Minimally invasive technique for gastric GIST at challenging locations: single incision surgical gastroscopy.

Organ sparing resection of gastrointestinal stromal tumors (GISTs) located in the proximal stomach or esophagogastric junction can be challenging, resulting in proximal or total gastrectomy to facilitate a radical resection without tumor spill. We developed and evaluated a single incision surgical gastroscopy (SISG) procedure to provide a technically feasible alternative for the removal of gastric GISTs at these challenging locations. We developed an endoluminal resection of gastric GISTs through a small single abdominal incision and longitudinal ventral gastrotomy. Patients with a proximal tumor location, in whom a wedge resection was deemed challenging on pre-operative investigation were included in the current series. Safety, short-term oncological and surgical outcome were evaluated. We performed SISG in six consecutive patients with histopathological proven or suspected gastric GIST. In all patients, the procedure was performed successfully with no tumor rupture. The mean operative time was 61 min and there were no significant complications. Pathological examination showed a microscopically radical resection in all patients. Single incision surgical gastroscopy is a feasible technique with excellent short-term oncological and surgical outcomes. This technique serves as a good alternative for complicated resections for gastric GISTs at challenging locations.

Molecular profiles of response to neoadjuvant chemoradiotherapy in oesophageal cancers to develop personalized treatment strategies.

Identification of molecular predictive markers of response to neoadjuvant chemoradiation could aid clinical decision-making in patients with localized oesophageal cancer. Therefore, we subjected pretreatment biopsies of 75 adenocarcinoma (OAC) and 16 squamous cell carcinoma (OSCC) patients to targeted next-generation DNA sequencing, as well as biopsies of 85 OAC and 20 OSCC patients to promoter methylation analysis of eight GI-specific genes, and subsequently searched for associations with histopathological response and disease-free (DFS) and overall survival (OS). Thereby, we found that in OAC, CSMD1 deletion (8%) and ETV4 amplification (5%) were associated with a favourable histopathological response, whereas SMURF1 amplification (5%) and SMARCA4 mutation (7%) were associated with an unfavourable histopathological response. KRAS (15%) and GATA4 (7%) amplification were associated with shorter OS. In OSCC, TP63 amplification (25%) and TFPI2 (10%) gene promoter methylation were associated with an unfavourable histopathological response and shorter DFS (TP63) and OS (TFPI2), whereas CDKN2A deletion (38%) was associated with prolonged OS. In conclusion, this study identified candidate genetic biomarkers associated with response to neoadjuvant chemoradiotherapy in patients with localized oesophageal cancer.

Recent trends and predictors of multimodality treatment for oesophageal, oesophagogastric junction, and gastric cancer: A Dutch cohort-study.

BACKGROUND: In recent years, evidence supporting multimodality treatment for oesophageal, oesophagogastric junction (OGJ), and gastric cancer has accumulated. This population-based cohort-study investigates trends and predictors of utilisation of multimodality treatment for oesophagogastric cancer in the Netherlands. PATIENTS AND METHODS: Data were obtained from the Netherlands Cancer Registry regarding patients with oesophageal (n = 5450), OGJ (n = 2168) and gastric cancer (n = 6683) without distant metastases who had undergone R0 or R1 surgery diagnosed between 2000 and 2012. Follow-up was completed until February 2014. Preoperative/postoperative chemotherapy and/or radiotherapy combined with surgery were considered multimodality treatment. Logistic regression analysis was performed to analyse the association of age, gender, socioeconomic status, clinical T and N classification, hospital type, comprehensive cancer centre network region, and year of diagnosis, with multimodality treatment receipt. Additional analyses were performed to explore differences in trends of utilisation of multimodality treatment between academic and non-academic hospitals. RESULTS: Multimodality treatment utilisation for oesophageal, OGJ and gastric cancer increased significantly to 90%, 85% and 56% in 2012, respectively. In oesophageal and OGJ cancer patients, preoperative chemoradiotherapy was most frequently administered (85% and 47% in 2012, respectively), and in gastric cancer patients preoperative chemotherapy (47% in 2012). Lower age, higher clinical T and N classification, and diagnosis in more recent years were significantly associated with more frequent multimodality treatment receipt. The adoption of most types of multimodality treatment in academic hospitals preceded non-academic hospitals by a year. CONCLUSION: In the Netherlands, the utilisation of multimodality treatment for oesophagogastric cancer has significantly increased during the past decade, especially in oesophageal and OGJ cancer. Multimodality treatment utilisation was especially dependent on patient and tumour characteristics and year of diagnosis, but multimodality treatment trends seem to be related to the publication of landmark studies, participation in nationally running clinical trials, and hospital type, preceding national guidelines.

