Usha Malhotra

Morbidity and Mortality Associated with Gastrectomy for Gastric Cancer

BackgroundSurgery alone is often inadequate for advanced-stage gastric cancer. Surgical complications may delay adjuvant therapy. Understanding these complications is needed for multidisciplinary planning.Material and MethodsThe American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried for patients who underwent gastrectomy for malignancy (ICD-9 code 151.x) from 2005 to 2010. Thirty-day mortality and morbidity were evaluated.ResultsOverall, 2,580 patients underwent gastrectomy for malignancy, divided as total gastrectomy 999 (38.7xa0%) and partial gastrectomy 1,581 (61.3xa0%). Overall, serious morbidity occurred in 23.6xa0%, and the 30-day mortality was 4.1xa0%. Patients receiving a total gastrectomy were younger and healthier than those receiving a partial gastrectomy for the following measured criteria: age, diabetes, chronic obstructive pulmonary disease and hypertension. Serious morbidity and mortality were significantly higher in the total gastrectomy group than the partial gastrectomy group (29.3 vs. 19.9xa0%, pxa0<xa00.001; and 5.4 vs. 3.4xa0%, pxa0<xa00.015, respectively). The inclusion of additional procedures increased the risk of mortality for the following: splenectomy (odds ratio [OR] 2.8; pxa0<xa00.001), pancreatectomy (OR 3.5; pxa0=xa00.001), colectomy (OR 3.6; pxa0<xa00.001), enterectomy (OR 2.7; pxa0=xa00.030), esophagectomy (OR 3.5; pxa0=xa00.035). Abdominal lymphadenectomy was not associated with increased morbidity (OR 1.1; pxa0=xa00.41); rather, it was associated with decreased mortality (OR 0.468; pxa0=xa00.028).ConclusionsGastrectomy for cancer as currently practiced carries significant morbidity and mortality. Inclusion of additional major procedures increases these risks. The addition of lymphadenectomy was not associated with increased morbidity or mortality. Strategies are needed to optimize surgical outcomes to ensure delivery of multimodality therapy for advanced-stage disease.

Baseline circulating IL-17 predicts toxicity while TGF-β1 and IL-10 are prognostic of relapse in ipilimumab neoadjuvant therapy of melanoma.

BackgroundWe evaluated candidate circulating serum cytokines, chemokines and growth factors in patients with locally/regionally advanced melanoma receiving neoadjuvant ipilimumab with toxicity and clinical outcome.MethodsPatients were treated with ipilimumab (10xa0mg/kg IV every 3xa0weeks, 2 doses) before and after surgery. xMAP multiplex serum testing for 36 functionally selected cytokines and chemokines was performed at baseline and at six weeks (following ipilimumab). Based on our prior data, the association of IL-17 and immune related colitis was tested. Serum cytokines were divided into functional groups (Th1, Th2, Regulatory, Proinflammatory) and were assessed at baseline and week 6 using sparse-group Lasso modeling to assess the association of various cytokine groups with progression free survival (PFS). The linear combination of the cytokines/chemokines in this model was then used as a risk score and a Kaplan-Meier curve was generated to examine the association of the dichotomized score and PFS.ResultsThirty-five patients were enrolled whose staging was: IIIB (3; N2b), IIIC (30; N2c, N3), IV (2). Median follow-up was 18xa0months. Among 33 evaluable patients, median PFS was 11xa0months (95xa0% CIu2009=u20096.2–19.2). IL-17 was found to correlate significantly with the incidence of grade 3 diarrhea/colitis when measured at baseline (pu2009=u20090.02) with a trend towards significance at 6xa0weeks (pu2009=u20090.06). In the modeling analysis, at baseline, the linear combination of 2 regulatory cytokines [TGF- β1 (ρu2009=u20090.19) and IL-10 (ρu2009=u2009-0.34)] was significantly associated with PFS (HR 2.66; pu2009=u20090.035). No significant correlations with clinical outcomes were found in examining the week 6 cytokines.ConclusionsBaseline IL-17 level was significantly associated with the later development of severe diarrhea/colitis while the combination of baseline TGF- β1 and IL-10 levels were associated with therapeutic clinical outcome after neoadjuvant ipilimumab. These findings warrant further investigation and validation.Trial registrationClinicalTrials.gov Identifier NCT00972933.

Prevention of Barrett esophagus and esophageal adenocarcinoma by smoothened inhibitor in a rat model of gastroesophageal reflux disease.

