The impact of tranexamic acid on administration of red blood cell transfusions for resection of colorectal liver metastases.

BACKGROUND: Red blood cell transfusions (RBCT) remain a concern for patients undergoing hepatectomy. The effect of tranexamic acid (TXA), an anti-fibrinolytic, on receipt of RBCT in colorectal liver metastases (CRLM) resection was examined. METHODS: Hepatectomies for CRLM over 2009-2014 were included. Primary outcome was 30-day receipt of RBCT. Secondary outcomes were 30-day major morbidity (Clavien-Dindo III-V) and 90-day mortality. Multivariable modelling examined the adjusted association between TXA and outcomes. RESULTS: Of 433 included patients, 146 (34%) received TXA. TXA patients were more likely to have inflow occlusion (41.8% vs. 23.1%; p < 0.01) and major hepatectomies (56.1% vs. 45.6%; p = 0.0193). TXA was independently associated with lower risk of RBCT (Relative risk (RR) 0.59; 95% confidence interval (95%CI): 0.42-0.85), but not with 30-day major morbidity (adjusted RR 1.02; 95%CI: 0.64-1.60) and 90-day mortality (univariable RR 0.99; 95%CI: 0.95-1.03). CONCLUSION: Intraoperative TXA was associated with a 41% reduction in risk of 30 -day receipt of RBCT after hepatectomy for CRLM. This finding is important to potentially improve healthcare resource allocation and patient outcomes. Pending further evidence, intraoperative TXA may be an effective method of reducing RBCT in hepatectomy for CRLM.

Benefits of High-Volume Medical Oncology Care for Noncurable Pancreatic Adenocarcinoma: A Population-Based Analysis.

BACKGROUND: Although pancreatic adenocarcinoma (PA) surgery performed by high-volume (HV) providers yields better outcomes, volume-outcome relationships are unknown for medical oncologists. This study examined variation in practice and outcomes in noncurative management of PA based on medical oncology provider volume. METHODS: This population-based cohort study linked administrative healthcare datasets and included nonresected PA from 2005 through 2016. The volume of PA consultations per medical oncology provider per year was divided into quintiles, with HV providers (≥16 patients/year) constituting the fifth quintile and low-volume (LV) providers the first to fourth quintiles. Outcomes were receipt of chemotherapy and overall survival (OS). The Brown-Forsythe-Levene (BFL) test for equality of variances was performed to assess outcome variability between provider-volume quintiles. Multivariate regression models were used to examine the association between management by HV provider and outcomes. RESULTS: A total of 7,062 patients with noncurable PA consulted with medical oncology providers. Variability was seen in receipt of chemotherapy and median survival based on provider volume (BFL, P<.001 for both), with superior 1-year OS for HV providers (30.1%; 95% CI, 27.7%-32.4%) compared with LV providers (19.7%; 95% CI, 18.5%-20.6%) (P<.001). After adjustment for age at diagnosis, sex, comorbidity burden, rural residence, income, and diagnosis period, HV provider care was independently associated with higher odds of receiving chemotherapy (odds ratio, 1.19; 95% CI, 1.05-1.34) and with superior OS (hazard ratio, 0.79; 95% CI, 0.74-0.84). CONCLUSIONS: Significant variation was seen in noncurative management and outcomes of PA based on provider volume, with management by an HV provider being independently associated with superior OS and higher odds of receiving chemotherapy. This information is important to inform disease care pathways and care organization. Cancer care systems could consider increasing the number of HV providers to reduce variation and improve outcomes.

Patterns of Symptoms Burden in Neuroendocrine Tumors: A Population-Based Analysis of Prospective Patient-Reported Outcomes.

