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BackgroundResection of colorectal liver metastasis (CLM) is beneficial when feasible. However, the benefit of second hepatectomy for hepatic recurrence in CLM remains unclear.MethodsThe Colorectal Liver Operative Metastasis International Collaborative retrospectively examined 1004 CLM cases from 2000 to 2018 from a total of 953 patients. Hepatic recurrence after initial hepatectomy was identified in 218 patients. Kaplan-Meier analysis was performed for overall survival (OS) and recurrence-free survival (RFS). Propensity score matching (PSM) was performed to offset selection bias. Cox proportional-hazards regression was performed to identify risk factors associated with OS.ResultsA total of 51 patients underwent second hepatectomy. Unadjusted median OS was 60.1 months in repeat-hepatectomy versus 38.3 months in the single-hepatectomy group (p = 0.015). In the PSM population, median OS remained significantly better in the repeat-hepatectomy group (60.1 vs. 33.1 months; p = 0.0023); median RFS was 12.4 months for the repeat-hepatectomy group, versus 9.8 months in the single-hepatectomy group (p = 0.0050). Repeat hepatectomy was associated with lower risk of death (hazard ratio: 0.283; p = 0.000012). Obesity, tobacco use, and high intraoperative blood loss were associated with significant risk of death (p

To sustain their proliferation, cancer cells overcome negative-acting signals that restrain their growth and promote senescence and cell death. Renalase (RNLS) is a secreted flavoprotein that functions as a survival factor after ischemic and toxic injury, signaling through the plasma calcium channel PMCA4b to activate the PI3K/AKT and MAPK pathways. We show that RNLS expression is increased markedly in primary melanomas and CD163+ tumor-associated macrophages (TAM). In clinical specimens, RNLS expression in the tumor correlated inversely with disease-specific survival, suggesting a pathogenic role for RNLS. Attenuation of RNLS by RNAi, blocking antibodies, or an RNLS-derived inhibitory peptide decreased melanoma cell survival, and anti-RNLS therapy blocked tumor growth in vivo in murine xenograft assays. Mechanistic investigations showed that increased apoptosis in tumor cells was temporally related to p38 MAPK-mediated Bax activation and that increased cell growth arrest was associated with elevated expression of the cell-cycle inhibitor p21. Overall, our results established a role for the secreted flavoprotein RNLS in promoting melanoma cell growth and CD163+ TAM in the tumor microenvironment, with potential therapeutic implications for the management of melanoma. Cancer Res; 76(13); 3884–94. ©2016 AACR.

More detailed description of some of the methods.

Charles Amteme, NPM: 42150013 "Analysis of Economic Sectoral Potential in Belu Regency" under the guidance of Mr. Prof.Dr. Sirilius Seran, SE.MS as supervisor I and Mr. Frederich W. Nalle, SE.ME as supervisor II. The problem raised from this study is how the sector shifts to the economy in Belu District and whether there are leading sectors in the economy in Belu District. The objectives to be achieved in this study are to determine the Sector Shift to the economy in Belu District and to find out whether there is a superior Sector in the economy in Belu Regency. The data used in this study are secondary data obtained from the Central Statistics Agency Office in Belu Regency. The data analysis technique used is the Shift Share analysis and Klassen Typology. Based on the results of shift share analysis, the sector that has the largest national share value is the agricultural sector, while the smallest value is in the electricity and gas and clean water sectors. According to the proportional shift analysis it is known that there are six sectors in Belu Regency whose growth is slower ompared to the NTT province, namely: agriculture, mining and grazing, the manufacturing industry sector, the electricity gas and water supply sector, the hotel and restaurant trade, and the sector finance, leasing and corporate services. While the differential shift analysis is known that there are four sectors in Belu Regency that grow faster based on internal locational factors, namely: the mining and mining sector, the manufacturing sector, the electricity, gas and water supply sector and also the transportation and communication sector. Based on the results of the typology analysis, the sectors included in the developed and rapidly growing sectors are other service sectors. Meanwhile, the sectors included in the advanced but depressed sectors are the financial sector, leasing and corporate services. Sectors classified as potential or still developing sectors are: agriculture and the relatively backward or underdeveloped sectors are the mining and quarrying sector, the processing industry, gas electricity and drinking water, construction, the restaurant and hotel trade and the communication and transportation sector.

Primary laterality of colorectal cancer is thought to be associated with differences in outcomes. Liver metastasis is the most common site of solitary colorectal cancer spread. However, how primary colorectal cancer laterality affects outcomes in colorectal liver metastasis remains unclear.The Colorectal Liver Operative Metastasis International Collaborative (COLOMIC) of operative hepatectomy cases for colorectal liver metastasis was compiled from five participating institutions. This included consecutive cases from 2000 to 2018 at all sites. A total of 884 patients were included in this study. Univariate, multivariate, and Kaplan-Meier analyses were performed.Patients with left-sided versus right-sided cancers had significantly better overall survival: 49.4 vs. 41.8 months (p 0.05). Patients with KRAS mutations had significantly worse median overall survival compared to KRAS wild-type (43.6 vs 56.1 months; p 0.001). In left-sided cancers, KRAS mutations were associated with significantly worse median overall survival compared to KRAS wild-type cancers (43.6 vs 56.6 months; p 0.01). This association was absent in patients with right-sided primary tumors. Multivariate Cox regression analysis revealed different variable sets (non-overlapping) were associated with overall survival, when comparing left-sided and right-sided cancers.Understanding how primary tumor laterality and related biological aspects affect long-term outcomes can potentially inform treatment decisions for patients with colorectal liver metastases.