Background:Activated hedgehog (Hh) pathway is associated with development of both Barrett esophagus (BE) and esophageal adenocarcinoma (EAC). We hypothesize that blockade of the Hh pathway with smoothened (Smo) inhibitor can prevent the development of BE/EAC in the Levrat model, in which induced gastroduodenoesophageal reflux (GDER) leads to esophageal carcinogenesis. Methods:GDER was induced in 6- to 8-week-old male Sprague-Dawley rats. The Smo inhibitor (10 mg/kg/d) was given orally on postoperative weeks 10 to 16, 18 to 22, and 24 to 28, and rats were killed on week 28. The primary outcome measure was the incidence of BE and EAC. To examine potential therapeutic effects of Smo inhibition on tumor tissue, semiquantitative immunohistochemistry for Ki-67 and caspase 3 was performed. In treated animals that developed cancer, gene expression was analyzed. Results:Thirty-eight of 48 controls and 32 of 46 treated animals survived to 28 weeks. messenger ribonucleic acid (mRNA) expression of Indian Hh, a ligand of transmembrane receptor patched 1, was 184× higher in BE and 99× higher in EAC compared with normal esophageal tissue (P = 0.0239 and P = 0.0004, respectively). Compared with controls, the incidence of BE and EAC was decreased in treated animals by 35.7% (relative risk reduction, 36%; P = 0.0015) and 36% (relative risk reduction, 62%; P = 0.0033), respectively. Compared with untreated EAC, Ki-67 was downregulated (P = 0.04) and cleaved caspase 3 was no different in treated EAC (P = 0.398). Of the 84 well-known genes involved in cancer drug resistance, 50 were dysregulated in treated EAC (P < 0.05 for each gene). Conclusions:Smo inhibitor prevents the development of BE and EAC in an in vivo model of GDER.

Role of Repeat 18F-Fluorodeoxyglucose Positron Emission Tomography Examination in Predicting Pathologic Response Following Neoadjuvant Chemoradiotherapy for Esophageal Adenocarcinoma

IMPORTANCEnPredicting complete pathologic response (CPR) preoperatively can significantly affect surgical decision making. There are conflicting data regarding positron emission tomography computed tomography (PET CT) characteristics and the ability of PET CT to predict pathologic response following neoadjuvant chemoradiotherapy in esophageal adenocarcinoma because most existing studies that include squamous histology have limited numbers and use nonstandardized PET CT imaging.nnnOBJECTIVEnTo determine if PET CT characteristics are associated with CPR in patients undergoing trimodality treatment for esophageal adenocarcinoma.nnnDESIGN, SETTING, AND PARTICIPANTSnA retrospective medical record review was conducted at a large tertiary cancer center from a prospectively maintained database from January 1, 2005, to December 31, 2012. Inclusion criteria were patients undergoing esophagectomy for locally advanced esophageal adenocarcinoma post-neoadjuvant chemoradiotherapy with 2 standardized PET CT studies done at our institution (pre-neoadjuvant chemoradiotherapy and post-neoadjuvant chemoradiotherapy) for review. Data collected included clinical, pathologic, imaging, and treatment characteristics.nnnMAIN OUTCOME AND MEASUREnThe primary study outcome was the association of PET CT characteristics with histologic confirmed pathologic response.nnnRESULTSnOf the total participants, 77 patients met the inclusion criteria. Twenty-two patients (28.6%) had CPR vs 55 patients (71.4%) who had incomplete pathologic response. The 2 groups were similar in age, sex, race/ethnicity, comorbid conditions, Eastern Cooperative Oncology Group status, tumor grade, chemotherapy, and radiation regimen and days between the 2 PET CTs. The mean prestandardized uptake variable (SUV; 14.5 vs 11.2; Pu2009=u2009.05), δ SUV (10.3 vs 5.4; Pu2009=u2009.02), and relative δ SUV (0.6 vs 0.4; Pu2009=u2009.02) were significantly higher in those with CPR vs incomplete pathologic response. Using the Youden Index, a δ SUV value less than 45% was predictive of residual disease with a positive predictive value of 91.7% (95% CI, 73-99; Pu2009<u2009.05).nnnCONCLUSIONS AND RELEVANCEnTo our knowledge, this is the largest study examining the role of PET CT characteristics in esophageal adenocarcinoma for patients undergoing neoadjuvant chemoradiotherapy that demonstrates that δ SUV of less than 45% is associated with patients with residual disease but not CPR. Based on the findings from our study, the current recommendation is still surgical resection regardless of the posttherapy PET SUV in the primary tumor. However, our study highlights the ability to detect patients with residual disease and the need to critically evaluate these patients for consideration of additional therapies.