BACKGROUND: How to best support patients with neuroendocrine tumors (NETs) remains unclear. Improving quality of care requires an understanding of symptom trajectories. Objective validated assessments of symptoms burden over the course of disease are lacking. This study examined patterns and risk factors of symptom burden in NETs, using patient-reported outcomes. SUBJECTS, MATERIALS, AND METHODS: A retrospective, population-based, observational cohort study of patients with NETs diagnosed from 2004 to 2015, who survived at least 1 year, was conducted. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to provincial administrative health data sets. Moderate-to-severe symptom scores were presented graphically for both the 1st year and 5 years following diagnosis. Multivariable Poisson regression identified factors associated with record of moderate-to-severe symptom scores during the 1st year after diagnosis. RESULTS: Among 2,721 included patients, 7,719 symptom assessments were recorded over 5 years following diagnosis. Moderate-to-severe scores were most frequent for tiredness (40%-51%), well-being (37%-49%), and anxiety (30%-40%). The proportion of moderate-to-severe symptoms was stable over time. Proportion of moderate-to-severe anxiety decreased by 10% within 6 months of diagnosis, followed by stability thereafter. Changes were below 5% for other symptoms. Similar patterns were observed for the 1st year after diagnosis. Primary tumor site, metastatic disease, younger age, higher comorbidity burden, lower socioeconomic status, and receipt of therapy within 30 days of assessment were independently associated with higher risk of elevated symptom burden. CONCLUSION: Patients with NETs have a high prevalence of moderate-to-severe patient-reported symptoms, with little change over time. Patients remain at risk of prolonged symptom burden following diagnosis, highlighting potential unmet needs. Combined with identified patient and disease factors associated with moderate-to-severe symptom scores, this information is important to support symptom management strategies to improve patient-centered care. IMPLICATIONS FOR PRACTICE: This study used population-level, prospectively collected, validated, patient-reported outcome measures to appraise the symptoms burden and trajectory of patients with neuroendocrine tumors (NETs) after diagnosis. It is the largest and most detailed analysis of patient-reported symptoms for NETs. Patients with NETs present a high burden of symptoms at diagnosis that persists up to 5 years later, highlighting unmet needs. Early and comprehensive symptom screening and management programs are needed. This information should serve to devise pathways and policies to better support patients, evaluate supportive interventions, and assess the effectiveness of symptom management at the provider, institutional, and system levels.

Symptom Burden at the End of Life for Neuroendocrine Tumors: An Analysis of 2579 Prospectively Collected Patient-Reported Outcomes.

BACKGROUND: Given a slow course of disease, end-of-life issues are understudied in neuroendocrine tumors (NETs). To date, there are no data regarding symptoms at the end of life. This study examined symptom trajectories and factors associated with high symptom burden in NETs at the end of life. METHODS: We conducted a retrospective cohort study of NET patients diagnosed from 2004 to 2015 and who died between 2007 and 2016, in Ontario, Canada. Prospectively collected patient-reported Edmonton Symptom Assessment System scores were linked to administrative healthcare datasets. Moderate-to-severe symptom scores (≥ 4 out of 10) in the 6 months before death were analyzed, with multivariable modified Poisson regression identifying factors associated with moderate-to-severe symptoms scores. RESULTS: Among 677 NET decedents, 2579 symptom assessments were recorded. Overall, moderate-to-severe scores were most common for tiredness (86%), wellbeing (81%), lack of appetite (75%), and drowsiness (68%), with these proportions increasing as death approached. For symptoms of lack of appetite, drowsiness, and shortness of breath, the increase was steepest in the 8 weeks before death. On multivariable analyses, the risk of moderate-to-severe symptoms was significantly higher in the last 2 months before death and for patients with shorter survival (< 6 months). Women had higher risks of anxiety, nausea, and pain. CONCLUSION: A high prevalence of moderate-to-severe symptoms was observed for NETs at the end of life, not previously described. The proportion of moderate-to-severe symptoms increases steeply as death nears, highlighting an opportunity for improved management. Combined with identified factors associated with moderate-to-severe symptoms, this information is important to improve patient-centred and personalized supportive care for NETs at the end of life.

Low rates of specialized cancer consultation and cancer-directed therapy for noncurable pancreatic adenocarcinoma: a population-based analysis.

BACKGROUND: Although advancements in systemic therapy have improved the outlook for pancreatic adenocarcinoma, it is not known if patients get access to these therapies. We aimed to examine the patterns and factors associated with access to specialized cancer consultations and subsequent receipt of cancer-directed therapy for patients with non-curative pancreatic adenocarcinoma. METHODS: We conducted a population-based analysis of noncurative pancreatic adenocarcinoma diagnosed over 2005-2016 in Ontario by linking administrative health care data sets. Our primary outcomes were specialized cancer consultation and receipt of cancer-directed therapy (chemotherapy or a combination of chemo- and radiation therapy [chemoradiation therapy]). We examined specialized cancer consultation with hepato-pancreatico-biliary surgery, medical and radiation oncology. We used multivariable logistic regression to identify factors associated with medical oncology consultation and cancer-directed therapy. RESULTS: Of 10 881 patients, 64.9% had a consultation with specialists in medical oncology, 35.1% with hepatopancreatico-biliary surgery and 24.7% with radiation oncology. Sociodemographic characteristics were not associated with the likelihood of medical oncology consultation. Of these patients, 4144 received cancer-directed therapy, representing 38.1% of all patients and 58.6% of those who consulted with medical oncology. Of 6737 patients not receiving cancer-directed therapy, 2988 (44.4%) had a consultation with medical oncology. Older age and lowest income quintile were independently associated with lower likelihood of cancer-directed therapy. If the first specialized cancer consultation was with medical or radiation oncology, the likelihood of cancer-directed therapy was significantly higher compared with surgery. INTERPRETATION: A considerable proportion of patients with noncurable pancreatic adenocarcinoma in Ontario did not have a specialized cancer consultation and most did not receive cancer-directed therapy. We identified disparities in specialized cancer consultation and receipt of systemic cancer-directed therapy that indicate potential gaps in assessment.