To assess the impact of academic setting and hospital on overall survival in patient with hepatocellular carcinoma (HCC).The 2004-2015 NCDB was queried for HCC. First line treatment was stratified as liver transplant, surgical resection, interventional oncology (IO) and chemotherapy. Hospital volume was stratified as high (ranking among top 10% in case numbers) and low volume. Overall survival was assessed via multivariable Cox regressions.63,877 patients treated at 1261 hospital systems were included (transplant n = 10,596, surgical resection n = 11,132, IO n = 12,286, chemotherapy n = 29,863; academic centers n = 226, non-academic n = 1035). Younger African American patients with private insurance, high income and education were more likely treated at academic centers. US geographical discrepancies were evident, with highest academic center treatment rates in New England states (83.6%) and lowest in South Atlantic states (48.6%). Overall survival was superior for academic versus non-academic centers (HR = 0.89, 95% CI: 0.87-0.91, p 0.001) and high versus low volume centers (HR = 0.79, 95% CI: 0.77-0.81, p 0.001), after multivariable adjustment for potential confounders. These effects were evident among all HCC treatment modalities.HCC treatment in academic centers shows distinct patterns according to patient demographics and US geography. Longest patient survival is observed in high-volume academic centers.

The pancreas is a digestive organ with both exocrine and endocrine functions that sits in the retroperitoneum at the level of the second lumbar vertebra. It has an extremely close spatial relationship with multiple organs (i.e., the duodenum, stomach, transverse colon, and bile duct) and multiple major blood vessels, including the celiac axis, superior mesenteric artery and vein, portal vein, and vena cava. Acknowledgment and understanding of these close proximities is vital when performing surgical procedures involving the pancreas. Knowledge of pancreatic embryology is also key for the identification of congenital anomalies and their relevance for patients. An in-depth understanding of overall pancreatic anatomy and normal variants is also critical for the proper diagnosis and treatment of any potential resulting pancreatic pathology. Anatomic anomalies and variations of the pancreas include pancreas divisum, annular pancreas, ectopic pancreas, pancreatic agenesis and hypoplasia, pancreatic cysts, and variations of the course and configuration of the duct.

Hepatobiliary disease affects many people worldwide. From primary hepatocellular carcinoma, to cholangiocarcinoma, an essential part of management is surgical. A strong knowledge of surgical anatomy is an essential part of managing these patients.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

IntroductionRenalase (RNLS), a novel secreted plasma flavoprotein, has anti-inflammatory effects in a variety of disease processes. Severe COVID-19 disease is associated with disordered inflammatory responses. We hypothesized that reduced plasma RNLS levels could be a marker of COVID-19 disease severity.MethodsPlasma was collected from 51 hospitalized COVID-19 patients and 15 uninfected non-hospitalized controls. Plasma RNLS and cytokine levels were measured and sociodemographic and clinical data were collected from chart review. Data were analyzed using nonparametric analyses and Kaplan Meir curve log rank analysis.ResultsPlasma RNLs levels were negatively correlated with inflammatory markers, including IL-1β, IL-6, and TNFα (p = 0.04, p = 0.03, p = 0.01, respectively). Patients with COVID-19 disease had lower levels of RNLS than controls. Lower levels of RNLS were associated with more severe disease among COVID-19 patients. Low RNLS was also associated with worse survival among COVID-19 patients (HR = 4.54; 95% CI: 1.06-19.43; p = 0.005).ConclusionLow plasma RNLS levels are associated with severe COVID-19 disease and may be a useful additional biomarker when identifying patients with severe COVID-19 disease. Given RNLS’ antiinflammatory properties and negative correlation with inflammatory markers, these findings also suggest evidence of a potential pathophysiological mechanism for severe COVID-19 disease.

The aim of this study was to evaluate socioeconomic discrepancies in current treatment approaches and survival trends among patients with intrahepatic cholangiocarcinoma (ICC). The 2004–2015 National Cancer Database was retrospectively analyzed for histopathologically proven ICC. Treatment predictors were evaluated using multinomial logistic regression and overall survival via multivariable Cox models. Overall, 12,837 ICC patients were included. Multiple factors influenced treatment allocation, including age, education, comorbidities, cancer stage, grade, treatment center, and US state region (multivariable p

Background: Adjuvant therapy for gastric adenocarcinoma has shown a survival advantage, though it may be underutilized. The purpose of this study is to examine how infrequently adjuvant therapy is administered with curative intent gastrectomy for node positive gastric cancer and the long-term effects to patients. Methods: The National Cancer Database was queried from 2006–2013 for patients with node positive gastric adenocarcinoma undergoing a potentially curative gastrectomy. Overall survival was compared between patients who received adjuvant chemotherapy or chemoradiation and those who did not. Results: Of 2,565 patients, 793 (30.9%) patients did not receive any adjuvant chemotherapy or radiation therapy, while 147 (5.7%) received peri-operative chemotherapy and 723 (28.2%) received post-operative chemoradiation. From 2006–2013, the percentage of patients receiving peri-operative chemotherapy rose from 1.1% to 9.9%, while those receiving post-operative chemoradiation decreased from 39.7% to 21.6%. The adjusted restricted mean survival time over 5 years for no adjuvant therapy was 27.7 months, peri-operative chemotherapy was 39.6 months, and post-operative chemoradiation was 37.7 months (P Conclusions: Approximately one third of patients treated for node positive gastric cancer undergo surgical resection without adjuvant therapy. This is associated with poorer survival, highlighting the need for improvement in multimodality care and cancer outcomes.

Background Colon and rectal gastrointestinal stromal tumors (GISTs) are rare and poorly characterized. Because the majority of treatment guidelines for GISTs are extrapolated from tumors of gastric and small bowel origin, our aim was to better characterize the unique clinicopathologic features and prognostic factors of colon and rectal GISTs to guide clinical care. Methods The National Cancer Data Base (NCDB) was queried from 2006 to 2013 for cases of GISTs in the stomach, colon, and rectum. Patient demographics, clinical characteristics, and survival were compared. Results A total of 11,302 gastric GISTs were compared to 398 colon and 393 rectal GISTs. After propensity matching, compared to gastric GISTs, rectal GISTs had improved overall survival (HR =0.695, P=0.0264), while colon GISTs had worse overall survival (HR =1.6, P=0.0005). Surgical treatment for rectal GISTs was more likely to be local excision compared to colonic GISTs (51.1% vs. 8.4%, P

