Benefit of a flash dose of corticosteroids in digestive surgical oncology: a multicenter, randomized, double blind, placebo-controlled trial (CORTIFRENCH).

BACKGROUND: The modulation of perioperative inflammation seems crucial to improve postoperative morbidity and cancer-related outcomes in patients undergoing oncological surgery. Data from the literature suggest that perioperative corticosteroids decrease inflammatory markers and might be associated with fewer complications in esophageal, liver, pancreatic and colorectal surgery. Their benefit on cancer-related outcomes has not been assessed. METHODS: The CORTIFRENCH trial is a phase III multicenter randomized double-blind placebo-controlled trial to assess the impact of a flash dose of preoperative corticosteroids versus placebo on postoperative morbidity and cancer-related outcomes after elective curative-intent surgery for digestive cancer. The primary endpoint is the frequency of patients with postoperative major complications occurring within 30 days after surgery (defined as all complications with Clavien-Dindo grade > 2). The secondary endpoints are the overall survival at 3 years, the disease-free survival at 3 years, the frequency of patients with intraabdominal infections and postoperative infections within 30 days after surgery and the hospital length of stay. We hypothesize a reduced risk of major complications and a better disease-survival at 3 years in the experimental group. Allowing for 5% of drop-out, 1 200 patients (600 per arm) should be included. DISCUSSION: This will be the first trial focusing on the impact of perioperative corticosteroids on cancer related outcomes. If significant, it might be a strong improvement on oncological outcomes for patients undergoing surgery for digestive cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03875690, Registered on March 15, 2019, URL: https://clinicaltrials.gov/ct2/show/NCT03875690 .

What are the Particularities of Oesophageal Surgery in Cirrhotic Patients.

The aim of this paper was to review the entire literature on esophageal surgery to best define the surgical indications and the specifics of their management. The bibliographic research was carried out on Pubmed between January 1995 and June 2015, using French and English as publication languages.

Depletion of MUC5B mucin in gastrointestinal cancer cells alters their tumorigenic properties: implication of the Wnt/ß-catenin pathway.

Secreted mucins are large O-glycosylated proteins that participate in the protection/defence of underlying mucosae in normal adults. Alteration of their expression is a hallmark of numerous epithelial cancers and has often been correlated to bad prognosis of the tumour. The secreted mucin MUC5B is overexpressed in certain subtypes of gastric and intestinal cancers, but the consequences of this altered expression on the cancer cell behaviour are not known. To investigate the role of MUC5B in carcinogenesis, its expression was knocked-down in the human gastric cancer cell line KATO-III and in the colonic cancer cell line LS174T by using transient and stable approaches. Consequences of MUC5B knocking-down on cancer cells were studied with respect to in vitro proliferation, migration and invasion, and in vivo on tumour growth using a mouse subcutaneous xenograft model. Western blotting, luciferase assay and qRT-PCR were used to identify proteins and signalling pathways involved. In vitro MUC5B down-regulation leads to a decrease in proliferation, migration and invasion properties in both cell lines. Molecular mechanisms involved the alteration of ß-catenin expression, localization and activity and decreased expression of several of its target genes. In vivo xenografts of MUC5B-deficient cells induced a decrease in tumour growth when compared with MUC5B-expressing Mock cells. Altogether, the present study shows that down-regulation of MUC5B profoundly alters proliferation, migration and invasion of human gastrointestinal cancer cells and that these alterations may be, in part, mediated by the Wnt/ß-catenin pathway emphasizing the potential of MUC5B as an actor of gastrointestinal carcinogenesis.

Is Extended Lymphadenectomy Needed for Elderly Patients With Gastric Adenocarcinoma?