Evaluation of a 4‐protein serum biomarker panel—biglycan, annexin‐A6, myeloperoxidase, and protein S100‐A9 (B‐AMP)—for the detection of esophageal adenocarcinoma

Esophageal adenocarcinoma (EAC) is associated with a dismal prognosis. The identification of cancer biomarkers can advance the possibility for early detection and better monitoring of tumor progression and/or response to therapy. The authors present results from the development of a serum‐based, 4‐protein (biglycan, myeloperoxidase, annexin‐A6, and protein S100‐A9) biomarker panel for EAC.

Small Cell Carcinoma of the Esophagus: A SEER Database Analysis

BackgroundSmall cell cancer (SCC) of the esophagus is an uncommon malignancy with perceived poor prognosis, but there are few data to guide therapeutic decisions. We examined the Surveillance, Epidemiology, and End Results (SEER) database to identify prognostic factors for survival.MethodsAll patients with esophageal cancer in the SEER database between 1973 and 2009 were included. Univariate and multivariate analyses were performed in patients with and without SCC, examining the relationship of small cell histology, surgery, and other potential prognostic factors with overall survival (censored at 72xa0months).ResultsOf 64,799 esophageal cancer patients identified in the SEER database, 387 (0.6xa0%) had small cell histology. As compared with non-small cell histology, patients with small cell histology were similar in age and race but had a higher proportion of women (pxa0<xa00.001), had a higher stage at diagnosis (pxa0<xa00.001), and were less likely to undergo surgical resection (pxa0<xa00.01). Multivariate predictors associated with poor survival in the overall cohort included age, female gender, black race, and stage. In patients treated with surgery, multivariate predictors associated with poor survival included age, male gender, race, and stage but not small cell histology. In patients with small cell histology, both age and stage were associated with poor survival, but surgery and preoperative radiotherapy were associated with improved survival.ConclusionsSCC of the esophagus presents at an advanced stage and confers a poor prognosis. The survival benefit of surgery and radiotherapy suggests that all esophageal SCC patients should be considered for preoperative radiotherapy and surgery in a stage-appropriate fashion.

Barrett's esophagus:progression to adenocarcinoma and markers

The following on progression to adenocarcinoma and markers of Barretts esophagus includes commentariess on the expression of claudin 4 in Barretts adenocarcinoma; the role of acid and bile salts; the role of insulin‐like growth factor; the value of reactive oxygen species; the importance of abnormal methylation; genetic alterations in stromal cells and genomic changes in the epithelial cells; the value of confocal laser endomicroscopy for the subsurface analysis of the mucosa; indications for statins as adjuvant chemotherapeutic agent; the sequence of molecular events in malignant progression in Barretts mucosa; and the value of the macroscopic markers and of p53 mutations.

Erlotinib and Radiation Therapy for Elderly Patients with Esophageal Cancer - Clinical and Correlative Results from a Prospective Multicenter Phase 2 Trial

Purpose: Elderly patients with esophageal cancer who are not candidates for chemoradiation may benefit from targeted agents; hence erlotinib combined with radiotherapy was evaluated in this trial. Materials and Methods: Patients >65 years with carcinoma of the thoracic esophagus or gastroesophageal junction who were not eligible for platinum-based treatment received erlotinib daily for 1 year starting on day 1 of radiotherapy [50.4 Gy days 1-28 (Mon-Fri) at 1.8 Gy per fraction]. Response was assessed by endoscopy and computed tomography. The primary endpoint was overall survival (OS), and secondary endpoints were complete response, progression-free survival (PFS) and toxicity. Results: The ECOG performance status in the 17 study patients was 0,1 and 2 in 2, 12 and 3 patients, respectively; 1, 5, 7 and 4 patients were in stage I, II, III and IV, respectively; adenocarcinoma was noted in 16 patients and squamous cell carcinoma in 1; there were 3 current, 12 past and 2 never smokers. Median OS was 7.3 months (95% confidence interval, CI: 3.8-22.3) with 14 deaths. There were 2 mucosal complete responses, 1 residual carcinoma in situ and 3 partial endoscopic responses in 9 patients who had endoscopy after radiotherapy. Estimated PFS was 4.5 months (95% CI: 2.4-7.3). Progression was distant (n = 3), locoregional (n = 6), unknown (n = 5) and too early (n = 3). Estimated 1-year survival was 29% (95% CI: 11-51%), 5 patients lived >12 months. Treatment-related toxicities of grade 3-4 occurred in 5 patients. Patients with epidermal growth factor receptor amplification and never smokers had the longest OS (22.3 and 16.6 months, respectively). Conclusions: Erlotinib with radiotherapy is tolerable and warrants further biomarker-driven evaluation in this population.