Renalase is a secreted flavoprotein with anti-inflammatory and pro-cell survival properties. COVID-19 is associated with disordered inflammation and apoptosis. We hypothesized that blood renalase levels would correspond to severe COVID-19 and survival. In this retrospective cohort study, clinicopathologic data and blood samples were collected from hospitalized COVID-19 subjects (March—June 2020) at a single institution tertiary hospital. Plasma renalase and cytokine levels were measured and clinical data abstracted from health records. Of 3,450 COVID-19 patients, 458 patients were enrolled. Patients were excluded if

Background Checkpoint inhibitors (CPI) have revolutionized the treatment of metastatic melanoma, but most patients treated with CPI eventually develop progressive disease. Local therapy including surgery, ablation or stereotactic body radiotherapy (SBRT) may be useful to manage limited progression, but criteria for patient selection have not been established. Previous work has suggested progression-free survival (PFS) after local therapy is associated with patterns of immunotherapy failure, but this has not been studied in patients treated with CPI. Methods We analyzed clinical data from patients with metastatic melanoma who were treated with antibodies against CTLA-4, PD-1 or PD-L1, either as single-agent or combination therapy, and identified those who had disease progression in 1 to 3 sites managed with local therapy. Patterns of CPI failure were designated by independent radiological review as growth of established metastases or appearance of new metastases. Local therapy for diagnosis, palliation or CNS metastases was excluded. Results Four hundred twenty-eight patients with metastatic melanoma received treatment with CPI from 2007 to 2018. Seventy-seven have ongoing complete responses while 69 died within 6 months of starting CPI; of the remaining 282 patients, 52 (18%) were treated with local therapy meeting our inclusion criteria. Local therapy to achieve no evidence of disease (NED) was associated with three-year progression-free survival (PFS) of 31% and five-year disease-specific survival (DSS) of 60%. Stratified by patterns of failure, patients with progression in established tumors had three-year PFS of 70%, while those with new metastases had three-year PFS of 6% (P = 0.001). Five-year DSS after local therapy was 93% versus 31%, respectively (P = 0.046). Conclusions Local therapy for oligoprogression after CPI can result in durable PFS in selected patients. We observed that patterns of failure seen during or after CPI treatment are strongly associated with PFS after local therapy, and may represent a useful criterion for patient selection. This experience suggests there may be an increased role for local therapy in patients being treated with immunotherapy.

Adenomatous polyposis coli (APC) mutations are causally associated with familial adenomatous polyposis (FAP) and are recurrent somatic events across numerous tumor types, including gastric adenocarcinoma. Severity of disease in FAP correlates with specific APC mutations, but the impact of given mutations on phenotype in gastric cancer is not well studied. Sequencing data from the Genomic Data Commons (GDC) demonstrate an APC mutational pattern in gastric cancer that differs dramatically from that seen in colon cancer. Exome sequencing data from APC-mutant colon and gastric adenocarcinomas in GDC was filtered for single nucleotide variants (SNVs) using MuTect2 Variant Aggregation and Masking pipeline, Somatic Aggregation Workflow. APC mutations were found in 57/441 gastric (12.9%) and 309/433 colon adenocarcinomas (71.4%). There was a significant difference in the proportion of stopgain, frameshift, and missense mutations between tumor types(P

Dysregulated expression of the secretory protein renalase can promote pancreatic ductal adenocarcinoma (PDAC) growth in animal models. We characterized renalase expression in premalignant and malignant PDAC tissue and investigated whether plasma renalase levels corresponded to clinical PDAC characteristics. Renalase immunohistochemistry was used to determine the presence and distribution of renalase in normal pancreas, chronic pancreatitis, PDAC precursor lesions, and PDAC tissues. Associations between pretreatment plasma renalase and PDAC clinical status were assessed in patients with varied clinical stages of PDAC and included tumor characteristics, surgical resection in locally advanced/borderline resectable PDAC, and overall survival. Data were retrospectively obtained and correlated using non-parametric analysis. Little to no renalase was detected by histochemistry in the normal pancreatic head in the absence of abdominal trauma. In chronic pancreatitis, renalase immunoreactivity localized to peri-acinar spindle-shaped cells in some samples. It was also widely present in PDAC precursor lesions and PDAC tissue. Among 240 patients with PDAC, elevated plasma renalase levels were associated with worse tumor characteristics, including greater angiolymphatic invasion (80.0% vs. 58.1%, p = 0.012) and greater node positive disease (76.5% vs. 56.5%, p = 0.024). Overall survival was worse in patients with high plasma renalase levels with median follow-up of 27.70 months vs. 65.03 months (p < 0.001). Renalase levels also predicted whether patients with locally advanced/borderline resectable PDAC underwent resection (AUC 0.674; 95%CI 0.42–0.82, p = 0.04). Overall tissue renalase was increased in both premalignant and malignant PDAC tissues compared to normal pancreas. Elevated plasma renalase levels were associated with advanced tumor characteristics, decreased overall survival, and reduced resectability in patients with locally advanced/borderline resectable PDAC. These studies show that renalase levels are increased in premalignant pancreatic tissues and that its levels in plasma correspond to the clinical behavior of PDAC.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

BACKGROUND: The benefits of palliative care (PC) in critical illness are validated across a range of diseases, yet it remains underutilized in surgical patients. This study analyzed patient and hospital factors predictive of PC utilization for elderly patients with colorectal cancer (CRC) requiring emergent surgery. METHODS: The National Inpatient Sample was queried for patients aged ≥65 years admitted emergently with CRC from 2009–2014. Patients undergoing colectomy, enterectomy or ostomy formation were included and stratified according to documentation of PC consultation during admission. Chi-squared testing identified unadjusted group differences, and multivariable logistic regression identified predictors of PC. RESULTS: Of 86,573 discharges meeting inclusion criteria, only 3,598 (4.2%) had PC consultation. Colectomy (86.6%) and ostomy formation (30.4%) accounted for the operative majority. PC frequency increased over time (2.9% in 2009 to 6.2% in 2014, P