Reducing repeat imaging in hepato-pancreatico-biliary surgical cancer care through shared diagnostic imaging repositories.

BACKGROUND: With regionalization of care, patients often undergo treatment in institutions other than where the initial investigation is conducted. This study assessed the impact of a shared diagnostic imaging repository (SDIR) on processes of care and outcomes in hepato-pancreatico-biliary (HPB) cancer surgery. METHODS: Provincial administrative datasets were linked to study HPB cancer patients operated at a regional cancer centre (2003-2014). SDIR and non-SDIR groups were based on where initial imaging (CT or MRI) was conducted. Outcomes were repeat imaging before surgery and wait times for surgery from initial imaging and surgical consultation. RESULTS: Of 839 patients, 474 were from SDIR institutions. Fewer SDIR patients underwent any repeat imaging (55.9% vs. 75.3%; p < 0.01) and repeat imaging with same modality and protocol (24.7% vs. 43.0%; p < 0.01). Median wait time to surgery from initial imaging (64 Vs. 79 days; p < 0.01) and surgical consultation (39 Vs. 45 days; p = 0.046) was shorter with SDIR. SDIR patients had lower adjusted odds of any repeat imaging (OR 0.20 [0.14-0.30]), and repeat imaging with same modality and protocol (OR 0.58 [0.41-0.80]). CONCLUSION: Radiology sharing with SDIR reduced repeat imaging for HPB cancer surgery, including potentially redundant repeat imaging with same protocol, and shortened wait time to surgical care.

Critical appraisal of predictive tools to assess the difficulty of laparoscopic liver resection: a systematic review.

BACKGROUND: Objective assessment of the difficulty of laparoscopic liver resection (LLR) preoperatively is key in improving its uptake. Difficulty scores are proposed but are not used routinely in practice. We identified and appraised predictive models to estimate LLR difficulty. METHODS: We systematically searched the literature for tools predicting LLR difficulty. Two independent reviewers selected studies, abstracted data and assessed methodology. We evaluated tools' quality and clinical relevance using the Critical Appraisal and Data Extraction for Systematic Reviews of Prediction Modelling Studies (CHARMS) guidelines. RESULTS: From 1037 citations, we included 8 studies reporting on 4 predictive tools using data from 1995 to 2016 in Asia and Europe. In 4 development studies, tools were designed to predict difficulty as assigned by experts using a 10-level difficulty index, operative time, post-operative morbidity or intra-operative complications. Internal validation and performance metrics were reported in one development study. One tool was subjected to external validations in 4 studies (1 independent and geographic). Validations compared post-operative outcomes (operative time, blood loss, transfusion, major morbidity and conversion) between the risk categories. One study validated discrimination (AUROC 0.53). Calibration was not assessed. CONCLUSION: Existing tools cannot be used confidently to predict LLR difficulty. Consistent objective clinical outcomes to predict to define LLR difficulty should be established, and better-quality tools developed and validated in a wide array of populations and clinical settings, following best practices for predictive tools development and validation. This will improve risk stratification for future trials and uptake of LLR.

Patient blood management for liver resection: consensus statements using Delphi methodology.

BACKGROUND: Blood loss and transfusion remain a significant concern in liver resection (LR). Patient blood management (PBM) programs reduce use of transfusions and improve outcomes and costs, but are not standardized for LR. This study sought to create an expert consensus statement on PBM for LR using modified Delphi methodology. METHODS: An expert panel representing hepato-biliary surgery, anesthesiology, and transfusion medicine was invited to participate. 28 statements addressing the 3 pillars of PBM were created. Panelists were asked to rate statements on a 7-point Likert scale. Three-rounds of iterative rating and feedback were completed anonymously, followed by an in-person meeting. Consensus was reached with at least 70% agreement. RESULTS: The 35 experts panel recommended routine pre-operative transfusion risk assessment, and investigation and management of anemia with iron supplementation. Intra-operatively, restrictive fluid administration without routine central line insertion was recommended, along with intermittent hepatic pedicle occlusion and surgical techniques considerations. Specific criteria for restrictive intra-operative and post-operative transfusion strategy were recommended. CONCLUSIONS: PBM for LR included medical and technical interventions throughout the perioperative continuum, addressing specificities of LR. Diffusion and adoption of these recommendations can standardize PBM for LR to improve patient outcomes and resource utilization.

