Perioperative docetaxel, cisplatin, and 5-fluorouracil compared to standard chemotherapy for resectable gastroesophageal adenocarcinoma.

BACKGROUND: Even though the perioperative chemotherapy improves the overall survival (OS) compared to surgery alone in patients with a resectable gastroesophageal adenocarcinoma (GEA), prognosis of these patients remains poor. Docetaxel (D), cisplatin (C), and 5-fluorouracil (F) regimen improves OS compared to CF among patients with advanced GEA. We evaluated the potential interest of a perioperative DCF regimen, compared to standard (S) regimens, in resectable GEA patients. METHODS: We identified 459 patients treated with preoperative DCF or S regimens. The primary endpoint was OS. Propensity scores were estimated with a logistic regression model in which all baseline covariates were included. We then used two methods to take PS into account and thus make DCF and S patients comparable. OS analyses were performed with Kaplan-Meier and Cox models in propensity score matched samples, and inverse probability of treatment weighted (IPTW) samples. RESULTS: In the propensity score matched sample, the p-value from the log rank test for OS was 0.0961, and the 3-year OS rate was 73% and 55% in DCF and S groups, respectively. The multivariate Cox regression underlined a Hazard Ratio of 0.55 (95% CI 0.27-1.13) for DCF patients compared to S patients. The results from IPTW analyses showed that DCF was significantly and independently associated with OS (HR = 0.52; 95% CI 0.40-0.69). CONCLUSIONS: In this retrospective multicenter, hypothesis-generating study, the propensity score analyses underlined encouraging results in favor of DCF compared to S regimens regarding OS. This promising result should be validated in a phase-3 trial.

Recent improvements in the management of esophageal anastomotic leak after surgery for cancer.

Anastomotic leakage following total gastrectomy or esophagectomy is a significant complication that considerably increases postoperative mortality. The location of the anastomosis together with the anatomy of the esophagus explains the severity of this complication. Surgical knowledge should include general and specific predictive factors of leakage to avoid any technical-related cause of leakage. Clinical presentations may vary from minimally symptomatic to life-threatening situations. Investigations should be undertaken as soon as the diagnosis is suspected because delay greatly worsens the prognosis. CT scans with oral contrast and low insufflation early endoscopy are the preferred diagnostic tools and can also aid in therapeutic procedures. Communication and multidisciplinary teamwork are the cornerstones of treatment. When the leak occurs early with acute and important sepsis, the recommendation is surgical treatment. On the contrary, if the leak is late, non-symptomatic or minimally symptomatic, conservative management with intensive surveillance could be proposed. When the situation is in between these two extremes, endoscopic treatment is often proposed. Based on a review of the literature and experience from high volume centers, in this educational review, we present the incidence, predictive factors, clinical presentations, diagnostic tools, management, and therapeutic algorithms for anastomotic leaks following elective esophagectomy and total gastrectomy for cancer.

Description and analysis of clinical pathways for oesophago-gastric adenocarcinoma, in 10 European countries (the EURECCA upper gastro intestinal group - European Registration of Cancer Care).

AIMS: Outcomes for patients with oesophago-gastric cancer are variable across Europe. The reasons for this variability are not clear. The aim of this study was to describe and analyse clinical pathways to understand differences in service provision for oesophageal and gastric cancer in the countries participating in the EURECCA Upper GI group. METHODS: A questionnaire was devised to assess clinical presentation, diagnosis, staging, treatment, pathology, follow-up and service frameworks across Europe for patients with oesophageal and gastric cancer. The questionnaire was issued to experts from 14 countries. The responses were analysed quantitatively and qualitatively and compared. RESULTS: The response rate was (10/14) 71.4%. The approach to diagnosis was similar. Most countries established a diagnosis within 3 weeks of presentation. However, there were different approaches to staging with variable use of endoscopic ultrasound reflecting availability. There has been centralisation of treatments in most countries for oesophageal surgery. The most consistent area was the approach to pathology. There were variations in access to specialist nurse and dietitian support. Although most countries have multidisciplinary teams, their composition and frequency of meetings varied. The two main areas of significant difference were research and audit and overall service provision. Observations on service framework indicated that limited resources restricted many of the services. CONCLUSION: The principle approaches to diagnosis, treatment and pathology were similar. Factors affecting the quality of patient experience were variable. This may reflect availability of resources. Standard pathways of care may enhance both the quality of treatment and patient experience.

Patterns of recurrence in early-stage oesophageal cancer after chemoradiotherapy and surgery compared with surgery alone.