395 Background: Toxicities associated with FOLFIRINOX have prompted use of modifications, despite absence of prospective data validating comparable efficacy and improved tolerability. To determine the impact of attenuated doses of irinotecan and bolus 5FU on efficacy and tolerability, we conducted a prospective phase II study of modified FOLFIRINOX in advanced PC. The efficacy of a FOLFIRINOX regimen has not been previously examined in locally advanced PC (LAPC). Previous studies in LAPC have compared chemo vs chemoRT with median OS in the 9-12 mo range (Loehrer et al, Chauffert et al, Hammel et al). Methods: Previously untreated pts with MPC or LAPC received modified FOLFIRINOX with pegylated filgrastim. Irinotecan and bolus FU were reduced by 25%. AEs were compared to historical control (Conroy et al NEJM 2011). Objective RR in MPC was compared to historical control. PFS and OS were calculated for both cohorts. Results: 31 and 44 pts with LAPC and MPC enrolled. Treatment-related grade 3 and 4 AEs were diarrhea (16.2%), neutropenia (12.2%), fatigue (12.2%), thrombocytopenia (9.5%), anemia (5.4%). Neutropenia (p < 0.0001), vomiting (p = 0.001), and fatigue (p = 0.01) were significantly decreased compared to historical control patients. In MPC, the RR (35.1%) was similar to the historical control group (36.3%; p 0.82); median PFS and OS were 6.1 months (95% CI, 5.19 to 8.31) and10.2 months (95% CI, 7.65 to 14.32) respectively. In LAPC, the RR was 17.2% and median PFS and OS were 17.8 mo (95% CI, 11.0 to 23.9) and 26.6 mo (95% CI, 16.7, NA) respectively. 13 pts went on to surgical resection with 10 now alive and 6 without recurrence. We found no significant association between early metabolic response by FDG-PET imaging and PFS and OS. Conclusions: In this first prospective study of modified FOLFIRINOX, the regimen was well tolerated and associated with decreased incidence of AEs compared to historical control of standard FOLFIRINOX. In MPC pts, the efficacy of the modified regimen appear uncompromised. In this first prospective study of a FOLFIRINOX regimen in LAPC, the PFS and OS surpasses that of previously studied regimens in LAPC. Clinical trial information: NCT01523457.

Objectives To conduct a systematic review of the existing literature regarding surgical therapy for oligometastatic lung cancer to the pancreas. Methods Data was collected on patients with singular pancreatic metastases from lung cancer from papers published between January 1970 and June 2014. This was performed following the Preferred Reporting Items for Systematic reviews and Meta-analysis (PRISMA) guidelines. Kaplan–Meier and Cox Regression analyses were then used to determine and compare survival. Results There were 27 papers that fulfilled the search criteria, from which data on 32 patients was collected. Non-small cell lung cancer (NSCLC) was the most prevalent type of primary lung malignancy, and metachronous presentations of metastases were most common. Lesions were most frequently located in the pancreatic head and consequently the most common curative intent metastasectomy was pancreaticoduodenectomy. There was a statistically significant survival benefit for patients whose metastasis were discovered incidentally by surveillance CT as opposed to those whose metastasis were discovered during a work up for new somatic complaints (p = 0.024). The overall median survival for patients undergoing curative intent resection was 29 months, with 2-year and 5-year survivals of 65% and 21% respectively. Palliative surgery or medical only management was associated with a median survival of 8 months and 2-year and 5-year survivals of 25% and 8% respectively. Conclusions Curative intent resection of isolated pancreatic metastasis from lung cancer may be beneficial in a select group of patients.

Background Tumor angiogenesis has been demonstrated to have an important role in the development, progression, and metastasis of pancreas cancer. Adrenomedullin-2 (ADM2) is a calcitonin gene-related peptide that has recently been shown to be a novel tumor angiogenesis factor, acting via mitogen-activated protein kinase/extracellular signal-regulated kinase, phosphoinositide 3-kinase/Akt, and vascular endothelial growth factor/vascular endothelial growth factor-2 signaling pathways. Through the use of tissue microarray (TMA) technology, we hypothesize that ADM2 is an important tumor angiogenesis factor in pancreatic cancer. Methods Multiple TMAs were created using tissue from pancreatic cancer patients resected between January 1996 and December 2006. Core tissue samples of formalin-fixed, paraffin-embedded blocks of pancreatic cancer tissue were collected through an institutional review board-approved protocol and linked to available clinicopathologic data. Two TMAs consisting of 112 and 60 patients with pancreatic adenocarcinoma were studied for ADM2 protein expression using a quantitative, automated immunofluorescent microscopy system, a technology that removes potential observer bias in TMA analysis. The results were analyzed using independent Student t-test, chi-square, log-rank regression, and Kaplan–Meier methods. Results One hundred sixteen patients were identified for complete analysis, and 56 patients had complete survival data. Median follow-up for survivors was 14.5 mo. Total cellular levels of ADM2 were found to be a predictor of survival in pancreatic cancer. Low ADM2 levels were associated with a higher 5-y survival compared with high ADM2 levels (18% versus 6%, P = 0.05). Median survival was also worse in high ADM2 expressers (18.7 versus 8.6 mo). In accordance with prior-published pancreatic cancer data, a worse histologic grade (P = 0.001), tumor (T) stage (P = 0.009), and overall disease stage (P = 0.004), all portended a worse survival. Conclusions For the first time, we have demonstrated that high levels of ADM2 expression predict a poorer survival in patients with pancreatic adenocarcinoma. This suggests a possible role of ADM2 in pancreas cancer and as a novel biomarker that predicts poorer survival. Additional study of ADM2 in pancreatic cancer will help reveal its true angiogenic role in pancreas cancer and its potential role as a novel therapeutic target.

Ductal adenocarcinoma and its variants account for most pancreatic malignancies. High-quality multiphase imaging can help to preoperatively distinguish between patients eligible for resection with curative intent and those with unresectable disease. Systemic therapy is used in the neoadjuvant or adjuvant pancreatic cancer setting, as well as in the management of locally advanced unresectable and metastatic disease. Clinical trials are critical for making progress in treatment of pancreatic cancer. The NCCN Guidelines for Pancreatic Adenocarcinoma focus on diagnosis and treatment with systemic therapy, radiation therapy, and surgical resection.