The Role of p53 in Determining Mitochondrial Adaptations to Endurance Training in Skeletal Muscle.

p53 plays an important role in regulating mitochondrial homeostasis. However, it is unknown whether p53 is required for the physiological and mitochondrial adaptations with exercise training. Furthermore, it is also unknown whether impairments in the absence of p53 are a result of its loss in skeletal muscle, or a secondary effect due to its deletion in alternative tissues. Thus, we investigated the role of p53 in regulating mitochondria both basally, and under the influence of exercise, by subjecting C57Bl/6J whole-body (WB) and muscle-specific p53 knockout (mKO) mice to a 6-week training program. Our results confirm that p53 is important for regulating mitochondrial content and function, as well as proteins within the autophagy and apoptosis pathways. Despite an increased proportion of phosphorylated p53 (Ser15) in the mitochondria, p53 is not required for training-induced adaptations in exercise capacity or mitochondrial content and function. In comparing mouse models, similar directional alterations were observed in basal and exercise-induced signaling modifications in WB and mKO mice, however the magnitude of change was less pronounced in the mKO mice. Our data suggest that p53 is required for basal mitochondrial maintenance in skeletal muscle, but is not required for the adaptive responses to exercise training.

Outcomes of Non-curative Gastrectomy for Gastric Cancer: An Analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP).

BACKGROUND: The surgical care of patients with metastatic gastric cancer (GC) remains debated. Despite level 1 evidence showing lack of survival benefit, surgery may be used for symptoms prevention or palliation. This study examined short-term postoperative outcomes of non-curative gastrectomy performed for metastatic GC. METHODS: A multi-institutional retrospective cohort study was conducted using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry, including gastrectomies for GC (2007-2015). The primary outcome was 30-day major morbidity. Multivariable analysis examined the association between metastatic status and outcomes adjusted for relevant demographic and clinical covariates. RESULTS: Of 5341 patients, 377 (7.1%) had metastases. Major morbidity was more common with metastases (29.4 vs. 19.6%; p < 0.001), driven by a higher rate of respiratory events. Prolonged hospital length of stay (beyond the 75th percentile: 11 days) was more likely with metastases than with no metastases (41.9 vs. 28.3%; p < 0.001). After adjustment, metastatic status was associated with major morbidity (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.16-1.90). This association remained for respiratory events (OR, 1.58; 95% CI, 1.07-2.33), 30-day mortality (OR, 2.19; 95% CI, 1.38-3.48), and prolonged hospital stay (OR, 1.65; 95% CI, 1.31-2.07). CONCLUSION: Non-curative gastrectomy for metastatic GC was associated with significant major morbidity and mortality as well as a prolonged hospital stay, longer than expected for gastrectomy for non-metastatic GC. These data can inform decision making regarding non-curative gastrectomy, helping surgeons to weigh the risks of morbidity against the potential benefits and alternative therapeutic options.

The impact of perioperative blood transfusions on short-term outcomes following hepatectomy.

BACKGROUND: Bleeding and need for red blood cell transfusions (RBCT) remain a significant concern with hepatectomy. RBCT carry risk of transfusion-related immunomodulation that may impact post-operative recovery. This study soughs to assess the association between RBCT and post-hepatectomy morbidity. METHODS: Using the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) registry, we identified all adult patients undergoing elective hepatectomy over 2007-2012. Two exposure groups were created based on RBCT. Primary outcomes were 30-day major morbidity and mortality. Secondary outcomes included 30-day system-specific morbidity and length of stay (LOS). Relative risks (RR) with 95% confidence interval (95% CI) were computed using regression analyses. Sensitivity analyses were conducted to understand how missing data might have impacted the results. RESULTS: A total of 12,180 patients were identified. Of those, 11,712 met inclusion criteria, 2,951 (25.2%) of whom received RBCT. Major morbidity occurred in 14.9% of patients and was strongly associated with RBCT (25.3% vs. 11.3%; P<0.001). Transfused patients had higher rates of 30-day mortality (5.6% vs. 1.0%; P<0.0001). After adjustment for baseline and clinical characteristics, RBCT was independently associated with increased major morbidity (RR 1.80; 95% CI: 1.61-1.99), mortality (RR 3.62; 95% CI: 2.68-4.89), and 1.29 times greater LOS (RR 1.29; 95% CI: 1.25-1.32). Results were robust to a number of sensitivity analyses for missing data. CONCLUSIONS: Perioperative RBCT for hepatectomy was independently associated with worse short-term outcomes and prolonged LOS. These findings further the rationale to focus on minimizing RBCT for hepatectomy, when they can be avoided.

