Prognosis after neoadjuvant chemoradiation or chemotherapy for locally advanced gastro-oesophageal junctional adenocarcinoma.

BACKGROUND: Trials typically group cancers of the gastro-oesophageal junction (GOJ) with oesophageal or gastric cancer when studying neoadjuvant chemoradiation and perioperative chemotherapy, so the results may not be fully applicable to GOJ cancer. Because optimal neoadjuvant treatment for GOJ cancer remains controversial, outcomes with neoadjuvant chemoradiation versus chemotherapy for locally advanced GOJ adenocarcinoma were compared retrospectively. METHODS: Data were collected from all patients who underwent neoadjuvant treatment followed by surgery for adenocarcinoma located at the GOJ at a single high-volume institution between 2002 and 2017. Postoperative major complications and mortality were compared between groups using Fisher's exact test. Overall survival (OS) and disease-free survival (DFS) were assessed by log rank test and multivariable Cox regression analyses. Cumulative incidence functions were used to estimate recurrence, and groups were compared using Gray's test. RESULTS: Of 775 patients, 650 had neoadjuvant chemoradiation and 125 had chemotherapy. These groups were comparable in terms of clinical tumour and lymph node categories, although the chemoradiation group had greater proportions of white men, complete pathological response to chemotherapy, and smaller proportions of diffuse cancer, poor differentiation, and neurovascular invasion. Postoperative major complications (20.0 versus 17.6 per cent) and 30-day mortality (1.7 versus 1.6 per cent) were not significantly different between the chemoradiation and chemotherapy groups. After adjustment, type of therapy (chemoradiation versus chemotherapy) was not significantly associated with OS (hazard ratio (HR) 1.26, 95 per cent c.i. 0.96 to 1.67) or DFS (HR 1.27, 0.98 to 1.64). Type of recurrence (local, regional, or distant) did not differ after neoadjuvant chemoradiation versus chemotherapy. CONCLUSION: In patients undergoing surgical resection for locally advanced adenocarcinoma of the GOJ, OS and DFS did not differ significantly between patients who had neoadjuvant chemoradiation compared with chemotherapy.

Treating advanced cancer of the gastro-oesophageal junction (GOJ) poses a challenge given its location in the distal oesophagus and proximal stomach, and whether it should be treated as oesophageal or gastric cancer. Given the indistinct location, it is unclear whether GOJ cancer should be treated with neoadjuvant chemoradiation, which is the treatment of choice for advanced oesophageal cancers, or perioperative chemotherapy, which is the treatment of choice for advanced gastric cancers. Few studies have addressed treatment options specifically for GOJ cancers. This study investigated whether there was a difference in survival between patients with GOJ cancer who were treated with chemoradiation versus chemotherapy.

Poor survival after resection of early gastric cancer: extremes of survivorship analysis reveal distinct genomic profile.

A subset of patients with early gastric cancer demonstrate early recurrence and poor survival despite margin-negative resection. This study used an extremes-of-survivorship approach to identify an association between TP53 hotspot mutations co-occurring with loss of heterozygosity and unexpectedly poor survival in early gastric cancer. This distinct genomic profile may be a novel biomarker of poor survival in patients with completely resected early gastric cancer, and warrants large-scale validation. Promising, validation needed.

Development and validation of a staging system for gastric adenocarcinoma after neoadjuvant chemotherapy and gastrectomy with D2 lymphadenectomy.