Does adjuvant chemoradiotherapy improve the prognosis of gastric cancer after an r1 resection? Results from a dutch cohort study.

OBJECTIVE: The aim of this study was to investigate the impact of adjuvant chemoradiotherapy (CRT) on survival of non-metastatic gastric cancer patients who had undergone an R1 resection. METHODS: We compared the survival of patients after an R1 gastric cancer resection from the population-based Netherlands Cancer Registry who did not receive adjuvant CRT (no-CRT group) with the survival of resected patients who had been treated with adjuvant CRT (CRT group) at our institute. Patients who had a resection between 2002 and 2011 were included. CRT consisted of radiotherapy (45 Gy) combined with concurrent cisplatin- or 5-fluorouracil-based chemotherapy. The impact of CRT treatment on overall survival was assessed using multivariable Cox regression and stratified propensity score analysis. RESULTS: A series of 409 gastric cancer patients who had undergone an R1 resection were studied (no-CRT, N = 369; CRT, N = 40). In the no-CRT group, median age was higher (70 vs. 57 years; p < 0.001) and the percentage of patients with diffuse-type tumors was lower (43 vs. 80 %; p < 0.001). There were no significant differences in pathological T- and N-classification. There was a significant difference in median overall survival between the no-CRT and CRT group (13 vs. 24 months; p = 0.003). In a multivariable analysis, adjuvant CRT was an independent prognostic factor for improved overall survival (hazard ratio 0.54; 95 % confidence interval 0.35-0.84). This effect of CRT was further supported by propensity score analysis. CONCLUSIONS: Adjuvant CRT was associated with an improved survival in patients who had undergone an R1 resection for gastric cancer.

Surgical Treatment of Gastrointestinal Stromal Tumors Located in the Stomach in the Imatinib Era.

BACKGROUND: Imatinib has changed the treatment of gastrointestinal stromal tumors (GISTs). Preoperative imatinib treatment can be administered to patients with locally advanced disease to reduce the risk of incomplete resection, tumor spill, and lessen the extent of resection. In metastatic GIST, surgery follows imatinib in responding patients with resectable disease. In this study, the outcome of surgically treated patients with a gastric GIST with and without preoperative imatinib was investigated. METHODS: Patients surgically treated for a gastric GIST at our institute between 1999 and 2011 were included. Patient data were retrieved from a prospectively maintained database. RESULTS: A consecutive series of 47 patients was identified: 17 patients were treated with primary surgery (group 1) and 30 patients received imatinib before surgery (group 2). Preoperative imatinib led to a 33% reduction in tumor size. All patients in group 1 and 23 patients (77%) in group 2 had a complete resection (R0) without tumor spill. At a median follow-up of 30 months, 4 patients in group 2 had died of GIST. In these 4 patients, either the resection had been irradical or tumor spill had occurred, and 3 of them had radiologic progressive disease at the time of surgery. CONCLUSIONS: In this surgical series of gastric GIST patients, preoperative imatinib led to a major reduction in tumor size. Irradical resection, tumor spill, and progressive disease at the time of surgery were associated with poor prognosis.

Detecting interval metastases and response assessment using 18F-FDG PET/CT after neoadjuvant chemoradiotherapy for esophageal cancer.

AIM: The aim of this study is to evaluate the potential of FDG PET/CT for the detection of interval distant metastases after neoadjuvant chemoradiotherapy (CRT) and the prediction of the pathologic response to CRT in esophageal cancer patients. PATIENTS AND METHODS: In this retrospective study, all esophageal cancer patients for whom CRT followed by surgery was planned between January 2008 and April 2013 and in whom an FDG PET/CT was performed before and after CRT were included. For the response analyses, both FDG PET/CT scans had to be made on a similar scanner. Metabolic response of the primary tumor was assessed using the SUVmax, metabolic tumor volume (MTV), and total lesion glycolysis (TLG). These parameters were correlated with the pathologic response using the tumor regression grade (TRG) scale according to Mandard et al (Cancer. 1994;73:2680-2686). RESULTS: In 6 (8%) of 76 consecutively treated patients, new distant metastases were detected on FDG PET/CT after neoadjuvant CRT; these patients therefore did not undergo operation. Forty-eight (63%) of 76 patients were eligible for response analysis. The relative change in SUVmax, MTV, and TLG was significantly different between patients with a major (TRG, 1-2) and a minor response (TRG, 3-5) but not between patients with and without a pathologic complete response. The area under the curve of the receiver operating characteristic for predicting a major response was 0.70 (95% confidence interval, 0.65-0.92) for a relative decrease in SUVmax, compared with 0.73 (95% confidence interval, 0.58-0.88) both for MTV and TLG. A relative decrease in SUVmax of 60% or more had the highest positive predictive value (75%). CONCLUSIONS: Futile surgery was prevented in 8% of our esophageal cancer patients because interval metastases were detected on an FDG PET/CT after neoadjuvant CRT. The accuracy for predicting a complete or major pathologic response was limited and does not support the use of FDG PET/CT for refraining from surgical treatment.

