Brian Weston

Hippo Coactivator YAP1 Upregulates SOX9 and Endows Esophageal Cancer Cells with Stem-like Properties

Cancer stem cells (CSC) are purported to initiate and maintain tumor growth. Deregulation of normal stem cell signaling may lead to the generation of CSCs; however, the molecular determinants of this process remain poorly understood. Here we show that the transcriptional coactivator YAP1 is a major determinant of CSC properties in nontransformed cells and in esophageal cancer cells by direct upregulation of SOX9. YAP1 regulates the transcription of SOX9 through a conserved TEAD binding site in the SOX9 promoter. Expression of exogenous YAP1 in vitro or inhibition of its upstream negative regulators in vivo results in elevated SOX9 expression accompanied by the acquisition of CSC properties. Conversely, shRNA-mediated knockdown of YAP1 or SOX9 in transformed cells attenuates CSC phenotypes in vitro and tumorigenicity in vivo. The small-molecule inhibitor of YAP1, verteporfin, significantly blocks CSC properties in cells with high YAP1 and a high proportion of ALDH1(+). Our findings identify YAP1-driven SOX9 expression as a critical event in the acquisition of CSC properties, suggesting that YAP1 inhibition may offer an effective means of therapeutically targeting the CSC population.

Ability of integrated positron emission and computed tomography to detect significant colonic pathology: the experience of a tertiary cancer center.

The ability of integrated positron emission tomography and computed axial tomography (PET‐CT) to detect colonic pathology is not fully defined. The purpose of this study was to assess the ability of PET‐CT to detect colonic pathology and to determine the significance of (18F)2‐fluoro‐2‐deoxyglucose (18F‐FDG) activity noted incidentally in the colon on PET‐CT.

ALDH-1 expression levels predict response or resistance to preoperative chemoradiation in resectable esophageal cancer patients

Operable thoracic esophageal/gastroesophageal junction carcinoma (EC) is often treated with chemoradiation and surgery but tumor responses are unpredictable and heterogeneous. We hypothesized that aldehyde dehydrogenase‐1 (ALDH‐1) could be associated with response.

Importance of Surveillance and Success of Salvage Strategies After Definitive Chemoradiation in Patients With Esophageal Cancer

PURPOSE Patients with esophageal carcinoma (EC) who are treated with definitive chemoradiotherapy (bimodality therapy [BMT]) experience frequent relapses. In a large cohort, we assessed the timing, frequency, and types of relapses during an aggressive surveillance program and the value of the salvage strategies. PATIENTS AND METHODS Patients with EC (N = 276) who received BMT were analyzed. Patients who had surgery within 6 months of chemoradiotherapy were excluded to reduce bias. We focused on local relapse (LR) and distant metastases (DM) and the salvage treatment of patients with LR only. Standard statistical methods were applied. RESULTS The median follow-up time was 54.3 months (95% CI, 48.4 to 62.4). First relapses included LR only in 23.2% (n = 64), DM with or without LR in 43.5% (n = 120), and no relapses in 33.3% (n = 92) of patients. Final relapses included no relapses in 33.3%, LR only in 14.5%, DM only in 15.9%, and DM plus LR in 36.2% of patients. Ninety-one percent of LRs occurred within 2 years and 98% occurred within 3 years of BMT. Twenty-three (36%) of 64 patients with LR only underwent salvage surgery, and their median overall survival was 58.6 months (95% CI, 28.8 to not reached) compared with those patients with LR only who were unable to undergo surgery (9.5 months; 95% CI, 7.8 to 13.3). CONCLUSION Unlike in patients undergoing trimodality therapy, for whom surveillance/salvage treatment plays a lesser role,(1) in the BMT population, approximately 8% of all patients (or 36% of patients with LR only) with LRs occurring more than 6 months after chemoradiotherapy can undergo salvage treatment, and their survival is excellent. Our data support vigilant surveillance, at least in the first 24 months after chemotherapy, in these patients.

Locoregional Failure Rate After Preoperative Chemoradiation of Esophageal Adenocarcinoma and the Outcomes of Salvage Strategies

PURPOSE The primary purpose of surveillance of patients with esophageal adenocarcinoma (EAC) and/or esophagogastric junction adenocarcinoma after local therapy (eg, chemoradiotherapy followed by surgery or trimodality therapy [TMT]) is to implement a potentially beneficial salvage therapy to overcome possible morbidity/mortality caused by locoregional failure (LRF). However, the benefits of surveillance are not well understood. We report on LRFs and salvage strategies in a large cohort. PATIENTS AND METHODS Between 2000 and 2010, 518 patients with EAC who completed TMT were analyzed for the frequency of LRF over time and salvage therapy outcomes. Standard statistical techniques were used. RESULTS For 518 patients, the median follow-up time was 29.3 months (range, 1 to 149 months). Distant metastases (with or without LRF) occurred in 188 patients (36%), and LRF only occurred in 27 patients (5%). Eleven of 27 patients had lumen-only LRF. Most LRFs (89%) occurred within 36 months of surgery. Twelve patients had salvage chemoradiotherapy, but only five survived more than 2 years. Four patients needed salvage surgery, and three who survived more than 2 years developed distant metastases. The median overall survival of 27 patients with LRF was 17 months, and 10 patients (37%) survived more than 2 years. Thus, only 2% of all 518 patients benefited from surveillance/salvage strategies. CONCLUSION Our surveillance strategy, which is representative of many others currently being used, raises doubts about its effectiveness and benefits (along with concerns regarding types and times of studies and costs implications) to patients with EAC who have LRF only after TMT. Fortunately, LRFs are rare after TMT, but the salvage strategies are not highly beneficial. Our data can help develop an evidence-based surveillance strategy.