BACKGROUND: Extensive surgery is associated with greater mortality for elderly patients. For gastric adenocarcinoma (GA), it is unclear whether the benefit of an extended lymphadenectomy in this population outweighs the associated risks. This study aimed to determine the impact of lymphadenectomy on postoperative outcomes and survival for the elderly. OBJECTIVE: To determine the impact of lymphadenectomy on postoperative outcomes and survival for elderly. METHODS: From a cohort of 19 centers, patients who underwent resection of GA with curative intent between 1997 and 2010 were included in this study. Lymphadenectomy was defined according to the total number of lymph nodes in the surgical specimen (limited, <15; intermediate, 15-25; extended, >25). Postoperative outcomes and survival were compared between elderly (≥75 years) and younger patients and regarding the extent of lymphadenectomy for the elderly. RESULTS: Of 1348 patients, 386 were elderly. The elderly presented with a higher American Society of Anesthesiologist (ASA) score (ASA 3-4: 45 vs. 16.5 %; p < 0.001) as well as greater postoperative morbidity (45 vs. 37 %; p = 0.009) and mortality (8 vs. 2.5 %; p < 0.001) despite less aggressive treatment including less neoadjuvant chemotherapy (5 vs. 20 %; p < 0.001) and adjuvant chemotherapy (7 vs. 44 %; p < 0.001), fewer total gastrectomies (41.5 vs. 60 %; p < 0.001), and less extended lymphadenectomy (38 vs. 48.5 %; p < 0.001). Among the elderly patients, limited lymphadenectomy (n = 116), intermediate lymphadenectomy (n = 125), and extended lymphadenectomy (n = 145) were comparable with respect to tumor stage, perioperative treatment, morbidity, and mortality. For the elderly patients, overall survival (OS) was 30.8 months, and disease-specific survival (DSS) was 63.9 months. The extent of the lymphadenectomy did not have an impact on OS or DSS for the elderly patients. CONCLUSION: The expected benefit in terms of long-term survival did not justify an extended lymphadenectomy for elderly patients.

Preoperative chemoradiation with paclitaxel-carboplatin or with fluorouracil-oxaliplatin-folinic acid (FOLFOX) for resectable esophageal and junctional cancer: the PROTECT-1402, randomized phase 2 trial.

BACKGROUND: Often curative treatment for locally advanced resectable esophageal or gastro-esophageal junctional cancer consists of concurrent neoadjuvant radiotherapy and chemotherapy followed by surgery. Currently, one of the most commonly used chemotherapy regimens in this setting is a combination of a fluoropyrimidin and of a platinum analogue. Due to the promising results of the recent CROSS trial, another regimen combining paclitaxel and carboplatin is also widely used by European and American centers. No clinical study has shown the superiority of one treatment over the other. The objective of this Phase II study is to clarify clinical practice by comparing these two chemotherapy treatments. Our aim is to evaluate, in operable esophageal and gastro-esophageal junctional cancer, the complete resection rate and severe postoperative morbidity rate associated with these two neoadjuvant chemotherapeutic regimens (carboplatin-paclitaxel or fluorouracil-oxaliplatin-folinic acid) when each is combined with the radiation regime utilized in the CROSS trial. METHODS/DESIGN: PROTECT is a prospective, randomized, multicenter, open arms, phase II trial. Eligible patients will have a histologically confirmed adenocarcinoma or squamous cell carcinoma and be treated with neoadjuvant radiochemotherapy followed by surgery for stage IIB or stage III resectable esophageal cancer. A total of 106 patients will be randomized to receive either 3 cycles of FOLFOX combined to concurrent radiotherapy (41.4 Grays) or carboplatin and paclitaxel with the same radiation regimen, using a 1:1 allocation ratio. DISCUSSION: This ongoing trial offers the unique opportunity to compare two standards of chemotherapy delivered with a common regimen of preoperative radiation, in the setting of operable locally advanced esophageal or gastro-esophageal junctional tumors. TRIAL REGISTRATION: NCT02359968 (ClinicalTrials.gov) (registration date: 9 FEB 2015), EudraCT: 2014-000649-62 (registration date: 10 FEB 2014).

Is signet-ring cell carcinoma a specific entity among gastric cancers?