Outcomes of Cytoreductive Surgery for Metastatic Low-Grade Neuroendocrine Tumors in the Setting of Extrahepatic Metastases.

BACKGROUND: Neuroendocrine tumors (NETs) have a uniquely indolent biology. Management focuses on tumor and hormonal burden reduction. Data on cytoreduction with extrahepatic disease remain limited. OBJECTIVE: We sought to define the outcomes of cytoreduction for metastatic NETs with extrahepatic metastases. METHODS: Patients undergoing cytoreductive surgery for grade 1 or 2 NETs with extrahepatic metastases (with or without intrahepatic disease) were identified from an institutional database (2003-2014). Primary outcomes included postoperative hormonal response (> 50% urinary 5HIAA decrease), progression-free survival (PFS) and overall survival (OS), while secondary outcomes were 30-day postoperative major morbidity (Clavien grade III-V), mortality, and length of stay. RESULTS: Fifty-five patients were identified (median age 59.3 years, 80% small bowel primaries, 56.4% grade 1); 87% of patients presented with combined intra- and extrahepatic metastases. Resection most commonly included the liver (87%), small bowel (22%), mesenteric (25%) and retroperitoneal (11%) lymph nodes, and peritoneum (7%). Thirty-day major morbidity (Clavien III-V) was 18%, with 3.6% mortality, and median length of stay was 7 days [interquartile range (IQR) 5-9]. Liver embolization was performed in 31% of patients after surgery, at a median of 23 months following surgery. Overall, postoperative hormonal response occurred in 70% of patients. At median follow-up of 37 months (IQR range 22-93), 42 (76%) patients were alive and 23 (41.8%) had progressed. Five-year OS was 77% and 5-year PFS was 51%. CONCLUSION: Patients undergoing cytoreduction of metastatic well-differentiated NET in the setting of extrahepatic metastatic disease experience good tumoral control with favorable PFS and OS. Cytoreductive surgery can be safely included in the therapeutic armamentarium for NET with extrahepatic metastases.

A systematic review of p53 regulation of oxidative stress in skeletal muscle.

