Anastomotic Stricture After Minimally Invasive Esophagectomy.

BACKGROUND: Despite improved outcomes, minimally invasive esophagectomy (MIE) continues to be associated with anastomotic strictures. Most resolve after a single dilation; however, some become refractory. Little is known about strictures after MIE in North America. METHODS: We performed a single-institution retrospective review of MIEs from 2015 to 2019. Primary outcomes were the proportion of patients requiring anastomotic dilation and the dilation rate per year. Univariate analyses of patients undergoing dilation by various risk factors were performed with nonparametric tests, and multivariate analyses of the dilation rate were conducted using generalized linear models. RESULTS: Of 391 included patients, 431 dilations were performed on 135 patients (34.5%, 3.2 dilations per patient who required at least 1 per patient). One complication occurred after dilation. Comorbidities, tumor histology, and tumor stage were not significantly associated with stricture. Three-field MIE was associated with a higher percentage of patients undergoing dilation (48.9% vs 27.1%, P < .001) and a higher rate of dilations (0.944 vs 0.441 dilations per year, P = .007) than 2-field MIE, and this association remained significant after controlling for covariates. When accounting for surgeon variability, this difference was no longer significant. Among patients with 1 or more dilations, those receiving dilation within 100 days of surgery needed more subsequent dilations (2.0 vs 0.6 dilations per year, P < .001). CONCLUSIONS: After controlling for multiple variables, a 3-field MIE approach was associated with a higher rate of repeat dilations in patients undergoing MIE. A shorter interval between esophagectomy and initial dilation is strongly associated with the need for repeated dilations.

Mortality risk associated with venous thromboembolism: a systematic review and Bayesian meta-analysis.

BACKGROUND: Venous thromboembolism is associated with increased mortality risk in some populations, but how frequently it is a direct cause of death is unclear. We used data from venous thromboembolism prevention trials to evaluate the causal effect of venous thromboembolism reduction on mortality. METHODS: We did a systematic review and meta-analysis of randomised controlled trials (RCTs) evaluating venous thromboembolism prevention. We searched MEDLINE, Embase, PubMed, and Web of Science starting from Jan 1, 1993, to March 19, 2018. We included studies of patients who were at elevated risk of venous thromboembolism and were randomly assigned to either anticoagulant or antiplatelet therapy versus placebo or no treatment. We excluded studies with an active control agent (which might mitigate the lethality of venous thromboembolism) and those for which mortality data were unavailable. We modelled heterogeneity in a Bayesian framework, taking overall mortality as a primary endpoint, and pulmonary embolism, fatal pulmonary embolism, and major bleeding as secondary endpoints. We focused our analyses on studies reporting statistically significant effects of prevention on venous thromboembolism endpoints. We report treatment effects as median risk ratios (RRs), wherein a null effect equals 1, with 95% credible intervals (CrIs). This meta-analysis was registered with PROSPERO, CRD42018089697. FINDINGS: From 4229 studies screened, we identified 86 eligible RCTs; 52, with data from over 70 000 patients, were positive, with significantly increased venous thromboembolism risk in patients in control groups versus treatment groups (RR 2·74, 95% CrI 2·32-3·31, p<0·0001). The meta-analysis established that the causal effect of venous thromboembolism prevention on mortality was null (control group mortality was 3391 [9·8%] of 34 537 patients; treatment group mortality was 3498 [9·8%] of 35 795 patients [RR 1·01, 95% CrI 0·97-1·06; p=0·58]) with low heterogeneity (τ 0·02, 95% CrI 0·00-0·07, p=0·89). Patients in control groups had more pulmonary embolism (RR 2·22, 95% CrI 1·78-2·89, p<0·0001) and fatal pulmonary embolism (1·58, 1·14-2·19, p=0·01), but less major bleeding (0·60, 0·47-0·75, p<0·0001) than those in treatment groups. A meta-analysis with the additional 34 negative studies yielded similar results for all endpoints except fatal pulmonary embolism, where evidence of an effect was weaker (1·42, 1·05-1·91, p=0·02). INTERPRETATION: The perception that venous thromboembolism is a common cause of mortality should be revised considering the null effect of venous thromboembolism prevention on mortality. Our findings call into question the use of composite endpoints in venous thromboembolism-prevention trials and provide rationale for de-escalation trials. FUNDING: None.