BACKGROUND: Patterns of disease recurrence in patients with oesophageal cancer following treatment with neoadjuvant chemoradiotherapy and surgery (nCRTS) or surgery alone are poorly reported. An understanding of patterns of disease recurrence is important for subsequent treatment planning. METHODS: An analysis was undertaken of patterns of disease recurrence from a phase III multicentre randomized trial (FFCD9901) comparing nCRTS with surgery alone in patients with stage I and II oesophageal cancer. RESULTS: Some 170 patients undergoing surgical resection were included in the study. R0 resection rates were similar in the two groups: 94 per cent following nCRTS versus 92 per cent after surgery alone (P = 0·749). After a median follow-up of 94·2 months, recurrent disease was found in 39·4 per cent of the overall cohort (31 per cent after nCRTS versus 47 per cent following surgery alone; P = 0·030). Locoregional recurrence was diagnosed in 41 patients (17 versus 30 per cent respectively; P = 0·047) and distant metastatic recurrence in 47 (23 versus 31 per cent respectively; P = 0·244). Metastatic recurrence was more frequent in patients with adenocarcinoma than in those with squamous cell cancer (40 versus 23·1 per cent respectively; P = 0·032). ypT0 N0 category was associated with prolonged time to mixed locoregional and metastatic recurrence (P = 0·009), and time to locoregional (P = 0·044) and metastatic (P = 0·055) recurrence. In multivariable analysis, node-positive disease predicted both locoregional (P = 0·001) and metastatic (P < 0·001) recurrence. CONCLUSION: Locoregional disease control following nCRTS indicated a local field effect not related solely to completeness of resection. pN+ disease was strongly predictive of time to locoregional and metastatic disease recurrence.

Variations among 5 European countries for curative treatment of resectable oesophageal and gastric cancer: A survey from the EURECCA Upper GI Group (EUropean REgistration of Cancer CAre).

INTRODUCTION: EURECCA (EUropean REgistration of Cancer CAre) is a network aiming to improve cancer care by auditing outcome. EURECCA initiated an international survey to share and compare patient outcome for oesophagogastric cancer. The present study assessed how a uniform dataset could be introduced for oesophagogastric cancer in Europe. METHODS: Participating countries presented data using common data items describing patients', disease, strategies, and outcome characteristics. Patients treated with curative surgery for squamous cell carcinoma (SCC) or adenocarcinoma (ACA) were included. RESULTS: United Kingdom, the Netherlands, France, Spain and Ireland participated. There were differences in data source ranging from national registries to large collaborative groups. 4668 oesophagogastric cancer cases over a 12 months period were included. The predominant histological type was ACA. Disease stage tended to be earlier in France and Ireland. In oesophageal and junctional cancers neoadjuvant chemoradiotherapy was preferred in the Netherlands and Ireland contrasting with chemotherapy in the UK and France. All countries used perioperative chemotherapy in gastric cancer but 1/3 of patients received this treatment. The mean R0 resection rate was 86% for oesophageal and junctional resections and 88% for gastric resections. Postoperative mortality varied from 1% to 7%. CONCLUSION: This European survey shown that implementing a uniform treatment and outcome data format of oesophagogastric cancer is feasible. It identified differences in disease presentation, treatment approaches and outcome, which need to be investigated, especially by increasing the number of participating countries. Future comparisons will facilitate developments in treatment for the benefit of patient outcomes.

Is there still a need for prophylactic intra-abdominal drainage in elective major gastro-intestinal surgery?

Prophylactic drainage of the abdominal cavity after gastro-intestinal surgery is widely used. The rationale is that intra-abdominal drainage enhances early detection of complications (gastro-intestinal leakage, hemorrhage, bile leak), prevents collection of fluid or pus, reduces morbidity and mortality, and decreases the duration of hospital stay. However, dogmatic attitudes favoring systematic drain placement should be questioned. The aim of this review was to evaluate the evidence supporting systematic use of prophylactic abdominal drainage following gastrectomy, pancreatectomy, liver resection, and rectal resection. Based on this review of the literature: (i) there was no evidence in favor of intra-peritoneal drainage following total or sub-total gastrectomy with respect to morbidity-mortality, nor was it helpful in the diagnosis or management of leakage, however the level of evidence is low, (ii) following pancreatic resection, data are conflicting but, overall, suggest that the absence of drainage is prejudicial, and support the notion that short-term drainage is better than long-term drainage, (iii) after liver resection without hepatico-intestinal anastomosis, high level evidence supports that there is no need for abdominal drainage, and (iv) following rectal resection, data are insufficient to establish recommendations. However, results from the French multicenter randomized controlled trial GRECCAR5 (NCT01269567) should provide new evidence this coming year. Accumulating data support that systematic drainage of the abdominal cavity in digestive surgery is a non-beneficial and obsolete practice, except following pancreatectomy where the consensus appears to indicate the usefulness of short-term drainage. While the level of evidence is high for liver resections, new randomized controlled trials are awaited regarding gastric, pancreatic and rectal surgery.