Background Bcl-2 has been implicated in the development and progression of a number of cancers including colorectal cancer. Reports of Bcl-2 expression in colorectal cancer and patient outcomes have been inconsistent due to small cohorts and semi-quantitative grading methods. Study Design We used a high throughput tissue microarray system (automated quantitative analysis [AQUA]), analyzing colorectal adenocarcinoma samples from 443 patients resected during the period of 1967 to 1986. This system uses fully quantitative, automated fluorescent microscopy to accurately assess Bcl-2 expression in colorectal cancer samples. Clinicopathologic variables were collected prospectively and were assessed using log-rank tests and Cox proportional hazards models. Results At a median follow-up of 54 months, the 5- and 10-year disease-specific survivals for all patients were 59.2% and 52.1%, respectively. Loss of Bcl-2 expression was seen in 70.4% of tumors and was associated with a decreased 5-year disease-specific survival (55.8% vs 75.6%, p = 0.001 and relative risk [RR] 1.8) and decreased 5-year overall survival (45.8% vs 56.5%, p = 0.046 and RR 1.2). On univariate analysis, T stage, N stage, and loss of Bcl-2 expression predicted poor disease-specific survival. On multivariate analysis, Bcl-2 expression was an independent prognostic factor for disease-specific survival (p = 0.034). Conclusions Our results indicate that loss of Bcl-2 expression in colorectal cancer is associated with decreased disease-specific and overall survival. This finding may help identify a subset of patients with a more aggressive phenotype and guide adjuvant chemotherapy choices.

Hepatocellular adenoma (HCA) is a rare benign liver tumor, predominantly seen in young women. Its major complications are malignant transformation, spontaneous hemorrhage, and rupture. We describe a case of a young female with no underlying liver disease who presented with acute abdominal pain and was found to have a 17cm heterogeneous mass in the left lobe of the liver. She underwent left hepatectomy and pathology revealed a 14cm moderately differentiated hepatocellular carcinoma (HCC) arising in a shell of a HCA. At that time, vascular invasion was already present. She rapidly developed recurrent multifocal hepatic lesions and subsequent spread to the brain, leading to her death 18months after surgery. To investigate the underlying genetic events occurring during hepatocellular adenoma-carcinoma transition and extra-hepatic dissemination, we performed whole exome sequencing of DNA isolated from peripheral blood leucocytes, HCA, HCC, tumor thrombus and brain metastasis. Our data show a step-wise addition of somatic mutations and copy number variations with disease progression, suggesting a linear tumor evolution, which is supported by clonality analysis. Specifically, using a model based clustering of somatic mutations, one single founding clone arising in the HCA, which included catenin beta 1 (CTNNB1) and IL6ST driver mutations, was identified and displayed an increasing clonality rate in HCC, tumor thrombus and brain metastasis. Our data highlight the feasibility of performing whole exome capture, sequencing and analysis using formalin-fixed paraffin-embedded (FFPE) samples, and we describe the first genomic longitudinal study of hepatocellular adenoma-carcinoma transition, vascular invasion and brain metastasis with detailed clinicopathologic annotation.

Radiofrequency ablation (RFA) is commonly used for treating unresectable hepatic malignancies. Some commonly associated complications of RFA include fever, symptomatic pleural effusion, abscess, hepatoma and hepatic insufficiency. Here, we report a case of diaphragmatic hernia in a patient following RFA for hepatic malignancy with cirrhosis.

417 Background: To assess the impact of hospital volume and type on survival in patients with hepatocellular carcinoma (HCC). Methods: Patients with histopathological or imaging-based diagnosis of HCC were identified from the 2003-2015 National Cancer Database (NCDB). First-line treatment was stratified as liver transplant, surgical resection, interventional oncology (IO) and chemotherapy. Hospital volume was stratified as high (ranking among top 10% in case numbers) and low volume, separately for each treatment modality. Hospital type was categorized as academic and non-academic. Overall survival was assessed using multivariable Cox proportional hazards models. Results: A total of 63,877 patients were included (transplant n = 10,596, surgical resection n = 11,132, IO n = 12,286, chemotherapy n = 29,863). Of 1,261 hospitals systems which treated HCC, 226 (17.9%) were academic centers and 1,035 (82.1 %) were non-academic centers. Mean number of cases treated annually was higher in academic centers (55.2; 34.6; 40.7; 79.9) versus non-academic centers (10.7; 6.25; 6.6; 11.9 for transplant; surgical resection; IO and chemotherapy; p < 0.001, respectively). Young African American patients and those with private insurance, high income and education were more likely to receive treatment at academic centers. Geographical difference were evident among US regions, with highest proportion of HCC treated at academic centers in New England states (83.6%) and lowest in South Atlantic states (48.6%). Overall survival was superior for academic versus non-academic centers (HR = 0.89, 95% CI: 0.87-0.91, p < 0.001) and high versus low volume centers (HR = 0.79, 95% CI: 0.77-0.81, p < 0.001), after multivariable adjustment for potential confounders. These effects were evident among all HCC treatment modalities. Conclusions: HCC treatment in academic centers shows distinct patterns according to patient demographics and US geography. Among all treatment modalities, both academic setting and hospital volume independently affected HCC outcomes, with highest patient survival observed in high-volume academic centers.

Objectives— Ephrin ligands and Eph receptors are signaling molecules that are differentially expressed on arteries and veins during development. We examined whether Eph-B4, a venous marker, and Ephrin-B2, an arterial marker, are regulated during vein graft adaptation in humans and aged rats. Methods and Results— Eph-B4 transcripts and immunodetectable protein are downregulated in endothelial and smooth muscle cells of patent vein grafts in both humans and in aged rats, whereas Ephrin-B2 transcripts and protein are not strongly induced. Other markers of arterial identity, including dll4 and notch-4, are also not induced during vein graft adaptation in aged rats. Because VEGF-A is upstream of the Ephrin–Eph pathway, and expression of VEGF-A is induced only at early time points after exposure of the vein to the arterial environment, we inhibited VEGF-A in vein grafts using an siRNA-based approach. Vein grafts treated with siRNA directed against VEGF-A demonstrated a thicker intima-media containing α-actin, consistent with arterialization, but did not contain Eph-B4 or Ephrin-B2. Conclusions— Venous identity is preserved in the veins of aged animals, but is lost during adaptation to the arterial circulation; arterial markers are not induced. Markers of vessel identity are plastic in adults and their selective regulation may mediate vein graft adaptation to the arterial environment in aged animals and humans.