Bile acid-induced "Minority MOMP" promotes esophageal carcinogenesis while maintaining apoptotic resistance via Mcl-1.

Barrett's esophagus (BE) is associated with reflux and is implicated the development of esophageal adenocarcinoma (EAC). Apoptosis induces cell death through mitochondrial outer membrane permeabilization (MOMP), which is considered an irreversible step in apoptosis. Activation of MOMP to levels that fail to reach the apoptotic threshold may paradoxically promote cancer-a phenomenon called "Minority MOMP." We asked whether reflux-induced esophageal carcinogenesis occurred via minority MOMP and whether compensatory resistance mechanisms prevented cell death during this process. We exposed preneoplastic, hTERT-immortalized Barrett's cell, CP-C and CP-A, to the oncogenic bile acid, deoxycholic acid (DCA), for 1 year. Induction of minority MOMP was tested via comet assay, CyQuant, annexin V, JC-1, cytochrome C subcellular localization, caspase 3 activation, and immunoblots. We used bcl-2 homology domain-3 (BH3) profiling to test the mitochondrial apoptotic threshold. One-year exposure of Barrett's cells to DCA induced a malignant phenotype noted by clone and tumor formation. DCA promoted minority MOMP noted by minimal release of cytochrome C and limited caspase 3 activation, which resulted in DNA damage without apoptosis. Upregulation of the antiapoptotic protein, Mcl-1, ROS generation, and NF-κB activation occurred in conjunction with minority MOMP. Inhibition of ROS blocked minority MOMP and Mcl-1 upregulation. Knockdown of Mcl-1 shifted minority MOMP to complete MOMP as noted by dynamic BH3 profiling and increased apoptosis. Minority MOMP contributes to DCA induced carcinogenesis in preneoplastic BE. Mcl-1 provided a balance within the mitochondria that induced resistance complete MOMP and cell death. Targeting Mcl-1 may be a therapeutic strategy in EAC.

Patterns of failure after immunotherapy with checkpoint inhibitors predict durable progression-free survival after local therapy for metastatic melanoma.

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.

Temporal Variations in Pediatric Trauma: Rationale for Altered Resource Utilization.

Trauma is a major cause of morbidity and mortality in the pediatric population. However, temporal variations of trauma have not been well characterized and may have implications for appropriate allocation of hospital resources. Data from patients evaluated at an ACS-verified Level I pediatric trauma center between 2011 and 2015 were retrospectively analyzed. Date and time of injury, type of injury (blunt vs penetrating), and postemergency department disposition were reviewed. To assess temporal trends, heatmaps were constructed and a mixed poisson regression model was used to assess statistical significance. Pediatric trauma from blunt and penetrating injuries occurred at significantly higher rates between the hours of 1800 and 0100, on weekends compared with weekdays, and from May to August compared with November to February. These data provide useful information for hospital resource utilization. The emergency department, operating room, and intensive care unit should be prepared for increased trauma-related volume between May and August, weekends, and evening hours by appropriately increasing staff volume and resource availability.

Induction of Thioredoxin-Interacting Protein by a Histone Deacetylase Inhibitor, Entinostat, Is Associated with DNA Damage and Apoptosis in Esophageal Adenocarcinoma.

In 2017, an estimated 17,000 individuals were diagnosed with esophageal adenocarcinoma (EAC), and less than 20% will survive 5 years. Positron emission tomography avidity is indicative of high glucose utilization and is nearly universal in EAC. TXNIP blocks glucose uptake and exhibits proapoptotic functions. Higher expression in EAC has been associated with improved disease-specific survival, lack of lymph node involvement, reduced perineural invasion, and increased tumor differentiation. We hypothesized that TXNIP may act as a tumor suppressor that sensitizes EAC cells to standard chemotherapeutics. EAC cell lines and a Barrett epithelial cell line were used. qRT-PCR, immunoblot, and immunofluorescence techniques evaluated gene expression. TXNIP was stably overexpressed or knocked down using lentiviral RNA transduction techniques. Murine xenograft methods examined growth following overexpression of TXNIP. Apoptosis and DNA damage were measured by annexin V and γH2AX assays. Activation of the intrinsic apoptosis was quantitated with green fluorescence protein-caspase 3 reporter assay. In cultured cells and an esophageal tissue array, TXNIP expression was higher in Barrett epithelia and normal tissue compared with EAC. Constitutive overexpression of TXNIP decreased proliferation, clonogenicity, and tumor xenograft growth. TXNIP overexpression increased, whereas knockdown abrogated, DNA damage and apoptosis following cisplatin treatment. An HDAC inhibitor, entinostat (currently in clinical trials), upregulated TXNIP and synergistically increased cisplatin-mediated DNA damage and apoptosis. TXNIP is a tumor suppressor that is downregulated in EACC. Its reexpression dramatically sensitizes these cells to cisplatin. Our findings support phase I/II evaluation of "priming" strategies to enhance the efficacy of conventional chemotherapeutics in EAC. Mol Cancer Ther; 17(9); 2013-23. ©2018 AACR.