BACKGROUND: Neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy is commonly used for patients with locally advanced gastric adenocarcinoma. The eighth AJCC ypTNM staging system was validated based on patients undergoing more limited lymphadenectomy (less than D2). The aim of this study was to develop a system for accurate staging of patients with locally advanced gastric adenocarcinoma who receive neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy. METHODS: A modified system of ypTNM was developed, based on overall survival (OS) of patients receiving neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy at Memorial Sloan Kettering Cancer Center, and validated using data from an international cohort of patients who had similar treatment. RESULTS: Of 325 patients in the derivation cohort, 33 (10·2 per cent) had ypT0 N0/+ tumours, which are not classifiable under the AJCC system. The 5-year OS rate for modified ypTNM stages I, II, IIIA and IIIB was 89, 71, 42·3 and 10 per cent respectively, compared with 82, 65·2 and 24·1 for AJCC stages I, II and III respectively. The concordance index (0·730 versus 0·709), estimated area under the curve (0·765 versus 0·740) and time-dependent receiver operating characteristic (ROC) curve throughout the observation period were all superior for modified ypTNM staging. For the validation cohort of 186 patients, the modified system was again better at separating patients into prognostic groups for OS. CONCLUSION: The modified ypTNM staging system improves the accuracy of OS prediction for patients treated with neoadjuvant chemotherapy followed by gastrectomy with D2 lymphadenectomy.

Esophagojejunal reconstruction after total gastrectomy for gastric cancer using a transorally inserted anvil delivery system.

INTRODUCTION: Total gastrectomy (TG) is commonly performed for the treatment of patients with gastric cancer. However, reconstruction of the esophagojejunal (EJ) anastomosis can be technically demanding, with reported anastomotic leak rates in the Western world still approaching 10-15%. We report our experience using the transoral anvil delivery system (OrVil™) for creation of the EJ anastomosis after TG. METHODS: From 2007 to 2011, 48 consecutive patients with gastric cancer underwent open (n=31) or laparoscopic (n=17) TG. EJ reconstruction was performed with the transoral anvil deliver system (OrVil™) in an end-to-side fashion. Demographic, clinic, and perioperative data were obtained from a prospectively maintained database. RESULTS: Of the 48 patients, 83% were male. Median age at resection was 64 years. Median body mass index was 27.1 kg/m2. Seventy-nine percent (n=38) of patients had at least one comorbidity. Fifteen patients (31%) had at least one perioperative complication. There was one perioperative death (2%) following a duodenal stump leak. There were four EJ leaks (8%) and two EJ stenoses (independent of leak; 4%). There was one EJ leak (6%) and one EJ stenosis (6%) following a case that was first attempted laparoscopically. There were no deaths as a consequence of an EJ leak. CONCLUSIONS: The use of the transoral anvil delivery system during EJ reconstruction is a safe and effective option for reconstruction after open or laparoscopic TG with acceptable mortality and morbidity. The anastomotic leak rate appears to be comparable to that of other techniques.

Tobacco use is associated with increased recurrence and death from gastric cancer.

BACKGROUND: Tobacco use increases the risk of developing gastric cancer. We examined the hypothesis that gastric cancer developing in patients with a history of tobacco use may be associated with increased risk of cancer-specific death after curative surgical resection. METHODS: From the Memorial Sloan-Kettering Cancer Center Gastric Cancer prospective surgical database, we collected baseline demographic data and tumor characteristics from all patients who had undergone curative resection for gastric cancer between 1995 and 2009 and who had not received pre- or postoperative chemo- or radiotherapy. A smoking history was defined as >100 cigarettes' lifetime use. The primary end point was gastric cancer disease-specific survival (DSS); secondary end points were 5-year disease-free survival (DFS) and overall survival (OS). Gastric cancer-specific hazard was modeled by Cox regression. RESULTS: A total of 699 eligible patients were identified with a median age of 70 years (range 25-96 years); 410 (59%) were current or previous smokers. Smoking was associated with gastroesophageal junction/cardia tumors and white non-Hispanic ethnicity. Multivariate analysis included the following variables: tumor stage, age, performance status, diabetes mellitus, gender, and tumor location. In this analysis, the hazard ratio for gastric cancer DSS in smokers was 1.43 (95% confidence interval 1.08-1.91, P=0.01). Smoking was also an independent significant risk factor for worse 5-year DFS (hazard ratio 1.46, P=0.007) and OS (hazard ratio 1.48, P=0.003). Among 516 patients for whom tobacco pack-year usage was available, both heavy (≥20 pack-years) and light (<20 pack-years) tobacco use was significantly associated with DSS, DFS, and OS. CONCLUSIONS: Smoking history appears to be an independent risk factor for death from gastric cancer in patients who have undergone curative surgical resection.