To sustain their proliferation, cancer cells overcome negative-acting signals that restrain their growth and promote senescence and cell death. Renalase (RNLS) is a secreted flavoprotein that functions as a survival factor after ischemic and toxic injury, signaling through the plasma calcium channel PMCA4b to activate the PI3K/AKT and MAPK pathways. We show that RNLS expression is increased markedly in primary melanomas and CD163+ tumor-associated macrophages (TAM). In clinical specimens, RNLS expression in the tumor correlated inversely with disease-specific survival, suggesting a pathogenic role for RNLS. Attenuation of RNLS by RNAi, blocking antibodies, or an RNLS-derived inhibitory peptide decreased melanoma cell survival, and anti-RNLS therapy blocked tumor growth in vivo in murine xenograft assays. Mechanistic investigations showed that increased apoptosis in tumor cells was temporally related to p38 MAPK-mediated Bax activation and that increased cell growth arrest was associated with elevated expression of the cell-cycle inhibitor p21. Overall, our results established a role for the secreted flavoprotein RNLS in promoting melanoma cell growth and CD163+ TAM in the tumor microenvironment, with potential therapeutic implications for the management of melanoma. Cancer Res; 76(13); 3884–94. ©2016 AACR.

Background The deleterious effects of perioperative malnutrition on recovery after general surgery are established. Since the effects of perioperative malnutrition on recovery after vascular surgery are not known, we examined the effects of nutritional status, and risk factors predictive of malnutrition, on outcome after vascular surgery. Methods The records of all open index vascular cases (abdominal aortic aneurysm [AAA] repair, carotid endarterectomy [CEA], lower extremity bypass) performed at the Veterans Affairs (VA) Connecticut between July 2004 and June 2005 were reviewed. The primary outcome was mortality; secondary outcomes included infection and nutritional risk index (NRI) scores. Results Sixty-eight open vascular cases were performed during the study period. Nutritional depletion developed in 55% of patients and was more likely in patients undergoing AAA (85%) or bypass (77%) than CEA (30%; P = .0005). Patients who developed malnutrition had similar mortality as patients who did not develop postoperative malnutrition (6.1% vs. 3.7%; P = .68); however, malnourished patients had higher rates of postoperative infection (24.2% vs. 3.7%; P = .03). Chronic renal failure was the only patient-associated risk factor predictive of postoperative nutritional depletion (odds ratio 5.9, confidence interval 1.0 to 33.6; P = .04). Conclusions Patients undergoing major open vascular surgery have high rates of postoperative malnutrition, with patients undergoing AAA repair having the highest rates of postoperative malnutrition and infection. Patients with chronic renal failure undergoing vascular surgery are associated with increased risk for postoperative malnutrition and may be a group to target for perioperative risk factor modification and nutritional supplementation.

Hepatic metastases from colorectal carcinoma (CRC) were once thought to portend a uniformly grim outcome; however, improvements in chemotherapeutic and surgical approaches have led to significant advances as well as new clinical challenges. Some 60% of the 150,000 patients diagnosed with CRC each year in the United States will develop hepatic metastases. Only a fraction of these metastases are resectable at the time of presentation, but an increasing number of patients are able to undergo resection after neoadjuvant chemotherapy. Additionally, recent trials have demonstrated the efficacy of using chemotherapy with bevacizumab as first-line therapy for metastatic CRC, but how this treatment will affect surgical resection is unknown. Herein, we review the recent literature regarding neoadjuvant chemotherapy for hepatic metastases from CRC, discuss key aspects of the basic science of hepatic regeneration with regard to angiogenic mediators, and outline the key problems to be solved so that a rational strategy can be developed to treat patients with hepatic colorectal metastases in the age of neoadjuvant chemotherapy and antiangiogenic drugs.

Summary Background A variety of factors influence the increased morbidity and mortality seen in patients undergoing emergent colon surgery. Understanding comorbid conditions and variations in preoperative laboratory values that effect both morbidity and mortality can influence clinical decision making. Methods During a 5-year period 185 patients underwent colon surgery at the Veterans Administration Hospital in West Haven, CT. Through a retrospective chart review patients were classified as having either emergent or elective surgery. Patient characteristics and postoperative outcomes were analyzed using Chi Square and logistic regression models. Results Differences existed in preoperative variables as well as postoperative outcomes when comparing emergent and elective paitents. In those patients undergoing emergent colorectal surgery, both morbidity and mortality were increased and overall survival decresed when compared to a non-emergent population. Conclusions Through identification of preoperative variables such as a hematocrit 1.4, those patients at risk for postoperative morbidity and mortality can be identified and clinical decision making can be appropriately adjusted.

Objective Patient, hospital, and surgeon factors affect outcome after carotid endarterectomy (CEA). The nature and importance of hospital-specific factors, especially those unrelated to procedural volume, that affect post-CEA outcome remains poorly defined. We used a statewide database to determine the impact of several hospital-associated factors on outcome after CEA. Methods Hospital factors were established by telephone survey and validated by repeated survey as well as by the Connecticut Hospital Association, Connecticut state, and individual hospital internet Websites. All CEA in Connecticut non-federal hospitals between 1991 and 2002 were examined, including perioperative mortality, stroke, and cardiac complications. Multivariable logistic regression was used to analyze data. Results There were 14,288 CEAs performed with 0.5% mortality, 1.3% stroke, and 2.4% cardiac complications. The only hospital factor independently predictive of perioperative mortality was few number of hospital beds (less than 132 beds; odds ratio (OR) 2.78, P = 0.032). Factors predictive of perioperative stroke included few number of beds (OR 1.96, P = 0.001) and absence of a critical pathway (OR 1.39, P = 0.038). Factors predictive of perioperative cardiac complications included few number of beds (OR 3.01, P = 0.003), absence of a critical pathway (OR 1.50, P = 0.001), and absence of dedicated vascular recovery beds (OR 1.35, P = 0.03). Combined mortality, stroke, or cardiac complications were independently predicted by few hospital beds (OR 4.58, P = 0.002), absence of a critical pathway (OR 1.81, P ≤ 0.0001), or inability to perform cardiac angiography (OR 3.92, P = 0.024). Conclusions Hospital-based factors, such as greater bed capacity, use of critical pathways, ability to perform cardiac angiography, or presence of a dedicated vascular recovery unit predict reduced perioperative mortality, stroke and cardiac complications from CEA. These results suggest that hospital-associated factors do impact surgical outcome and that surgeons need to optimize these factors, extrinsic to the patient and surgeon, to provide maximal quality of care.