Prognostic impact of preoperative platelets to lymphocytes ratio (PLR) on survival for oesophageal and junctional carcinoma treated with neoadjuvant chemotherapy: A retrospective monocentric study on 153 patients.

This study was designed to investigate the prognostic impact of elevated platelet to lymphocyte ratio (PLR) on survival for oesophageal and junctional adenocarcinoma (OJA) treated with neoadjuvant chemotherapy in a curative intent. From 2004 to 2014, 153 consecutive patients with OJA were included. PLR was measured at first diagnosis. Receiver Operating Characteristic curve analysis was performed to determinate PLR threshold. Cox multivariate model was used to assess correlation between PLR and survival. Cut-off value for PLR was 192, which identified 2 groups of patients: low (n = 122) and high PLR value (n = 31). Both groups were comparable by patient (age, sex, ASA score) and tumour characteristics (differentiation, TNM stage, location). Five year overall survival (OS) was 65%. OS and DFS were reduced in the high PLR group: p = 0.019 and p = 0.016, respectively. PLR was associated with increased recurrence (54.8% vs. 35.2%, p = 0.046) and cancer-related death (41.9% vs. 23.8%, p = 0.043) rates. On multivariate analysis, elevated PLR was associated with decreased DFS (HR = 2.85, 95%CI = 1.54-5.26, p = 0.001) and OS (HR = 2.47, 95%CI = 1.21-5.01, p = 0.012). This study demonstrates that elevated PLR is associated with poor OS and DFS for OJA treated with a curative intent and has the potential to be a useful prognostic biomarker for treatment planning.

miR-219-1-3p is a negative regulator of the mucin MUC4 expression and is a tumor suppressor in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers in the world with one of the worst outcome. The oncogenic mucin MUC4 has been identified as an actor of pancreatic carcinogenesis as it is involved in many processes regulating pancreatic cancer cell biology. MUC4 is not expressed in healthy pancreas whereas it is expressed very early in pancreatic carcinogenesis. Targeting MUC4 in these early steps may thus appear as a promising strategy to slow-down pancreatic tumorigenesis. miRNA negative regulation of MUC4 could be one mechanism to efficiently downregulate MUC4 gene expression in early pancreatic neoplastic lesions. Using in silico studies, we found two putative binding sites for miR-219-1-3p in the 3'-UTR of MUC4 and showed that miR-219-1-3p expression is downregulated both in PDAC-derived cell lines and human PDAC tissues compared with their normal counterparts. We then showed that miR-219-1-3p negatively regulates MUC4 mucin expression via its direct binding to MUC4 3'-UTR. MiR-219-1-3p overexpression (transient and stable) in pancreatic cancer cell lines induced a decrease of cell proliferation associated with a decrease of cyclin D1 and a decrease of Akt and Erk pathway activation. MiR-219-1-3p overexpression also decreased cell migration. Furthermore, miR-219-1-3p expression was found to be conversely correlated with Muc4 expression in early pancreatic intraepithelial neoplasia lesions of Pdx1-Cre;LSL-Kras(G12D) mice. Most interestingly, in vivo studies showed that miR-219-1-3p injection in xenografted pancreatic tumors in mice decreased both tumor growth and MUC4 mucin expression. Altogether, these results identify miR-219-1-3p as a new negative regulator of MUC4 oncomucin that possesses tumor-suppressor activity in PDAC.

Anastomotic leakage after gastrointestinal surgery: diagnosis and management.

Anastomotic leakage represents a major complication of gastrointestinal surgery, leading to increased postoperative morbidity; it the foremost cause of mortality after intestinal resection. Identification of risk factors is essential for the prevention of AL. AL can present with various clinical pictures, ranging from the absence of symptoms to life-threatening septic shock. Contrast-enhanced CT scan is the most complete investigation to define AL and its consequences. Early and optimal multidisciplinary management is based on three options: medical management, radiologic or endoscopic intervention, or surgical re-intervention. Prompt treatment should help decrease postoperative morbidity and mortality, with the choice depending on the septic status of the patient. If the patient is asymptomatic, treatment can be medical only, coupled with close surveillance. Interventional management is indicated when the fistula is symptomatic but not life-threatening. On the other hand, when the vital prognosis is engaged, surgery is indicated, emergently, associated with intensive care. Even more than their prevention, early and appropriate management counts most to decrease their consequences.

Signet ring cell adenocarcinomas: different clinical-pathological characteristics of oesophageal and gastric locations.