Recurrence and survival after pathologic complete response to preoperative therapy followed by surgery for gastric or gastrooesophageal adenocarcinoma.

BACKGROUND: To characterise recurrence patterns and survival following pathologic complete response (pCR) in patients who received preoperative therapy for localised gastric or gastrooesophageal junction (GEJ) adenocarcinoma. METHODS: A retrospective review of a prospective database identified patients with pCR after preoperative chemotherapy for gastric or preoperative chemoradiation for GEJ (Siewert II/III) adenocarcinoma. Recurrence patterns, overall survival, recurrence-free survival, and disease-specific survival were analysed. RESULTS: From 1985 to 2009, 714 patients received preoperative therapy for localised gastric/GEJ adenocarcinoma, and 609 (85%) underwent a subsequent R0 resection. There were 60 patients (8.4%) with a pCR. Median follow-up was 46 months. Recurrence at 5 years was significantly lower for pCR vs non-pCR patients (27% and 51%, respectively, P=0.01). The probability of recurrence for patients with pCR was similar to non-pCR patients with pathologic stage I or II disease. Although the overall pattern of local/regional (LR) vs distant recurrence was comparable (43% LR vs 57% distant) between pCR and non-pCR groups, there was a significantly higher incidence of central nervous system (CNS) first recurrences in pCR patients (36 vs 4%, P=0.01). CONCLUSION: Patients with gastric or GEJ adenocarcinoma who achieve a pCR following preoperative therapy still have a significant risk of recurrence and cancer-specific death following resection. One third of the recurrences in the pCR group were symptomatic CNS recurrences. Increased awareness of the risk of CNS metastases and selective brain imaging in patients who achieve a pCR following preoperative therapy for gastric/GEJ adenocarcinoma is warranted.

Validation of laparoscopic surgical skills training outside the operating room: a long road.

BACKGROUND: Surgical skills training outside the operating room is beneficial. The best methods have yet to be identified. The authors aimed to document the predictive validity of simulation training in three different studies. METHODS: Study 1 was a prospective, randomized, multicenter trial comparing performance in the operating room after training on a laparoscopic simulator and after no training. The Global Operative Assessment of Laparoscopic Skills (GOALS) was used to evaluate operative performance. Study 2 retrospectively reviewed the operative performance of junior residents before and after implementation of a laparoscopic skills training curriculum. Operative time was the variable used to determine resident improvement. Study 3 was a prospective, randomized trial evaluating intern operative performance of laparoscopic cholecystectomy in a porcine model before and after training on a simulator. Operative performance was assessed using GOALS. RESULTS: All three studies failed to demonstrate predictive validity. With GOALS used as the assessment tool, no difference was found between trained and untrained residents in studies 1 and 3. In study 2, the trained group took significantly longer to complete a laparoscopic cholecystectomy than the untrained group. CONCLUSIONS: No correlation was found between the three types of training outside the operating room, and no improved operative performance was observed. Possible explanations include too few subjects, training introduced too late in the learning curve, and training criteria that were too easy. Additionally, simulator training focuses on precision, which may actually increase task time. Awareness of these issues can improve the design of future studies.

Prostaglandin E2 receptors EP2 and EP4 are down-regulated in human mononuclear cells after injury.

BACKGROUND: Recent characterization of prostaglandin receptor subtypes shows that each is critical to cellular functions and operates through separate signaling pathways that may explain differing effects of prostanoids. This study aimed to determine whether prostaglandin receptors EP2 and EP4 are modulated after injury and to evaluate the effect of prostaglandin E(2) (PGE(2)) addition and blockade on EP receptor expression. METHODS: Peripheral blood mononuclear cells (PBMCs) isolated from 10 patients sustaining fracture or burn injury and 10 control subjects were stimulated with lipopolysaccharide +/- NS-398, an inhibitor of PGE(2) production. Samples were evaluated for production of PGE(2), tumor necrosis factor--alpha, and leukotriene B(4) as well as mRNA expression of EP receptors and COX-2. EP receptor expression was also evaluated after treating control PBMCs with PGE(2). RESULTS: PBMCs from injured patients exhibited significant increases in PGE(2) production and COX-2 mRNA compared with control subjects, and these increases were inhibited by NS-398. In contrast, EP2 and EP4 receptors were markedly down-regulated after injury and NS-398 restored expression to control levels. Decreased EP2 and EP4 receptor expression after injury was replicated by coincubation of PBMCs with PGE(2). CONCLUSIONS: Specific PGE(2) receptors are down-regulated after injury and NS-398 reverses this response. Furthermore, PGE(2) mediates EP2 and EP4 down-regulation. These data suggest that specific EP receptor subtypes may provide critical targets for augmenting the immune response after injury in humans.