BACKGROUND: The prognosis and chemoresistance of signet-ring cell (SRC) gastric adenocarcinoma have been reported and debated, and the utility of perioperative chemotherapy for such a tumor has been questioned . This study was performed to assess the impact of the SRC type on survival following resection of gastric adenocarcinoma, and to assess whether the prognostic factors (including perioperative chemotherapy) for non-SRC adenocarcinoma differed from those for SRC adenocarcinoma. METHODS: 1799 cases of adenocarcinoma that were consecutively treated from 1997 to 2010 in 19 French centers by subtotal or total gastrectomy were included in a retrospective study. A D2 lymphadenectomy was performed for antropyloric tumors, and a modified D2 for upper tumors. SRC adenocarcinoma was diagnosed based on the presence of isolated carcinoma cells containing mucin. RESULTS: A total gastrectomy was performed in 979 (54.4 %) patients. SRC adenocarcinoma was diagnosed in 899 (50 %) patients. Patients with an SRC tumor were more frequently female, younger, and malnourished, had lower ASA scores, and had larger tumors than non-SRC patients. Median survival in patients with non-SRC carcinoma was 51 months, as compared to 26 months in patients with SRC carcinoma (p < 0.001). At multivariate analysis, SRC type remained an independent adverse prognostic factor (HR = 1.182). Factors that were prognostic in the SRC subgroup but not in the non-SRC subgroup were age >60 years, linitis, and involvement of adjacent organs. In contrast to non-SRC tumors, pre- and postoperative chemotherapy did not significantly impact on survival following resection of SRC adenocarcinoma. CONCLUSION: In comparison to non-SRC adenocarcinoma, the SRC type has a worse prognosis, different prognostic factors, and is only poorly sensitive to perioperative chemotherapy. Non-SRC and SRC adenocarcinomas should be considered different entities in future therapeutic trials.

Malignancy is a risk factor for postoperative infectious complications after elective colorectal resection.

PURPOSE: Patient and technical factors influencing the postoperative infectious complications (ICs) after elective colorectal resections are satisfactorily described. However, the underlying disease-related factors have not been extensively evaluated. This study aimed to measure the effect of malignancy on postoperative surgical site and extra surgical site infections after elective colorectal resection. METHODS: This study is a bicentric retrospective matched pair study of prospectively gathered data. Between 2004 and 2013, 1104 consecutive patients underwent colorectal resection in two centers. Patients undergoing elective resection with supraperitoneal anastomosis for benign diseases (excluding inflammatory bowel disease) (group B, n = 305) were matched to randomly selected patients with malignancy (group M, n = 305). The matching variables were age, gender, American Society of Anesthesiologists (ASA) score, malnutrition, type of resection, and surgical approach. We compared the 30-day IC rates between patients with benign diseases (group B) and malignancy (group M). Multivariate logistic regression analysis was performed to identify the risk factors for ICs. RESULTS: Group M had a higher overall rate of IC (25.6 vs 16.1 %, P = 0.004) as well as a higher risk of extra surgical site infections (P = 0.007) and anastomotic leakage (P = 0.039). The independent risk factors for ICs were malignancy (odds ratio (OR) = 2.02; P = 0.002), age ≥70 years (OR = 1.73, P = 0.018), tobacco history (OR = 1.87; P = 0.030), and obesity (OR = 1.68; P = 0.039). CONCLUSION: Malignancy, age, tobacco history, and obesity increase the risk of ICs after colorectal resection. Improvement of the modifiable risk factors, increased compliance with an enhanced recovery after surgery (ERAS) program in the overall population, and optimization of immune function in patients with malignancy should be considered.

Laparoscopic Gastric Mobilization Reduces Postoperative Mortality After Esophageal Cancer Surgery: A French Nationwide Study.

OBJECTIVE: This study was designed to investigate the impact of laparoscopic gastric mobilization (LGM) on 30-day postoperative mortality (POM) after surgery for esophageal cancer (EC). BACKGROUND: Meta-analyses of nonrandomized studies have failed to demonstrate any significant benefit of hybrid minimally invasive esophagectomy on POM, potentially due to small population samples. Moreover, none of the published randomized trials have been designed to answer this question. METHODS: All consecutive patients who underwent EC resection between 2010 and 2012 in France were included in this nationwide study (n = 3009). Data were extracted from the French National Health Service Database with internal and external quality controls. Patients treated with LGM (LGM group, n = 663) were compared with those treated with open approach (open group, n = 2346). Propensity score matching and multivariable analyses were used to compensate for the differences in baseline characteristics. RESULTS: The 30-day POM rate was 5.2%, significantly lower after LGM, compared with open surgery (3.3% vs 5.7%, P = 0.005), as well as in-hospital (5.6% vs 8.1%, P = 0.028), and 90-day POM (6.9% vs 10.0%, P = 0.016). After propensity score matching, 30-day POM rates were 3.3% versus 5.9%, respectively (P = 0.029). By multivariable analysis, age ≥60 years, malnutrition and cardiovascular comorbidity were independently associated with higher POM, whereas LGM was associated with a decrease in POM (OR 0.60, 95% CI 0.37-0.98, P = 0.041). CONCLUSIONS: This all-inclusive nationwide study strongly suggests that POM is significantly reduced after LGM for EC. This is high valuable evidence that helps decision making regarding the optimal approach for EC surgery.

