermal growth factor receptor 2 negative (HER2) breast cancer (BC). Studies validating RS are limited to women. Our objective was to assess RS distribution and factors associated with high-risk RS in male BC. METHODS: Using the Surveillance, Epidemiology, and End Results database, we identified men and women with ER+/HER2- BC from 2010 to 2013. Patients were categorized into risk groups using the traditional and the Trial Assigning Individualized Options for Treatment (TAILORx) cutoffs. Multivariable logistic regression determined factors associated with testing and high-risk TAILORx RS. RESULTS: We identified 1388 men and 154,196 women with ER+/HER2- BC. Twenty-five percent of men and 30% of women had RS testing. Mean age of tested men was 63; most were white (81%), had grade I or II tumors (67%), and had stage I or II (95%) BC. Factors associated with increased RS testing were younger age, recent year of diagnosis, lymph node negativity, and lower-stage tumors (p ≤ 0.05). By TAILORx, 21% of men had high-risk RS compared with 14% of tested women. Men with grade III and PR negative tumors were more likely to have a high-risk RS (p ≤ 0.05). Chemotherapy utilization was correlated with RS. CONCLUSIONS: Using a large population-based dataset, we found that compared with women, men were significantly more likely to have high-risk RS. Grade III and PR-negative BC were significantly associated with high-risk RS. Higher RS in men correlated with increased chemotherapy utilization.

Liver Regeneration in the Acute Liver Failure Patient.

Liver regeneration after simple resection represents a unique process in which the organ returns to its original size and histologic structure. Over the past 30 years, there has been significant progress in elucidating the mechanisms associated with regeneration after loss of hepatic mass. Liver regeneration after acute liver failure shares several of these classical pathways. It differs, however, in key processes, including the role of both differentiated and stemlike cells. This article outlines these differences in addition to new molecular mechanisms, including immunomodulation, microRNAs, and the gut-liver axis. In addition, applications to the patient population, including prognostication and stem cell therapies, are explored.