The prognostic significance of an R1 resection in gastric cancer patients treated with adjuvant chemoradiotherapy.

BACKGROUND: A microscopically irradical (R1) resection is a well-known adverse prognostic factor after gastric cancer surgery. However, the prognostic significance of an R1 resection in gastric cancer patients who are treated with chemoradiotherapy (CRT) after the operation has been poorly studied. Therefore, the aim of this study was to evaluate the effect of an R1 resection on (recurrence-free) survival in gastric cancer patients who were treated with CRT after surgery. METHODS: Gastric cancer patients who had undergone a resection with curative intent followed by adjuvant CRT at our institute between 2001 and 2011 were included. CRT consisted of radiotherapy (45 Gy/25 fractions) combined with concurrent capecitabine (with or without cisplatin) or 5-fluorouracil/leucovorin. RESULTS: A consecutive series of 110 patients was studied, including 80 (73 %) patients who had undergone an R0 resection and 30 (27 %) patients with an R1 resection. Pathologic T-classification (p = 0.26), N-classification (p = 0.77), and histologic subtype according to Laurén (p = 0.071) were not significantly different between these groups. Three-year recurrence-free survival (45 vs. 35 %, p = 0.34) and overall survival (47 vs. 48 %, p = 0.58) did not significantly differ between patients who had undergone an R0 or R1 resection. In a multivariate analysis, pathologic T-classification and N-classification were independent prognostic factors for survival. CONCLUSIONS: A R1 resection was not an adverse prognostic factor in gastric cancer patients who had undergone CRT after the operation.

Quality of care indicators for the surgical treatment of gastric cancer: a systematic review.

BACKGROUND: Quality assurance is increasingly acknowledged as a crucial factor for the (surgical) treatment of gastric cancer. The purpose of the current study was to define a minimum set of evidence-based quality of care indicators for the surgical treatment of locally advanced gastric cancer. METHODS: A systematic review of the literature published between January 1990 and May 2011 was performed, using search terms on gastric cancer, treatment, and quality of care. Studies were selected based on predefined selection criteria. Potential quality of care indicators were assessed based on their level of evidence and were grouped into structure, process, and outcome indicators. RESULTS: A total of 173 articles were included in the current study. For structural measures, evidence was found for the inverse relationship between hospital volume and postoperative mortality as well as overall survival. Regarding process measures, the most common indicators concerned surgical technique, perioperative care, and multimodality treatment. The only outcome indicator with supporting evidence was a microscopically radical resection. CONCLUSIONS: Although specific literature on quality of care indicators for the surgical treatment of locally advanced gastric cancer is limited, several quality of care indicators could be identified. These indicators can be used in clinical audits and other quality assurance programs.

Factor Xa stimulates proinflammatory and profibrotic responses in fibroblasts via protease-activated receptor-2 activation.

Coagulation proteases have been suggested to play a role in the pathogenesis of tissue remodeling and fibrosis. We therefore assessed the proinflammatory and fibroproliferative effects of coagulation protease factor (F)Xa. We show that FXa elicits a signaling response in C2C12 and NIH3T3 fibroblasts. FXa-induced ERK1/2 phosphorylation was dependent on protease-activated receptor (PAR)-2 cleavage because desensitization with a PAR-2 agonist (trypsin) but not a PAR-1 agonist (thrombin) abolished FXa-induced signal transduction and PAR-2 siRNA abolished FXa-induced ERK1/2 phosphorylation. The PAR-2-dependent cellular effects of FXa led to fibroblast proliferation, migration, and differentiation into myofibroblasts, as demonstrated by the expression of alpha-smooth muscle actin and desmin, followed by the secretion of the cytokines monocyte chemotactic protein-1 and interleukin-6 as well as the expression of the fibrogenic proteins transforming growth factor-beta and fibronectin. To assess the relevance of FXa-induced proliferation and cell migration, we examined the effect of FXa in a wound scratch assay. Indeed, FXa facilitated wound healing in a PAR-2- and ERK1/2-dependent manner. Taken together, these results support the notion that, beyond its role in coagulation, FXa-dependent PAR-2 cleavage might play a role in the progression of tissue fibrosis and remodeling.