International Multicenter Study on the Impact of Extracapsular Lymph Node Involvement in Primary Surgery Adenocarcinoma of the Esophagus on Overall Survival and Staging Systems.

OBJECTIVE: The current pathological lymph node (pN) staging is based on the number of positive lymph nodes but does not take into consideration characteristics of the involved lymph nodes itself. The current study aims to examine the prognostic value of extracapsular lymph node involvement (EC-LNI) and intracapsular lymph node involvement (IC-LNI) for esophageal adenocarcinoma treated by primary surgery. METHODS: From the databases of five European high volume centers, 1639 adenocarcinoma patients with primary R0-resection were withheld after excluding 90-day mortality. Oncologic variables, including number of resected lymph nodes, number of resected positive lymph nodes, and EC-LNI/IC-LNI were examined. The Union Internationale contre le Cancer (UICC) 7th edition prognostic staging was used as baseline staging system. Statistical analysis was performed by Cox proportional hazards modeling and verified using the Random Survival Forest technique. RESULTS: EC-LNI showed significantly worse overall 5-year survival compared with IC-LNI overall (13.4% vs 37.2%, P < 0.0001), including in each pN-category [16.4% vs 45.6% in pN1 (P < 0.0001), 16.1% vs 23.8% (P = 0.047) in pN2 (P = 0.065), and 8.7% vs 26.3% in pN3 categories, respectively]. pN1 IC-LNI patients show a 5-year overall survival comparable (P = 0.92) with stage IIB (ie, pT3N0). Reclassifying the UICC prognostic stages according to these findings into an adapted staging model showed a significant (P < 0.0001) increase in homogeneity, discriminatory ability, and monotonicity compared with the original UICC TNM 7th edition prognostic staging. CONCLUSIONS: These data suggest that lymph node capsular status is an important prognostic factor and should be considered for the future edition of the TNM staging system for esophageal cancer.

High-Grade Toxicity to Neoadjuvant Treatment for Upper Gastrointestinal Carcinomas: What is the Impact on Perioperative and Oncologic Outcomes?

BACKGROUND: Perioperative oncologic treatments provide a survival benefit for junctional and gastric adenocarcinoma (JGA) and esophageal cancer (EC). Whether neoadjuvant therapy toxicity (NTT) correlates with increased perioperative risk remains unclear. We aimed to evaluate the impact of grade III/IV NTT on postoperative and oncologic outcomes in resected upper gastrointestinal malignancies. METHODS: A multicenter retrospective analysis was performed on consecutive patients who benefited from neoadjuvant chemo(radio)therapy followed by surgery between 1997 and 2010 for JGA (first cohort, n = 653) and for EC (second cohort, n = 640). Data between patients who experienced NTT were compared to those who did not. RESULTS: NTT was associated with higher postoperative mortality after resection of JGA (P = 0.001) and after esophagectomy (P < 0.001), more non-R0 resections (JGA P = 0.019, EC P = 0.024), a decreased administration of adjuvant treatment among the JGA cohort (P = 0.012), and higher surgical morbidity (JGA P = 0.005, EC P = 0.020). Median survival was reduced in patients who experienced NTT in both cohorts (JGA P = 0.018, EC P = 0.037). After adjustment on confounding variables, NTT was independently associated with postoperative mortality in both cohorts (P ≤ 0.007). CONCLUSIONS: NTT is a predictor of postoperative mortality, correlates with higher postoperative morbidity, and negatively affects oncologic outcomes for upper gastrointestinal carcinomas.

Is there a role for surgery for patients with a complete clinical response after chemoradiation for esophageal cancer? An intention-to-treat case-control study.