BACKGROUND: p53 is a tumor suppressor protein involved in regulating a wide array of signaling pathways. The role of p53 in the cell is determined by the type of imposed oxidative stress, its intensity and duration. The last decade of research has unravelled a dual nature in the function of p53 in mediating the oxidative stress burden. However, this is dependent on the specific properties of the applied stress and thus requires further analysis. METHODS: A systematic review was performed following an electronic search of Pubmed, Google Scholar, and ScienceDirect databases. Articles published in the English language between January 1, 1990 and March 1, 2017 were identified and isolated based on the analysis of p53 in skeletal muscle in both animal and cell culture models. RESULTS: Literature was categorized according to the modality of imposed oxidative stress including exercise, diet modification, exogenous oxidizing agents, tissue manipulation, irradiation, and hypoxia. With low to moderate levels of oxidative stress, p53 is involved in activating pathways that increase time for cell repair, such as cell cycle arrest and autophagy, to enhance cell survival. However, with greater levels of stress intensity and duration, such as with irradiation, hypoxia, and oxidizing agents, the role of p53 switches to facilitate increased cellular stress levels by initiating DNA fragmentation to induce apoptosis, thereby preventing aberrant cell proliferation. CONCLUSION: Current evidence confirms that p53 acts as a threshold regulator of cellular homeostasis. Therefore, within each modality, the intensity and duration are parameters of the oxidative stressor that must be analyzed to determine the role p53 plays in regulating signaling pathways to maintain cellular health and function in skeletal muscle. ABBREVIATIONS: Acadl: acyl-CoA dehydrogenase, long chain; Acadm: acyl-CoA dehydrogenase, C-4 to C-12 straight chain; AIF: apoptosis-inducing factor; Akt: protein kinase B (PKB); AMPK: AMP-activated protein kinase; ATF-4: activating transcription factor 4; ATM: ATM serine/threonine kinase; Bax: BCL2 associated X, apoptosis regulator; Bcl-2: B cell Leukemia/Lymphoma 2 apoptosis regulator; Bhlhe40: basic helix-loop-helix family member e40; BH3: Borane; Bim: bcl-2 interacting mediator of cell death; Bok: Bcl-2 related ovarian killer; COX-IV: cytochrome c oxidase IV; cGMP: Cyclic guanosine monophosphate; c-myc: proto-oncogene protein; Cpt1b: carnitine palmitoyltransferase 1B; Dr5: death receptor 5; eNOS: endothelial nitric oxide synthase; ERK: extracellular regulated MAP kinase; Fas: Fas Cell surface death receptor; FDXR: Ferredoxin Reductase; FOXO3a: forkhead box O3; Gadd45a: growth arrest and DNA damage-inducible 45 alpha; GLS2: glutaminase 2; GLUT 1 and 4: glucose transporter 1(endothelial) and 4 (skeletal muscle); GSH: Glutathione; Hes1: hes family bHLH transcription factor 1; Hey1: hes related family bHLH transcription factor with YRPW motif 1; HIFI-α: hypoxia-inducible factor 1, α-subunit; HK2: Hexokinase 2; HSP70: Heat Shock Protein 70; H2O2: Hydrogen Peroxide; Id2: inhibitor of DNA-binding 2; IGF-1-BP3: Insulin-like growth factor binding protein 3; IL-1ß: Interleukin 1 beta; iNOS: inducible nitric oxide synthase; IRS-1: Insulin receptor substrate 1; JNK: c-Jun N-terminal kinases; LY-83583: 6-anilino-5,8-quinolinedione; inhibitor of soluble guanylate cyclase and of cGMP production; Mdm 2/ 4: Mouse double minute 2 homolog (mouse) Mdm4 (humans); mtDNA: mitochondrial DNA; MURF1: Muscle RING-finger protein-1; MyoD: Myogenic differentiation 1; MyoG: myogenin; Nanog: Nanog homeobox; NF-kB: Nuclear factor-κB; NO: nitric oxide; NoxA: phorbol-12-myristate-13-acetate-induced protein 1 (Pmaip1); NRF-1: nuclear respiratory factor 1; Nrf2: Nuclear factor erythroid 2-related factor 2; P21: Cdkn1a cyclin-dependent kinase inhibitor 1A (P21); P38 MAPK: mitogen-activated protein kinases; p53R2: p53 inducible ribonucleotide reductase gene; P66Shc: src homology 2 domain-containing transforming protein C1; PERP: p53 apoptosis effector related to PMP-22; PGC-1α: Peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PGM: phosphoglucomutase; PI3K: Phosphatidylinositol-4,5-bisphosphate 3-kinase; PKCß: protein kinase c beta; PTEN: phosphatase and tensin homolog; PTIO: 2-phenyl-4, 4, 5, 5,-tetramethylimidazoline-1-oxyl 3-oxide (PTIO) has been used as a nitric oxide (NO) scavenger; Puma: The p53 upregulated modulator of apoptosis; PW1: paternally expressed 3 (Peg3); RNS: Reactive nitrogen species; SIRT1: sirtuin 1; SCO2: cytochrome c oxidase assembly protein; SOD2: superoxide dismutase 2; Tfam: transcription factor A mitochondrial; TIGAR: Trp53 induced glycolysis repulatory phosphatase; TNF-a: tumor necrosis factor a; TRAF2: TNF receptor associated factor 2; TRAIL: type II transmembrane protein.

Indications for Contralateral Prophylactic Mastectomy: A Consensus Statement Using Modified Delphi Methodology.

OBJECTIVE: To reach a consensus about contralateral prophylactic mastectomy in unilateral breast cancer. SUMMARY BACKGROUND DATA: There has been a substantial increase in the number of North American women with unilateral breast cancer undergoing a therapeutic mastectomy and a contralateral prophylactic mastectomy (CPM) either simultaneously or sequentially. The purpose of this project was to create a nationally endorsed consensus statement for CPM in women with unilateral breast cancer using modified Delphi consensus methodology. METHODS: A nationally representative expert panel of 19 general surgeons, 2 plastic surgeons, 2 medical oncologists, 2 radiation oncologists, and 1 psychologist was invited to participate in the generation of a consensus statement. Thirty-nine statements were created in 5 topic domains: predisposing risk factors for breast cancer, tumor factors, reconstruction/symmetry issues, patient factors, and miscellaneous factors. Panelists were asked to rate statements on a 7-point Likert scale. Two electronic rounds of iterative rating and feedback were anonymously completed, followed by an in-person meeting. Consensus was reached when there was at least 80% agreement. RESULTS: Our panelists did not recommend for average risk women with unilateral breast cancer. The panel recommended CPM for women with a unilateral breast cancer and previous Mantle field radiation or a BrCa1/2 gene mutation. The panel agreed that CPM could be considered by the surgeon on an individual basis for: women with unilateral breast cancer and a genetic mutation in the CHEK2/PTEN/p53/PALB2/CDH1 gene, and in women who may have significant difficulty achieving symmetry after unilateral mastectomy. CONCLUSION: Contralateral prophylactic mastectomy is rarely recommended for women with unilateral breast cancer.

Laparoscopic Intragastric Resection: An Alternative Technique for Minimally Invasive Treatment of Gastric Submucosal Tumors.