NS-398 treatment after trauma modifies NF-kappaB activation and improves survival.

Prostaglandin E(2) (PGE(2)) production after trauma contributes to immune alterations that increase susceptibility to infections. We hypothesize that blocking PGE(2) with NS-398, a selective COX-2 inhibitor, will modulate this response and improve outcome. This study evaluated the effect of NS-398 given over 7 days on proinflammatory cytokines, intracellular signaling, and survival after a septic challenge. Balb/C mice (n = 8/group) were given 10 mg/kg NS-398 intraperitoneally over 7 days, starting after anesthesia or trauma (femur fracture + 40% hemorrhage). Four groups, anesthesia + vehicle (C), anesthesia + NS-398 (CN), trauma + vehicle (T), or trauma + NS-398 (TN), were studied. On Day 7 after trauma, mice were sacrificed, serum was collected, and splenic macrophages were evaluated for PGE(2), LTB(4), IL-6, TNF-alpha, and NO production. Additionally, macrophage COX-2 mRNA, IkappaB-alpha, and NF-kappaB were evaluated. In a separate study, mice (n = 10-11/group) were traumatized and given NS-398 over 7 days, and then cecal ligation and puncture (CLP) were performed. Mice were then followed for survival over 10 days (via log-rank test). NS-398 treatment of injured mice decreased PGE(2) production compared to T (3.9 +/- 0.3 vs 3.1 +/- 0.4 pg/microg protein), and significantly decreased IL-6, NO, and TNF-alpha production. NS-398 treatment also attenuated COX-2 mRNA levels and NF-kappaB activation. These cellular events correlate with a significant survival advantage in TN versus T mice after CLP. These data suggest that a specific COX-2 inhibitor not only suppresses PGE(2), but normalizes proinflammatory cytokines after trauma through changes that may partly be mediated via transcriptional events. This correlates with significantly increased survival in TN mice given a septic challenge and suggests that COX-2 inhibitors contribute to modulating the inflammatory response and improving survival after trauma.

Blocking prostaglandin E2 after trauma attenuates pro-inflammatory cytokines and improves survival.

Major injury leads to impaired immune responses and increases the risk of infectious complications. Following trauma, increased prostaglandin E2 (PGE2) levels may be important in immunodysregulation. We hypothesized that blocking PGE2 with NS-398, a selective COX-2 inhibitor, during the first 24 h after injury may modify the immune response and protect the host from a subsequent septic challenge. BALB/c mice were given NS-398 (10 mg/kg) immediately after injury, at 12, and at 24 h after sham injury or trauma (femur fracture and 40% hemorrhage). On day 7 after injury, splenic macrophages were evaluated for cytokine production and COX-2 mRNA. In a separate study mice were injured, then given 3 doses of NS-398. After 7 days, cecal ligation and puncture was performed and mice were followed for survival. Traumatized mice given NS-398 had a significant survival advantage compared with trauma mice alone (P < 0.001). Macrophages from traumatized mice showed increased COX-2 mRNA and proinflammatory cytokines compared with controls (P < 0.05), whereas treatment of injured mice with NS-398 significantly decreased proinflammatory cytokine production (P < 0.05) and COX-2 mRNA. Therefore NS-398 given within 24 h of injury suppressed PGE2 through inhibition of cyclooxygenase, in addition to decreasing proinflammatory cytokines, and providing a survival advantage to the host.