OBJECTIVE: To compare the outcomes of a strategy of surveillance versus surgical resection in patients with esophageal cancer (EC) experiencing complete clinical response (cCR) after chemoradiation (CRT). BACKGROUND: In EC, it remains unclear whether a strategy of surveillance or esophagectomy is appropriate after cCR to CRT. METHODS: From 1995 to 2009, 222 operable patients had a cCR based on the results of a computed tomographic scan, endoscopy with biopsies and, when performed, a positron emission tomographic scan. Through an intention-to-treat case-control study, 59 patients treated with CRT and surveillance (group Surv) were matched 1:2 with 118 patients treated by CRT followed by surgery (group Surg), according to age, gender, tumor location and stage, histology, American Society of Anesthesiologists score, and nutritional status. RESULTS: The 2 groups were comparable according to the matched variables (P > 0.276). In group Surg, the postoperative mortality rate was 4.2% with evidence of residual tumor in 34.6% of specimens. In group Surv, 2 salvage esophagectomies were performed. Despite the higher dose of radiotherapy received in group Surv (50 vs 45 Gys, P = 0.003), median survival was lower (31 vs 83 months, P = 0.001), with disease recurrence that was more frequent (50.8% vs 32.7%, P = 0.021), occurred earlier (7.8 vs 19.0 months, P = 0.002) and more often locoregional (46.7% vs 16.2%, P = 0.007) in nature. Surgical resection was independently associated with less recurrence [odds ratio = 0.4, 95% confidence interval (CI): 0.2-0.8, P = 0.006] and better survival (hazard ratio = 0.5, 95% CI: 0.3-0.8, P = 0.006). CONCLUSIONS: Survival of EC patients with a cCR after CRT is better after surgery compared to simply surveillance. In patients of low operative risk and operable disease, surgery should be considered to improve control of locoregional disease and to overcome the inherent limitations of clinical response assessment.

Palliative resection for advanced gastric and junctional adenocarcinoma: which patients will benefit from surgery?

BACKGROUND: Whereas palliative chemotherapy offers a median survival of approximately 10 months in advanced gastric and junctional adenocarcinoma (AGJA), the survival impact of primary tumor resection is controversial. Our purpose was to identify which AGJA patients benefit from palliative resection. METHODS: In 3,202 AGJA patients scheduled for surgery in 21 French centers between 1997 and 2010, prognostic factors were identified in palliative group and the impact of each combination of these factors on survival was studied. RESULTS: Surgery was defined as palliative due to solid organ metastasis (5.6 %), localized (4.6 %) or diffuse (2.3 %) peritoneal carcinomatosis (PC), or incomplete tumoral resection (12.8 %). Median survival of AGJA patients resected with a palliative intent (n = 677) was longer than in nonresected patients (n = 532; 11.9 vs. 8.5 months, P < 0.001). Multivariable analyses identified ASA score III-IV (P < 0.001) as a predictor of postoperative mortality and solid organ metastasis (P = 0.009), localized PC (P = 0.004), diffuse PC (P = 0.046), and signet ring cell histology (SRC; P = 0.02) as predictors of survival. Only ASA I-II patients with incomplete resection without metastasis or PC, one site solid organ metastasis without PC, or localized PC without SRC had a survival benefit after palliative surgery with median survivals from 12.0 to 18.3 months. Nonresected ASA I-II patients with same risk factors had median survivals from 3.5 to 8.8 months (P < 0.05 for each). CONCLUSIONS: In AGJA, patient and tumor-related factors should be used to select candidates for palliative surgery in association with chemotherapy.

Clinical complete responders to definite chemoradiation or radiation therapy for oesophageal cancer: predictors of outcome.

BACKGROUND: To identify predictors of long-term outcome for patients with clinical complete response (cCR) after definite chemoradiotherapy (CRT) or radiation therapy (RT) for oesophageal cancer (EC). METHODS: In this retrospective study, we reviewed the files of all patients from our institution that underwent definitive RCT or RT for EC, from January 1998 to December 2003. Among 402 consecutive patients with EC, 110 cCR responses were observed, i.e. without evidence of tumour on morphological examination of the biopsy specimens, 8 to 10 weeks after radiation. Baseline patient and tumour characteristics were as follows: male = 98/110, median age = 60, squamous histology = 103/110, tumour site (upper/middle/lower third) = 41/50/19, weight loss none/<10%/≥10% = 36/45/29, dysphagia grade 1/2/≥3 = 30/14/66. Patients were staged according to endosonography and/or computed tomography. There were 9 stage I, 31 stage IIA, 15 stage IIB, 41 stage III, 6 stage IV. Post treatment nutritional characteristics were as follows: weight loss during treatment none/<10% ≥ 10% = 35/38/37, remaining dysphagia grade 1/2/≥3 = 54/24/32. Univariate and multivariate analyses were performed using log-rank and Cox proportional hazards models, and survival curves were estimated using the Kaplan-Meier method. RESULTS: During follow up (median: 6 [0.4-9.8] years), 16 patients had salvage surgery. Median OS was 2.5 years, and 5-year OS was 33.5%. Histological type, stage, age, gender, and treatment characteristics had no significant impact on outcome. The risk of death was increased two-fold for patients with grade ≥ 3 dysphagia after treatment (HR = 1.9 [1.2-3.1], p = 0.007). Weight loss ≥10% during treatment also negatively affected outcome (HR = 1.8 [1.0-3.2], p = 0.040). CONCLUSION: One EC patient among 3 with cCR after definite CRT/RT is still alive at 5 years. Variables related to reduced OS were: remaining significant dysphagia after treatment and weight loss ≥10% during treatment.