Preoperative Therapy and Pancreatoduodenectomy for Pancreatic Ductal Adenocarcinoma: a 25-Year Single-Institution Experience

BackgroundThe purpose of this study was to evaluate a single-institution experience with delivery of preoperative therapy to patients with pancreatic ductal adenocarcinoma (PDAC) prior to pancreatoduodenectomy (PD).MethodsConsecutive patients (622) with PDAC who underwent PD following chemotherapy and/or chemoradiation between 1990 and 2014 were retrospectively reviewed. Preoperative treatment regimens, clinicopathologic characteristics, operative details, and long-term outcomes in four successive time periods (1990–1999, 2000–2004, 2005–2009, 2010–2014) were evaluated and compared. ResultsThe average number of patients per year who underwent PD following preoperative therapy as well as the proportion of operations performed for borderline resectable and locally advanced (BR/LA) tumors increased over time. The use of induction systemic chemotherapy, as well as postoperative adjuvant chemotherapy, also increased over time. Throughout the study period, the mean EBL decreased while R0 margin rates and vascular resection rates increased overall. Despite the increase in BR/LA resections, locoregional recurrence (LR) rates remained similar over time, and overall survival (OS) improved significantly (median 24.1, 28.1, 37.3, 43.4 months, respectively, p < 0.0001).ConclusionsDespite increases in case complexity, relatively low rates of LR have been maintained while significant improvements in OS have been observed. Further improvements in patient outcomes will likely require disruptive advances in systemic therapy.

A validated miRNA profile predicts response to therapy in esophageal adenocarcinoma

In the current study we present a validated miRNA signature to predict pathologic complete response (pCR) to neoadjuvant chemoradiation in esophageal adenocarcinoma.

Outcome of Trimodality-Eligible Esophagogastric Cancer Patients Who Declined Surgery after Preoperative Chemoradiation

Background: For patients with localized esophageal cancer (EC) who can withstand surgery, the preferred therapy is chemoradiation followed by surgery (trimodality). However, after achieving a clinical complete response [clinCR; defined as both post-chemoradiation endoscopic biopsy showing no cancer and physiologic uptake by positron emission tomography (PET)], some patients decline surgery. The literature on the outcome of such patients is sparse. Method: Between 2002 and 2011, we identified 622 trimodality-eligible EC patients in our prospectively maintained databases. All patients had to be trimodality eligible and must have completed preoperative staging after chemoradiation that included repeat endoscopic biopsy and PET among other routine tests. Results: Out of 622 trimodality-eligible patients identified, 61 patients (9.8%) declined surgery. All 61 patients had a clinCR. The median age was 69 years (range 47–85). Males (85.2%) and Caucasians (88.5%) were dominant. Baseline stage was II (44.2%) or III (52.5%), and histology was adenocarcinoma (65.6%) or squamous cell carcinoma (29.5%). Forty-two patients are alive at a median follow-up of 50.9 months (95% CI 39.5–62.3). The 5-year overall and relapse-free survival rates were 58.1 ± 8.4 and 35.3 ± 7.6%, respectively. Of 13 patients with local recurrence during surveillance, 12 had successful salvage resection. Conclusion: Although the outcome of 61 EC patients with clinCR who declined surgery appears reasonable, in the absence of a validated prediction/prognosis model, surgery must be encouraged for all trimodality-eligible patients.

Rate of bilirubin regression after stenting in malignant biliary obstruction for the initiation of chemotherapy: how soon should we repeat endoscopic retrograde cholangiopancreatography?

This study was conducted to evaluate the rate of regression of bilirubin after stent placement for malignant biliary obstruction.

Clinical outcomes of nitinol and stainless steel uncovered metal stents for malignant biliary strictures: is there a difference?

BACKGROUND Self-expandable metal stents (SEMSs) made from nitinol (N) were developed as a potentially more effective alternative to conventional stainless steel (SS) stents. OBJECTIVE To compare clinical outcomes of N versus SS stents in the management of malignant biliary strictures. DESIGN Retrospective study. SETTING Tertiary-care cancer center. PATIENTS All patients with first-time N (Flexxus) and SS (Wallstent) uncovered biliary SEMSs placed between January 2006 and October 2007. INTERVENTIONS SEMS placement. RESULTS A total of 81 N and 96 SS stents were placed. The most common cancer diagnosis was pancreatic (80.2% N; 62.5% SS; P = .06). The most frequent site of stricture was the common bile duct (85.2% N; 86.5% SS; P = .31). Biliary decompression was achieved in 93.8% of the N group and 86.4% of the SS group (P = .22). Immediate stent manipulation was required in 4 patients in each group. Subsequent intervention for poor drainage was performed in 17 N (21%) and 26 SS (27%) stents at mean times of 142.1 days (range, 5-541 days; median, 77 days) and 148.1 days (range, 14-375; median, 158.5), respectively (P = .17). The occlusion rate between N and SS stents was not significant (P = .42). The overall durations of stent patency in the N and SS group were similar (median 129 and 137 days, respectively; P = .61), including the subgroup analysis performed on patients with pancreatic cancer (P = .60) and common duct strictures (P = .77). Complication rates were low in both groups (early: 3.7% N, 6.3% SS; late: 2.5% N, 3.1% SS). Ninety percent underwent chemotherapy and 38% radiation therapy in each group. LIMITATIONS Retrospective design. CONCLUSION Similar outcomes were achieved with N and SS stents regarding efficacy, duration of stent patency, occlusion rates, and complications. Our results are most applicable to patients with common duct strictures and pancreatic cancer.