OBJECTIVE: To present the technique for and early results of laparoscopic intragastric resection (LIGR). BACKGROUND: Treatment of confirmed or suspected submucosal gastric malignancies relies on clear margin resection, for which minimally invasive surgery is widely accepted. However, resection in some localization remains challenging. METHODS: We present the steps of LIGR for gastric submucosal tumors (GSMTs). We report the results of LIGR in consecutive patients operated at 2 institutions, including intraoperative, pathologic, 30-day major morbidity and mortality characteristics. RESULTS: After laparoscopic access to the abdominal cavity, cuffed gastric ports are placed to approximate the anterior gastric wall to the abdominal wall. A pneumogastrum is created. The tumor is resected in the submucosal plane and the deficit closed with intragastric suturing. Specimen extraction is performed perorally or through a gastrotomy site. In 8 proximal intraluminal GSMTs with median size of 3.1 cm (range: 1.8-6.0 cm), median operative time was 167.5 minutes (range: 120-300 mins). There was no major morbidity and no mortality. All resections were R0. CONCLUSIONS: We illustrate the technique of a novel, feasible, and safe minimally invasive approach to GSMTs. LIGR is an alternative to resect challenging GSMTs by limiting surgical invasiveness and preserving gastrointestinal function.

Exercise induces TFEB expression and activity in skeletal muscle in a PGC-1α-dependent manner.

The mitochondrial network in muscle is controlled by the opposing processes of mitochondrial biogenesis and mitophagy. The coactivator peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) regulates biogenesis, while the transcription of mitophagy-related genes is controlled by transcription factor EB (TFEB). PGC-1α activation is induced by exercise; however, the effect of exercise on TFEB is not fully known. We investigated the interplay between PGC-1α and TFEB on mitochondria in response to acute contractile activity in C2C12 myotubes and following exercise in wild-type and PGC-1α knockout mice. TFEB nuclear localization was increased by 1.6-fold following 2 h of acute myotube contractile activity in culture, while TFEB transcription was also simultaneously increased by twofold to threefold. Viral overexpression of TFEB in myotubes increased PGC-1α and cytochrome- c oxidase-IV gene expression. In wild-type mice, TFEB translocation to the nucleus increased 2.4-fold in response to acute exercise, while TFEB transcription, assessed through the electroporation of a TFEB promoter construct, was elevated by fourfold. These exercise effects were dependent on the presence of PGC-1α. Our data indicate that acute exercise provokes TFEB expression and activation in a PGC-1α-dependent manner and suggest that TFEB, along with PGC-1α, is an important regulator of mitochondrial biogenesis in muscle as a result of exercise.

Why Do General Surgeons Decide to Retire?: A Population-level Survey.

: Limited recent data exist regarding intended retirement plans for general surgeons (GS). We sought to understand when and why surgeons decide to stop operating as primary surgeon and stop all clinical work.A paper-based survey of practicing GS in the province of Ontario, Canada, was conducted. A questionnaire was developed using a systematic approach of item generation and reduction. Face and content validity were tested. The survey was administered via mail, with a planned reminder.Overall response rate was 33.5% (242/723). The median age at which respondents planned to/did stop operating was 65 (interquartile range 60-67.5). The median age at which respondents planned to/did retire from all clinical work was 70 (interquartile range 65-72.5). Career satisfaction (97%), sense of identity (90%), and financial need (69%) were factors that influenced the decision to continue operating. Enjoyment of work (79%), camaraderie with surgical colleagues (66%), and financial need (45%) were reasons to continue working after ceasing to operate as the primary surgeon. On multivariate analysis, younger respondents (36-50 years old) perceived they were less likely to continue operating past age 65 (odds ratio 0.13), and academic surgeons were more likely to stop operating after age 65 (odds ratio 2.39). Call coverage by nonstaff surgeons was not associated with retirement age.Overall, GS plan to stop operating at age 65, and to cease all clinical activities at age 70. Younger, nonacademic surgeons plan to stop operating earlier. Career satisfaction, sense of identity, and financial need are the principal reported motivations to continue operating.

The impact of advanced age on short-term outcomes following gastric cancer resection: an ACS-NSQIP analysis.