Phase II/III multicentre randomised controlled trial evaluating a strategy of primary surgery and adjuvant chemotherapy versus peri-operative chemotherapy for resectable gastric signet ring cell adenocarcinomas - PRODIGE 19 - FFCD1103 - ADCI002.

BACKGROUND: A dramatic increase in the incidence of the diffuse form of gastric adenocarcinomas and particularly signet ring cell carcinomas has been observed in Western countries. Evidence is accruing that signet ring cell carcinomas may have inherent chemo resistance leaving many clinicians unsure of the benefits of delaying surgery to pursue a neoadjuvant approach. METHODS/DESIGN: PRODIGE-19-FFCD1103-ADCI002 is a prospective multicentre controlled randomised phase II/III trial comparing current standard of care of perioperative chemotherapy (2x3 cycles of Epirubicin, cisplatin, 5-fluorouracil) with a strategy of primary surgery followed by adjuvant chemotherapy (6 cycles of Epirubicin, cisplatin, 5-fluorouracil) in patients with a stage IB-III gastric signet ring cell tumour. The principal objective of the phase II study (84 patients) is to determine if the experimental arm (primary surgery followed by adjuvant chemotherapy) has sufficient interest in terms of percentage of living patients at 24 months to be evaluated in a phase III trial. If 7 or less patients in the experimental arm are alive at 24 months, phase III will not be initiated. The primary objective of phase III (230 additional patients) is to demonstrate superiority of the experimental arm in terms of overall survival. Secondary endpoints include overall survival at 36 months, disease free survival at 24 and 36 months, R0 resection rates, treatment tolerance, postoperative mortality and morbidity evaluated by Clavien-Dindo severity index, the prognostic impact of positive peritoneal cytology and the assessment of quality of life. An ancillary study will assess the emotional and cognitive impact of surgery and perioperative chemotherapy for both the patient and their partner. DISCUSSION: As inherent chemo resistance of signet ring cell tumours and delay in definitive surgery may favour tumour progression we hypothesise that a policy of primary surgery followed by adjuvant chemotherapy will improve overall survival compared to a standard perioperative chemotherapeutic strategy. This randomised phase II/III trial is the first dedicated to this histological subtype. Whilst the development of new biomarkers and targeted therapies are awaited, the results of this trial should further help in devising individualised protocols of patient care in a tumour group whose diversity increasingly demands assessment of alternative strategies. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01717924.

[Does early signet ring cell gastric carcinoma carry a worse prognosis?]. / Tumeurs adénocarcinomateuses superficielles de l'estomac: un contingent majoritaire à cellules indépendantes est-il associé à un mauvais pronostic?

INTRODUCTION: The signet ring cell (SRC) histological subtype is a factor of poor prognosis in advanced gastric adenocarcinomas, but its prognostic value in early gastric cancer is unclear. The aim of this study was to evaluate the prognostic impact of SRC in superficial gastric adenocarcinomas, based on a comparison of patients with SRC and non SRC histologies. PATIENTS AND METHODS: From a large national cohort of 3,010 patients operated on for gastric adenocarcinoma between January 1997 and January 2010, we selected patients with pTis or pT1 tumors and compared those with SRC and non SRC histology on the basis of demographic, surgical and histologic factors and outcomes. The primary endpoint was the 3-year survival rate. RESULTS: Among 421 patients with a pTis or pT1 tumor, 104 (24.7%) had the SRC subtype and 317 (75.3%) a non SRC subtype. Median age was significantly lower in the SRC group than in the non SRC group (59.6 vs 68.8 years, p<0.001). Other demographic variables were similar in the two groups. Extensive surgical resection was more frequent in the non SRC group (31.9% vs 12.5%, p<0.001), but R0 resection rates were similar (97.5% vs 98.1%, p=0.900). The submucosa was more frequently involved in the SRC group (94.2% vs 84.9%, p=0.043), while lymph node involvement and the number of invaded nodes were similar in the two groups. Recurrences (5.8% vs 8.8%, p=0.223) and sites of recurrence (especially peritoneal carcinomatosis, 1.9% vs 1.6% ; p=0.838) were similar in the two groups. The 3-year survival rate was similar in the SRC and non SRC groups (94.1% vs 89.9%, p=0. 403), although the median survival time had not been reached CONCLUSION: SRC is not a prognostic factor in superficial gastric adenocarcinoma.