Adjuvant intraperitoneal chemotherapy for the treatment of colorectal cancer at risk for peritoneal carcinomatosis: a systematic review.

BACKGROUND: The peritoneal surface is the second most common site of disease recurrence, after the liver, following definitive surgery for colorectal cancer. Adjuvant intraperitoneal (IP) chemotherapy delivered at time of surgical resection has the potential to delay or prevent future spread to the peritoneal surface and improve clinical outcome. The exact role of adjuvant IP chemotherapy in colorectal cancer, including its associated morbidity and mortality, is not well defined. STUDY DESIGN: Systematic review and pooled random effect analysis of comparative trials examining the addition of adjuvant IP chemotherapy compared to surgery alone in colorectal cancer. The primary outcome was overall survival, and the secondary outcomes were of post-operative morbidity and mortality. RESULTS: In nine colorectal cancer studies identified, seven were two-arm trials comparing adjuvant IP chemotherapy to surgery alone. Of these, four trials had outcome reporting and met criteria that allowed inclusion into a random effects model. Heterogeneity was measured by Cochran's Q-test (Q = 13.9; p = 0.01) and random effect models were utilised. Pooling eligible trials together revealed a 0.55 odds ratio of death associated with the administration of IP chemotherapy compared to surgery alone (CI = 0.31, 0.98; p = 0.04). Trials selecting patients at elevated risk for the development of peritoneal carcinomatosis by clinicopathological biomarkers for administration of adjuvant IP chemotherapy reported more favourable overall outcomes. There was no increase in mortalities or IP chemotherapy-related abdominal complication rates among patients undergoing IP chemotherapy (OR = 1.4; CI = 0.52, 3.8; p = 0.5). CONCLUSIONS: This systematic review supports the use of adjuvant IP chemotherapy in resectable colorectal cancer at risk for peritoneal spread. Future trials should seek to standardise inclusion criteria and IP chemotherapy modalities to better define the role of this treatment in patients with resectable colorectal cancer.

Bile acid and cigarette smoke enhance the aggressive phenotype of esophageal adenocarcinoma cells by downregulation of the mitochondrial uncoupling protein-2.

Limited information is available regarding mechanisms that link the known carcinogenic risk factors of gastro-esophageal reflux and cigarette smoking to metabolic alterations in esophageal adenocarcinoma (EAC). In the present study, we utilized a novel in-vitro model to examine whether bile acid and cigarette smoke increase the aggressiveness of EAC and whether these changes are associated with metabolic changes. EAC cells (EACC) were exposed to 10 µg/ml cigarette smoke condensate (CSC) and/or 100 µM of the oncogenic bile acid, deoxycholic acid (DCA), for 5 days. These exposure conditions were chosen given their lack of effect on proliferation or viability. DCA and CSC increased invasion, migration, and clonogenicity in EAC cells. These changes were associated with concomitant increases in ATP, ROS, and lactate production indicative of increased mitochondrial respiration as well as glycolytic activity. DCA and CSC exposure significantly decreased expression of uncoupling protein-2 (UCP2), a mitochondrial inner membrane protein implicated in regulation of the proton gradient. Knockdown of UCP2 in EACC phenocopied DCA and CSC exposure as evidenced by increased cell migration, invasion, and clonogenicity, whereas over-expression of UCP2 had an inverse effect. Furthermore, over-expression of UCP2 abrogated DCA and CSC-mediated increases in lactate and ATP production in EACC. DCA and CSC promote the aggressive phenotype of EACC with concomitant metabolic changes occurring via downregulation of UCP2. These results indicate that UCP2 is integral to the aggressive phenotype of EACC. This mechanism suggests that targeting alterations in cellular energetics may be a novel strategy for EAC therapy.