Background The incidence of vascular disease increases with age. Because atherosclerosis and neointimal hyperplasia colocalize in areas of disturbed shear stress, the effects of orbital shear stress (SS) on endothelial cell proliferation, protein kinase B (Akt) activation, and functional activity were analyzed using a senescence model. Methods Early- (p3 to 7) and late- (p28 to 32) passage bovine aortic endothelial cells were exposed to orbital SS (210 rpm) or static conditions (0 to 5 days). Cell proliferation was directly counted and confirmed with proliferating cell nuclear antigen reactivity. Phosphorylated and total Akt were assessed with Western blotting. Endothelial cell–induced smooth muscle cell migration was assessed with a Boyden chamber. Results Late-passage endothelial cells demonstrated no increase in orbital SS stimulated proliferation compared with early-passage cells ( P = .42). Late-passage endothelial cells demonstrated decreased Akt phosphorylation in response to SS compared with early passage cells (n = 6, P = .01). Late-passage cells induced 26% less smooth muscle cell migration than early-passage cells (n = 3, P = .03). Conclusions Late-passage endothelial cells demonstrate decreased proliferation, Akt phosphorylation, and secretion of smooth muscle cell chemoattractants in response to orbital SS compared with early passage cells. These results suggest that late-passage endothelial cells respond to SS differently than early-passage cells and confirm the utility of the in vitro senescence model.

Hepatocellular carcinoma (HCC) is one of the most common cancers in the world. It usually develops in patients with chronic viral hepatitis, aflatoxin exposure, or excessive alcohol use. Most patients with HCC present with advanced disease and have a poor prognosis. The implementation of antiviral drugs and the availability of a vaccine for hepatitis B should help reduce the incidence of HCC. Considerable effort has now focused on unraveling the molecular pathogenesis of HCC in order to design better treatments, or to prevent the disease altogether. However, so far, the pathogenesis of HCC appears to be quite heterogeneous among patients. In particular, several mechanisms of tumorigenesis seem to be involved, including loss of tumor suppressor gene function, oncogene activation, direct viral effects, DNA methylation, and angiogenesis. It is not clear which events are critical in tumor initiation versus tumor progression. RNA expression arrays and proteomics hold promise to provide further clues about this common and complex cancer.

Radiation therapy is increasingly used as adjuvant treatment of many childhood and adult malignancies. Radiation-induced sarcoma is a well recognized if uncommon event. The objective of this study is to determine the prevalence and long-term outcome for patients who develop radiation-induced sarcomas.From July 1982 to December 2001, 4884 adult patients with sarcoma were admitted and treated at our institution and recorded in a prospective database. There were 123 (2.5%) patients who had radiation-induced soft tissue sarcomas. Survival was determined by Kaplan-Meier analysis. Patient, tumor, and treatment characteristics were tested for their prognostic significance by log rank and the Cox proportional hazards model.The median interval between radiation and development of sarcoma was 103 (6 to 534) months. In 114 patients with radiation-induced sarcoma who underwent curative resection, the 5-year actuarial survival was 41%, with a median survival of 48 months at a median follow-up of 36 months for survivors. The most common malignancy for which radiation was used was breast cancer (29%), followed by lymphoma (16%) and prostate cancer (15%). Malignant fibrous histiocytoma (23%) was the most common histologic diagnosis, followed by fibrosarcoma (15%) and angiosarcoma (15%). High-grade tumors (n = 85; 79%), age60 years (n = 61; 50%), and gross positive resection margin (n = 36; 32%) were predictive of poor sarcoma-specific survival on univariate and multivariate analysis.The increasing utilization of adjuvant radiation therapy, especially for early-stage breast cancer mandates long-term follow-up to detect radiation-induced sarcoma. Surgical resection remains the primary therapy, but 5-year survival remains approximately 40%.

Background The majority of patients with hepatocellular carcinoma (HCC) who undergo complete tumor resection subsequently develop tumor recurrence. The objectives of this study were to determine the risk factors for recurrence of HCC after hepatectomy and to examine the outcomes once tumor recurrence occurs. Study design From February 1990 to May 2001 a total of 164 patients underwent liver resection for HCC at our institution and were prospectively followed. Time to recurrence and survival after recurrence were determined by Kaplan-Meier analysis. Patient, tumor, and treatment characteristics were tested for their prognostic significance by univariate and multivariate analysis using the logrank test and the Cox proportional hazards model, respectively. Results The median patient age was 64 years (range 21 to 87 years) and 106 patients (65%) were male. After a median followup of 26 months, 90 patients (55%) have developed recurrent cancer. Among them, 75 patients (83%) had tumor detectable in the liver, which was the only site of disease in 67 (74%). In all, 15 patients (20%) had extrahepatic disease (7 lung, 4 peritoneum, 2 pancreas, 1 bone, and 1 brain). The median time to recurrence was 24 months (range 1 to 274 months). Predictors of recurrence on univariate analysis were tumor size greater than 5 cm, more than one tumor, cirrhosis, vascular invasion (microscopic or macroscopic), and tumor satellites. On multivariate analysis only tumor size greater than 5 cm (p = 0.04) and vascular invasion (p = 0.01) predicted recurrence. The median survival after recurrence was 11 months (range 0 to 60 months). Of the 90 patients who developed tumor recurrence 49 (67%) were able to undergo additional ablative or surgical therapy (33 embolization, 9 ethanol injection, and 14 re-resection). On multivariate analysis vascular invasion in the original tumor predicted poor survival after recurrence (p = 0.009). Conclusions The liver is the predominant site of first recurrence after resection of hepatocellular carcinoma, and once recurrence occurs survival is limited. The current study underscores the need for effective adjuvant therapy for patients with HCC treated with partial hepatectomy.