Is pretreatment endoscopic biopsy a good predictor of signet ring cell histology in gastric carcinoma?

BACKGROUND: Signet ring cell (SRC) carcinoma is defined as an adenocarcinoma in which >50% of the total operative specimen consists of isolated or small groups of malignant cells containing intracytoplasmic mucins (hSRCs). We previously demonstrated that hSRCs are a predictor of poor prognosis with specific tumoral characteristics suggesting the need for a dedicated therapeutic strategy before surgery. However diagnostic accuracy and prognostic value of SRCs on pretreatment biopsies (bSRCs) is unknown. The aim of the study was to determine if bSRCs can accurately predict hSRCs and survival. METHODS: A retrospective analysis was performed among 254 patients with an adenocarcinoma. We performed pretreatment endoscopic biopsies and histopathologic analysis of the surgical specimen. Pretreatment endoscopic biopsy results were compared with definitive pathologic results and were correlated with long-term survival. RESULTS: From 254 patients enrolled, 96 had bSRCs (37.8%), and 101 (39.8%) had hSRCs. Pretreatment biopsy results were correct in 89 of 101 patients with hSRC (sensitivity 88.1%) and in 146 of 153 with histologic non-SRCs (hNSRCs) (specificity 95.4%). The positive and negative predictive values for the biopsies were 92.7, and 92.4%, respectively, with an overall accuracy of 92.5%. When compared to the biopsy results, non-SRCs (bNSRCs), bSRCs were associated with poorer survival and were identified as an independent factor for poor prognosis (hazard ratio 1.89 with 95% confidence interval 1.35 to 2.64, P < 0.001). CONCLUSIONS: The presence of signet ring cells in samples obtained from routine pretreatment endoscopic biopsies accurately predicts SRC histology and poor prognosis. The specific therapeutic strategy can consequently be considered from the initial diagnosis.

Isolated granulocytic sarcoma of the pancreas: a tricky diagnostic for primary pancreatic extramedullary acute myeloid leukemia.

We report two clinical cases of primary granulocytic sarcoma of the pancreas that were diagnosed on the surgical specimen. Atypical clinical and morphological presentations may have lead to pretherapeutic biopsies of the pancreatic mass in order to indicate primary chemotherapy. Literature review of this rare clinical presentation may help physicians to anticipate diagnostic and therapeutic strategies.

The impact of perioperative chemotherapy on survival in patients with gastric signet ring cell adenocarcinoma: a multicenter comparative study.

OBJECTIVE: The aim of this retrospective study was to evaluate the survival impact of perioperative chemotherapy (PCT) in patients with gastric signet ring cell (SRC) adenocarcinoma. BACKGROUND: PCT is a standard treatment for advanced resectable gastric adenocarcinoma (GA). SRC has a worse prognosis compared to non-SRC and the chemosensitivity of SRC is uncertain. METHODS: Among 3010 patients registered in 19 French centers between January 1997 and January 2010, 1050 (34.9%) were diagnosed with SRC. Of those treated with curative intent (n = 924), 171 (18.5%) received PCT with surgery (PCT group), whereas 753 (81.5%) were treated with primary surgery (S group). PCT was based mainly on a fluorouracil-platinum doublet or triplet regimen. RESULTS: The groups were comparable regarding age, gender, American Society of Anesthesiologists (ASA) score, malnutrition, tumor location and cTNM stage. 60 patients did not undergo resection because of tumor progression (10) or metastases (50) found at operation. The R0 resection rates were 65.9% and 62.3% in the S and PCT groups, respectively (P = 0.308). Fewer patients received adjuvant chemotherapy in the S group than in the PCT group (35.2% vs. 66.5%, P < 0.001). At a median follow-up of 31.5 months, the median survival was shorter in the PCT group (12.8 vs. 14.0 months, P = 0.043). On multivariate analysis, PCT was found to be an independent predictor of poor survival (HR = 1.4, 95% CI 1.1-1.9, P = 0.042). CONCLUSIONS: PCT provides no survival benefit in patients with gastric SRC. Clinical Trial.gov record: ADCI001, Clinical Trial.gov identifier NCT01249859.

Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation.

OBJECTIVE: To test the hypothesis that signet ring cell (SRC) histology has a negative prognostic value in patients with gastric adenocarcinoma (ADC). SUMMARY BACKGROUND DATA: In western countries, gastric ADC with SRC often occurs after the disease has advanced. Consequently, the prognosis of SRC is generally regarded as poor, although survival studies comparing SRC and non-SRC have yielded inconsistent results. METHODS: : An intent to treat analysis was performed among 215 patients with gastric ADC scheduled for surgical resection from 1996 to 2007. Of these, 180 patients underwent the resection and 35 were not resected due to diffuse metastatic illness. From 59 resected patients with SRC (SRC group), control non-SRC resected patients matched by age, gender, American Society of Anaesthesiologists (ASA) classification, tumoral location, and pTNM stage were randomly selected by computer (non-SRC group: n = 100) during the same study period. RESULTS: The overall median survival was 21 months, which was significantly higher in resected compared to non-resected patients (31 vs. 5 months, P < 0.001). In non-resected patients, SRC histological subtype was associated with higher rates of diffuse peritoneal carcinomatosis (90.1% vs. 62.5%, P = 0.053) and neoplastic ascitis (63.6% vs. 34.7%, P = 0.059) and poorer median survival (5 vs. 7 months, P = 0.062). For resected patients, the 2 groups (SRC and non-SRC) were comparable regarding matching variables, demographic variables, and postoperative course. The median survival was significantly lower for SRC patients (21 vs. 44 months, P = 0.004). SRC resected patients exhibited higher rates of localized peritoneal carcinomatosis (P = 0.013) and lymph node involvement (P < 0.001) at diagnosis, lower R0 resection rate (P = 0.019) and earlier tumor relapse (P = 0.009), which was generally in a peritoneal carcinomatosis form (P = 0.011). By multivariate analysis, we concluded that SRC histology was independently associated with a dismal prognosis after adjustment on confounding variables (hazard ratio = 1.5, 95% confidence interval 1.1-2.0, P = 0.004). The prognostic role of SRC was maintained after exclusion of patients with advanced stage at initial diagnosis such as localized peritoneal carcinomatosis or lymph node invasion. CONCLUSIONS: This study is currently the best evidence showing that SRC is a major and independent predictor of poor prognosis due to specific characteristics such as more infiltrating tumors showing affinity for lymphatic tissue accompanied by a higher rate of peritoneal carcinomatosis. Our results suggest the need for a specific therapeutic strategy for such tumors.

Safety of Islet Autotransplantation After Pancreatectomy for Adenocarcinoma.

BACKGROUND: Total pancreatectomy with intraportal islet autotransplantation (TPIAT) rather than partial pancreatectomy could represent a major shift in the management of patients with resectable pancreatic ductal adenocarcinoma (PDAC) when risks of postoperative pancreatic fistula are well identified. This approach provides a theoretical risk of tumor cell dissemination when islet cells are transplanted into the portal vein. Our objective was to explore the safety of TPIAT in PDAC in a mouse preclinical model of subcutaneous xenotransplantation of human cells isolated from pancreatic specimen during partial pancreatectomy performed for PDAC. METHODS: Patients requiring pancreatectomy for PDAC were prospectively included. Immunocompromised mice were transplanted with pancreatic cells isolated from the nonmalignant part of the surgical specimen (experimental group). Results were compared with pancreatic tumor implants (control group). Pancreatic grafts were explanted at 6 weeks for histological analyses. RESULTS: Nine patients were included, and 31 mice were transplanted. In the experimental group, explants were microscopically devoid of tumor cell, and no metastasis was observed. In the control group, all explants were composed of tumor. CONCLUSIONS: We report in a preclinical model the absence of local and distant spreading of malignant cells after pancreatic islets xenograft isolated from PDAC patients. These data supports the oncological safety of TPIAT as valuable alternative to partial pancreatectomy for PDAC patients with a high risk of postoperative pancreatic fistula.