AIMS: The incidence of oesogastric (OG) signet ring cell adenocarcinoma (SRC) is increasing in Western countries. The differential characteristics between oesophageal and gastric SRC tumours are unknown. We aimed to investigate the role of tumour location on prognosis in OG SRC. METHODS: Among 924 OG SRC resected in 21 centres from 1997 to 2010, consecutive patients who had oesophageal tumours (group OESO, n = 136) were matched to randomly selected patients who had gastric tumours (group GASTRIC, n = 363). Matching variables were gender, age, American Society of Anaesthesiologists score, malnutrition, pretherapeutic clinical TNM stage and neoadjuvant treatment. Patients and tumour characteristics were compared between groups and prognostic factors were identified. RESULTS: The two groups were well matched. Tumours in group GASTRIC were more advanced at surgical exploration, with higher rates of linitis plastica (P < 0.001), peritoneal carcinomatosis (P = 0.001), and advanced pTNM stages (P = 0.034). Radicality of resection and recurrence rates were similar (P > 0.480). Recurrences were more frequently distant (P < 0.001) and peritoneal (P < 0.001) in group GASTRIC. After adjustment on confounding variables, gastric location (P = 0.034) was independently associated with a better prognosis than oesophageal location. CONCLUSION: Gastric and oesophageal SRC tumours are distinct diseases. Despite similar pretherapeutic factors, gastric tumours were more advanced with a greater propensity for the peritoneal surface at the diagnosis and recurrence and associated with a better prognosis.

Risk factors of peritoneal recurrence in eso-gastric signet ring cell adenocarcinoma: results of a multicentre retrospective study.

INTRODUCTION: The poor prognosis of signet ring cell (SRC) eso-gastric adenocarcinoma (EGA) might be explained by its great affinity for the peritoneum. The aim of this study was to identify predictors of peritoneal carcinomatosis recurrence (PCR) after curative surgery and hence identify high risk patients. METHODS: A retrospective national survey was conducted over 19 French surgical centers between 1997 and 2010. Patients with non-metastatic disease who benefited from curative surgery without postoperative death were included. Event-free patients who did not reach the time point of 24 months were excluded. RESULTS: In a cohort of 3010 patients, 1050 were SRC EGA and 424 patients met the selection criteria. The tumor location was mainly gastric (68.9%) and a total gastrectomy was performed in 218 patients (51.4%). Chemoradiotherapy or chemotherapy alone was given preoperatively to 71 (16.7%) and postoperatively to 150 (35.4%) patients. After a median follow-up of 54 months, recurrence was diagnosed in 214 patients (50.5%) within a mean delay of 17 ± 10.7 months. PCR was diagnosed in 81 patients (19.1%). In multivariable analysis, four factors were identified as predictors of PCR: linitis plastica (p < 0.001; OR = 4.83), tumor invasion of/or through the peritoneal serosa (p = 0.022; OR = 1.58), lymph node involvement (p = 0.005; OR = 1.7) and tumors of gastric origin (p = 0.026; OR = 2.36), with PCR rates of 55%, 26%, 23% and 22%, respectively. CONCLUSION: Identification of strong predictors for PCR among this large series of SRC EGA patients helps to identify subgroups of patients that may benefit from specific therapeutic strategies such as prophylactic hyperthermic intraperitoneal chemotherapy.

RT-PCR analysis of corticotroph-associated genes expression in carcinoid tumours in the ectopic-ACTH syndrome.

OBJECTIVE: ACTH is frequently produced in non-pituitary tumours, leading to the ectopic-ACTH syndrome, but the molecular mechanisms of its expression remain obscure. This study was aimed at understanding the transcription mechanisms of the ACTH-precursor gene in carcinoid tumours of the lung or thymus. DESIGN: Transcripts coding for a series of corticotroph-associated transcription factor genes were detected, together with markers of the corticotroph phenotype. We studied a series of 41 carcinoid tumours including 15 with proven ectopic-ACTH syndrome. METHODS: Specific RT-PCR reactions were designed for each gene including alternatively spliced isoforms. RESULTS: The markers of the corticotroph phenotype were detected in all ACTH-positive tumours. Expression of the Tpit and Pitx1 genes were not restricted to ACTH-positive tumours but were also detected in many ACTH-negative carcinoids. Only a subset of ACTH-negative tumours expressed NAK-1/Nur77, and NeuroD1 expression was detected in approximately 50% of the tumours regardless of their secretory status. The glucocorticoid receptor alpha was detected in every tumour in contrast to its beta isoform detectable in a few tumours only. Chicken ovalbumin upstream promoter-transcription factor 1 (COUP-TF1) and peroxisome proliferator-activated receptor (PPAR) gamma2 were expressed in 50% of the tumours of each group whereas PPARgamma1 was expressed in almost every tumour. CONCLUSIONS: ACTH-positive carcinoids do not share a characteristic expression pattern of the corticotroph-associated transcription factor genes, suggesting that the transcriptional mechanisms of the ACTH-precursor gene differ from those in normal pituitary corticotrophs. Expression of Tpit and Pitx1 genes in most carcinoids suggests that some aspects of the pituitary corticotroph phenotype may belong to general carcinoid differentiation.