Metastasectomy Following Immunotherapy with Adoptive Cell Transfer for Patients with Advanced Melanoma.

BACKGROUND: Immunotherapeutic treatment strategies including adoptive cell transfer (ACT) for metastatic melanoma are capable of mediating complete and durable responses, as well as partial responses and prolonged disease stabilization. Unfortunately, many patients ultimately develop progressive disease. The role of salvage metastasectomy in managing these patients has not been evaluated. METHODS: Records of patients with metastatic melanoma treated with ACT at a single institution between 2000 and 2014 were reviewed. Patients with an objective response by RECIST criteria or disease stabilization of at least 6 months and who subsequently developed progressive melanoma and were managed with metastasectomy as the next therapeutic strategy were studied for progression-free survival (PFS) and overall survival (OS). Five additional clinical parameters were also reviewed for association with outcomes. RESULTS: Of 115 patients treated with ACT who met our response criteria and then developed progressive disease, 26 (23%) had surgery. There were no mortalities related to surgical intervention. Median follow-up after surgery was 62 months. Median PFS after surgery was 11 months and five-year OS was 57%. The development of a new site of metastasis after ACT was associated with poor PFS and OS. CONCLUSIONS: Surgery after immunotherapy is safe. Long PFS and OS can be achieved by metastasectomy in selected patients with progressive melanoma following treatment with ACT. Clinical variables important for patient selection for metastasectomy after immunotherapy remain largely undefined. Improvements in immunotherapeutic treatment strategies may increase the role of surgery for patients with advanced disease.

Adjuvant intraperitoneal chemotherapy for the treatment of gastric cancer at risk for peritoneal carcinomatosis: A systematic review.

The peritoneal surface is a frequent site of recurrence following surgery for gastric cancer. A systematic review and random effect analysis was undertaken to analyze current literature regarding the role of adjuvant intraperitoneal chemotherapy in gastric cancer. While pooled analysis supports the use of adjuvant IP chemotherapy in resectable gastric cancer, maximal benefit occured with intra-operative delivery, and possibly the use of MMC. J. Surg. Oncol. 2017;115:192-201. © 2016 Wiley Periodicals, Inc.

Thoracic Surgery in Chronic Granulomatous Disease: a 25-Year Single-Institution Experience.

INTRODUCTION: Chronic granulomatous disease (CGD) is a genetic disorder in which phagocyte dysfunction leads to recurrent infection. Persistent pulmonary infections sometimes require thoracic surgical intervention. We reviewed our 25-year experience to identify outcomes and prognostic factors associated with thoracic surgery in these patients. METHODS: A retrospective single-institution review of all patients with CGD from 1990 through 2015 was performed. Univariate analysis identified prognostic variables to include in a Cox model. Overall survival was estimated by the Kaplan-Meier method. RESULTS: We identified 258 patients who had 2221 admissions (both scheduled and emergent). During the period examined, 51 thoracic operations were performed in 13.6 % (35/258) of patients and 2.3 % (35/2221) of overall admissions. Patients undergoing surgery did not have statistically significant differences in disease genotype compared to those that did not require surgery. Pathogens were identified from 67 % (34/51) of specimens. Complications occurred in 27 % (14/51), including 10 % (5/51) with wound and 12 % (6/51) with pulmonary infections. Mortality at 30 and 90 days was 0 and 6 % (3/51), respectively. Overall survival probabilities were 75 and 62 % at 5- and 10-year follow-up (median potential follow-up: 16.5 years), respectively. Undergoing thoracic surgery was associated with an increased hazard ratio for death of 3.71 (p < 0.0001). Both chest wall resection and EBL > 500 mL were negative prognostic factors (p < 0.05). CONCLUSIONS: A minority of CGD patients required thoracic surgery for infections refractory to antibiotic or antifungal therapy. Patients who had these operations had significant morbidity and relatively poor long-term survival, particularly in the cases of chest wall resection or significant blood loss.

Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for gastric cancer and other less common disease histologies: is it time?