Association Between Clinically Staged Node-Negative Esophageal Adenocarcinoma and Overall Survival Benefit From Neoadjuvant Chemoradiation.

IMPORTANCEnWhile neoadjuvant chemoradiation for esophageal cancer improves oncologic outcomes for a broad group of patients with locally advanced and/or node-positive tumors, it is less clear which specific subset of patients derives most benefit in terms of overall survival (OS).nnnOBJECTIVEnTo determine whether neoadjuvant chemoradiation based on esophageal adenocarcinoma histology has similar oncologic outcomes for patients treated with surgery alone when stratified by clinical nodal status.nnnDESIGN, SETTING, AND PARTICIPANTSnA retrospective analysis using the American College of Surgeons National Cancer Database from 1998 to 2006. Patients with esophageal adenocarcinoma histology and clinical stage T1bN1-N3 or T2-T4aN-/+M0 were divided into 2 treatment groups: (1) neoadjuvant chemoradiation followed by surgery and (2) surgery alone. Subset analysis within each treatment group was performed for clinically node-negative patients (cN-) vs node-positive patients (cN+) in conjunction with pathological nodal status. A propensity score-adjusted analysis, which included patient demographics, comorbidity status, and clinical T stage, was also performed.nnnMAIN OUTCOME AND MEASURESnThe primary outcome was 3-year OS. Secondary outcomes included margin status, postoperative length of stay, unplanned readmission rate, and 30-day mortality.nnnRESULTSnA total of 1309 patients were identified, of whom 539 received neoadjuvant chemoradiation followed by surgery and 770 received surgery alone. Of the 1309 patients, 41.2% (nu2009=u2009539) received neoadjuvant chemoradiation and 47.2% (nu2009=u2009618) were cN+. Median follow-up for the entire cohort was 73.3 months (interquartile range, 64.1-93.5 months). The 3-year OS was better for neoadjuvant chemoradiation followed by surgery compared with surgery alone (49% vs 38%, respectively; Pu2009<u2009.001). Stratifying based on clinical nodal status, the propensity score-adjusted OS was significantly better for cN+ patients who received neoadjuvant chemoradiation (hazard ratio, 0.52; 95% CI, 0.42-0.66; Pu2009<u2009.001). In contrast, there was no difference in OS for cN- patients based on treatment (hazard ratio, 0.84; 95% CI, 0.65-1.10; Pu2009=u2009.22).nnnCONCLUSIONS AND RELEVANCEnPatients with cN+ esophageal adenocarcinoma benefit significantly from neoadjuvant chemoradiation. However, patients with cN- tumors treated with neoadjuvant chemoradiation plus surgery do not derive a significant OS benefit compared with surgery alone. This finding may have significant implications on the use of neoadjuvant chemoradiation in patients with cN- disease.

Pathologic Complete Response Is an Independent Predictor of Improved Survival Following Neoadjuvant Chemoradiation for Esophageal Adenocarcinoma.

IntroductionReports of improved survival in patients with pathologic complete response (pCR) to neoadjuvant therapy for esophageal and gastroesophageal junction (GEJ) adenocarcinoma is extrapolated from heterogeneous studies that include squamous cell histology. We sought to determine if pCR is associated with a survival advantage in a homogenous group of patients with esophageal adenocarcinoma.MethodsThis is a single institution analysis of all patients with T2–T4 or node positive esophageal adenocarcinoma treated with neoadjuvant chemoradiotherapy and esophagectomy between 2004 and 2014. Patients were divided into two groups based on pathological response, pCR vs. incomplete pathological response (iPR). Survival outcomes were evaluated using standard Kaplan-Meier methods and multivariable Cox regression models.ResultsA total of 205 patients were included in the study: 38 (19xa0%) patients with pCR and 167 patients (81xa0%) with iPR. The two groups were similar with respect to clinical stage, age, gender, comorbid conditions, ECOG status, smoking, and alcohol use. Patients in the pCR group had a higher percentage of tumors located in middle third of esophagus (11 vs. 2xa0%, pu2009=u20090.04) while tumor grade was similar in both groups. Median follow-up was 50xa0months, range 2–109xa0months. The 3-year overall (OS) and recurrence-free survival (RFS) for iPR was 48 and 39xa0%, respectively, vs. 86 and 80xa0% for pCR group, respectively.ConclusionThis analysis of a cohort of homogeneous patients with esophageal adenocarcinoma undergoing multimodality therapy showed that pCR is an independent predictor of improved RFS and OS. This data contributes to a growing body of evidence highlighting the benefits of neoadjuvant therapy specific to esophageal adenocarcinoma particularly when pCR is achieved.