Hepatocellular carcinoma (HCC) is the fifth-leading cause of cancer in the world.1,2 In the United States, there will be 20,200 new cases of HCC this year, which is a 75% increase over the past decade and reflects the increased prevalence of chronic hepatitis infection.3 Three million people have chronic hepatitis C, and 1.2 million have chronic hepatitis B in the United States. These patients are estimated to develop HCC at a rate of 5% per year for chronic hepatitis C and 0.5% per year for hepatitis B.4,5 It is predicted that the number of deaths from HCC will rise dramatically over the next 10-15 years in this country.2,6,7 Partial hepatectomy has been the standard therapy for patients with HCC and good hepatic reserve when complete tumor resection is feasible. Five-year survival rates after resection have ranged from approximately 30 to 40%.8-14 Unfortunately, the majority of patients subsequently develop recurrent cancer in the liver remnant after resection.12,15 Adjuvant therapy has not been proven to be effective.16,17 In an attempt to achieve better results, surgeons have used liver transplantation for patients with HCC. The initial experience, in which transplantation was used liberally for patients with all stages of HCC, was discouraging, with 5-year survival rates ranging from 20-36%.18-22 It was noted, however, that patients with incidentally discovered HCC in the explanted liver and those with small tumors had similar survival comparable with patients undergoing liver transplantation for benign disease.23 Soon thereafter, the eligibility criteria for transplantation in patients with HCC were restricted. Mazzaferro et al24 published one of the first series to propose the currently accepted criteria for transplantation: a solitary tumor ≤ 5 cm, 2 or 3 tumors ≤ 3 cm in size, and the absence of vascular invasion. Four-year survival was reported at 75%, and 4 year recurrence free survival was 83%. Several other studies have confirmed these findings.20-23,25-28 Some authors have found the results to be so convincing that they are using liver transplantation as a first line treatment of patients with HCC and cirrhosis, regardless of the degree of liver dysfunction.29 However, the seemingly better results with transplantation versus partial hepatectomy may simply reflect the more stringent selection of patients with earlier stage HCC. In an attempt to determine whether partial hepatectomy or transplantation is a better treatment of early HCC, we examined the outcome of patients with early HCC treated with partial hepatectomy who would have been candidates for transplantation.

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, responsible for an estimated one million deaths annually. The incidence in the United States has steadily increased over the past two decades. Although HCC has historically had a dismal prognosis, it is now being detected earlier as a result of improved radiologic imaging and surveillance. This affords the opportunity to treat patients with curative intent, and may improve survival. Partial hepatectomy and transplantation each provide potentially curative therapy for selected patients with HCC. Transplantation is indicated when there is severe underlying liver dysfunction. Local ablative therapy, such as ethanol injection, hepatic artery embolization, and radiofrequency ablation, offer palliation for patients when surgery is not feasible. The rational application of the myriad of therapies to a patient with HCC is designed to maximize both quality of life and survival.

The recurrence of breast cancer and its metastatic spread are invariably associated with death from the disease. Even so, there are features of metastatic breast cancer that uniquely separate it from the metastatic process of most solid tumors. For example, it is common for metastatic breast cancer to follow a slow and indolent course. When the disease first recurs in patients whose primary tumor was estrogen receptor (ER)–positive and who received aggressive adjuvant chemotherapy, the pattern of initial failure often involves bone and soft tissues rather than critical organ structures. In addition, metastatic breast cancer is generally seen in older, postmenopausal women with a fairly long disease-free interval and a small initial metastatic tumor load. Metastatic breast cancer is also one of the more responsive cancers to systemic therapy, and these responses are often of reasonably long duration. For most patients there will be multiple opportunities for therapeutic intervention, including both a series of hormonal manipulations and cytotoxic chemotherapy. As a result, the treatment of metastatic breast cancer can be quite rewarding, can involve many stages of therapy, and can take place over many years—often a decade or more. This scenario, of course, is not true for all women with recurrent disease. In some, the disease has a much more aggressive course. Patients with aggressive disease tend to be premenopausal, have a short disease-free interval, have ER-negative primary tumors, and present with multiple sites of disease, including major organs such as the liver and lung. Metastatic breast cancer can be found at the time of primary tumor diagnosis, but this is becoming less common today, occurring in less than 5% to 10% of newly diagnosed breast cancer patients (3.7% in white women and 5.9% in black women.) 119 Metastatic breast cancer is almost always associated with locally advanced disease. In the United States the incidence of this stage IV disease is 10,000 to 15,000 cases annually. To estimate the total number of women receiving treatment for metastatic breast cancer each year in the United States, it is possible to use the figure of 180,000 new breast cancers per year, of which 45,000 to 50,000 are stage II and III disease. More than half of these, approximately 25,000, will eventually recur. These numbers suggest that nearly 35,000 to 40,000 women are diagnosed with recurrent breast cancer each year, a number that certainly equates with the approximately 45,000 deaths from metastatic breast cancer per year in the United States. 88 Metastatic breast cancer thus requires significant health care resources in evaluation, therapy, and supportive care.

Hepatocellular carcinoma is one of the most common malignancies worldwide, and its incidence continues to rise in the United States. Partial hepatectomy and liver transplantation remains the mainstay of treatment for localized disease and provides significant improvement in long-term survival, as well as the potential for cure. The indications and criteria for resection and transplantation are well established, but continue to undergo significant modification over time. Surgical resection is the primary therapeutic modality in patients with well-compensated liver disease, and transplantation is highly effective in early-stage tumors in patients with severe underlying liver disease. The relative role for each of these modalities must be tailored to individual patients based on a rational approach designed to balance quality of life, organ allocation, and patient survival.