BACKGROUND: Evidence on short-term outcomes for GC resection in elderly patients is limited by small samples from single-institutions. This study sought to examine the association between advanced age and short-term outcomes of gastrectomy for gastric cancer (GC). METHODS: Using ACS-NSQIP data, patients undergoing gastrectomy for GC (2007-2013) were identified. Primary outcome was 30-day major morbidity. Outcomes were compared across age categories (<65, 65-70, 71-75, 76-80, >80 years old). Univariable and multivariable regression was used to estimate the morbidity risk associated with age. RESULTS: Of 3637 patients, 60.6% were ≥65 years old. Major morbidity increased with age, from 16.3% (<65 years old) to 21.5% (76-80 years old), and 24.1% (>80 years old) (p < 0.001), driven by higher respiratory and infectious events. Perioperative 30-day mortality increased from 1.2% (<65years old) to 6.5% (>80 years old) (p < 0.0001). After adjustments, age was independently associated with morbidity for 76-80 years of age (RR 1.31, 95% CI, 1.08-1.60) and >80 years old (RR 1.49, 95% CI, 1.23-1.81). Predicted morbidity increased by 18.6% in those 75-80 years old and 27.5% in those >80 years old (compared to <65 years old) for total gastrectomy, and by 11.6% and 17.2% for subtotal gastrectomy, for worst case scenario. Morbidity increased by 5.1% in those 75-80 years old and 7.6% in those >80 years old for total gastrectomy, and by 3.1% and 4.7% for subtotal gastrectomy, for best case scenario. CONCLUSIONS: Advanced age, defined as more than 75 years, was independently associated with increased morbidity after GC resection. The magnitude of this impact is further modulated by clinical scenarios. Increased risk in elderly GC patient should be recognized and considered in indications for resection.

Patient Adherence and Experience with Extended Use of Prophylactic Low-Molecular-Weight Heparin Following Pancreas and Liver Resection.

BACKGROUND: Guidelines recommend 28 days venous thromboembolism (VTE) prophylaxis with low-molecular-weight heparin (LMWH) following major abdominal surgery for cancer. Overall adherence with these recommendations is poor, but little is known about feasibility and tolerability from a patient perspective. METHODS: An institution-wide policy for routine administration of 28 days of post-operative LMWH following major hepatic or pancreatic resection for cancer was implemented in April 2013. Patients having surgery from July 2013 to June 2015 were approached to participate in an interview examining adherence and experience with extended duration LMWH. RESULTS: There were 100 patients included, with 81.4 % reporting perfect adherence with the regimen. The most frequent reasons for non-adherence were that a healthcare provider stopped the regimen or because of poor experience with injections. Most patients were able to correctly recall the reason for being prescribed LMWH (82.6 %), and 78.4 % of patients performed all injections themselves. Over half the patients (55.7 %) did not find the injections bothersome. CONCLUSION: Patients reported high adherence and a manageable experience with post-operative extended-duration LMWH in an ambulatory setting following liver or pancreas resection. These findings suggest that patient adherence is not a major contributor to poor compliance with VTE prophylaxis guidelines.

Short and long-term outcomes of laparoscopic compared to open liver resection for colorectal liver metastases.

BACKGROUND: Minimally invasive surgery (MIS) is now established as standard of care for a variety of gastrointestinal procedures for benign and malignant indications. However, due to concerns regarding superiority to open liver resection (OLR), the uptake of laparoscopic liver resection (LLR) has been slow. Data on long-term outcomes of LLR for colorectal liver metastases (CRLM) remain limited. We conducted a systematic review and meta-analysis of short and long-term outcomes of LLR compared to OLR for CRLM. METHODS: Five electronic databases were systematically searched for studies comparing LLR and OLR for CRLM and reporting on survival outcomes. Two reviewers independently selected studies and extracted data. Primary outcomes were overall survival (OS) and recurrence free survival (RFS). Secondary outcomes were operative time, estimated blood loss, post-operative major morbidity, mortality, length of stay (LOS), and resection margins. RESULTS: Eight non-randomized studies (NRS) were included (n=2,017 total patients). Six were matched cohort studies. LLR reduced estimated blood loss [mean difference: -108.9; 95% confidence interval (CI), -214.0 to -3.7) and major morbidity [relative risk (RR): 0.68; 95% CI, 0.56-0.83], but not mortality. No difference was observed in operative time, LOS, resection margins, R0 resections, and recurrence. Survival data could not be pooled. No studies reported inferior survival with LLR. OS varied from 36% to 60% for LLR and 37% to 65% for OLR. RFS ranged from 14% to 30% for LLR and 22% to 38% for OLR. According to the grade classification, the strength of evidence was low to very low for all outcomes. The use of parenchymal sparing resections with LLR and OLR could not be assessed. CONCLUSIONS: Based on limited retrospective evidence, LLR offers reduced morbidity and blood loss compared to OLR for CRLM. Comparable oncologic outcomes can be achieved. Although LLR cannot be considered as standard of care for CRLM, it is beneficial for well-selected patients and lesions. Therefore, LLR should be part of the liver surgeon's armamentarium.