Gastric cancer is the fourth most commonly diagnosed cancer worldwide, and once spread to the peritoneum, has a 5-year survival of less than 5%. Recent years have demonstrated advances in the use of cytoreductive surgery (CRS) in combination with heated intraperitoneal chemotherapy (HIPEC) for the treatment of peritoneal carcinomatosis due to various malignancies. The frequent desmoplastic stroma and poor vascularization impeding drug delivery particularly in the diffuse form of gastric cancer is thought to provide a sound rationale for a regionalized treatment approach in this disease. Here, we seek to review the available data to define the role of CRS and HIPEC in gastric cancer metastatic to the peritoneal surface, and furthermore, analyze the use of CRS and HIPEC in malignancies less commonly treated with the regionalized perfusion approach.

Long-term survival following in-hospital cardiac arrest: A matched cohort study.

BACKGROUND: Each year, 200,000 patients undergo an in-hospital cardiac arrest (IHCA), with approximately 15-20% surviving to discharge. Little is known, however, about the long-term prognosis of these patients after discharge. Previous efforts to describe out-of-hospital survival of IHCA patients have been limited by small sample sizes and narrow patient populations METHODS: A single institution matched cohort study was undertaken to describe mortality following IHCA. Patients surviving to discharge following an IHCA between 2008 and 2010 were matched on age, sex, race and hospital admission criteria with non-IHCA hospital controls and follow-up between 9 and 45 months. Kaplan-Meier curves and Cox PH models assessed differences in survival. RESULTS: Of the 1262 IHCAs, 20% survived to hospital discharge. Of those discharged, survival at 1 year post-discharge was 59% for IHCA patients and 82% for controls (p<0.0001). Hazard ratios (IHCA vs. controls) for mortality were greatest within the 90 days following discharge (HR=2.90, p<0.0001) and decreased linearly thereafter, with those surviving to one year post-discharge having an HR for mortality below 1.0. Survival after discharge varied amongst IHCA survivors. When grouped by discharge destination, out of hospital survival varied; in fact, IHCA patients discharged home without services demonstrated no survival difference compared to their non-IHCA controls (HR 1.10, p=0.72). IHCA patients discharged to long-term hospital care or hospice, however, had a significantly higher mortality compared to matched controls (HR 3.91 and 20.3, respectively; p<0.0001). CONCLUSION: Among IHCA patients who survive to hospital discharge, the highest risk of death is within the first 90 days after discharge. Additionally, IHCA survivors overall have increased long-term mortality vs. CONTROLS: Survival rates were varied widely with different discharge destinations, and those discharged to home, skilled nursing facilities or to rehabilitation services had survival rates no different than controls. Thus, increased mortality was primarily driven by patients discharged to long-term care or hospice.

Ice packs reduce postoperative midline incision pain and narcotic use: a randomized controlled trial.

BACKGROUND: Postoperative pain is an unavoidable consequence of open abdominal surgery. Although cryotherapy, the application of ice to a surgical wound site, has been shown to be effective in reducing postoperative pain in orthopaedic, gynecologic, and hernia operations, it has not been assessed in patients who undergo major open abdominal operations. We hypothesized that patients who receive cryotherapy would report lower pain scores as a primary outcomes measure. STUDY DESIGN: Patients undergoing abdominal operations with midline incisions were randomized to receive cryotherapy for a minimum of 24 hours in time intervals dictated by patient preference vs no cryotherapy. The primary outcome of pain relief was assessed with visual analog pain scores (VAS). The study was powered to detect a clinically significant difference in VAS between the control and cryotherapy group. Comparisons between groups were measured by Student's t-test or Mann-Whitney U test for parametric and nonparametric data, respectively. RESULTS: There were 55 patients randomized: 28 to the control group and 27 to the cryotherapy group. For the primary measure, mean postoperative pain score on postoperative days (PODs) 1 and 3 after surgery was significantly lower between the control and cryotherapy groups on the visual analog pain scale (p < 0.005). Narcotic use was decreased in the cryotherapy group on POD 1 by 3.9 morphine equivalents (p = 0.008). No statistically significant difference was found between the 2 treatment groups with respect to length of hospital stay, pulmonary complications, and wound infection rate in terms of secondary measures. CONCLUSIONS: Ice packs are a simple, cost-effective adjuvant for decreasing postoperative pain and narcotic use in patients undergoing major abdominal operations.