Loss of SRY-box2 (SOX2) expression and its impact on survival of patients with oesophageal adenocarcinoma.

BACKGROUND: Oesophageal adenocarcinoma (OAC) is a highly aggressive malignancy with poor survival, which is highly variable amongst patients with comparable conventional prognosticators. Therefore molecular biomarkers are urgently needed to improve the prediction of survival in these patients. SRY (sex determining region Y)-box 2, also known as SOX2, is a transcription factor involved in embryonal development of the gastrointestinal tract as well as in carcinogenesis. The purpose of this study was to see whether SOX2 expression is associated with survival in patients with OAC. METHODS: SOX2 was studied by immunohistochemistry in patients who had undergone potentially curative oesophagectomy for adenocarcinoma. Protein expression of SOX2 was evaluated using tissue microarrays from resection specimens, and results were analysed in relation to the clinical data by Cox regression analysis. SOX2 was evaluated in two independent OAC cohorts (Rotterdam cohort and a multicentre UK cohort). RESULTS: Loss of SOX2 expression was independently predictive of adverse overall survival in the multivariable analysis, adjusted for known factors influencing survival, in both cohorts (Rotterdam cohort: hazard ratio (HR) 1·42, 95 per cent c.i. 1·07 to 1·89, P = 0·016; UK cohort: HR 1·54, 1·08 to 2·19, P = 0·017). When combined with clinicopathological staging, loss of SOX2 showed an increased effect in patients with pT1-2 tumours (P = 0·010) and node-negative OAC (P = 0·038), with an incrementally adverse effect on overall survival for stage I OAC with SOX2 loss (HR 3·18, 1·18 to 8·56; P = 0·022). CONCLUSION: SOX2 is an independent prognostic factor for long-term survival in OAC, especially in patients with stage I OAC

Alterations of E-cadherin and β-catenin in gastric cancer

BACKGROUND: The E-cadherin-catenin complex plays a crucial role in epithelial cell-cell adhesion and in the maintenance of tissue architecture. Perturbation in the expression or function of this complex results in loss of intercellular adhesion, with possible consequent cell transformation and tumour progression. METHODS: We studied the alterations of E-cadherin and β-catenin in a set of 50 primary gastric tumours by using loss of heterozygosity (LOH) analysis, gene mutation screening, detection of aberrant transcripts and immunohistochemistry (IHC). RESULTS: A high frequency (75%) of LOH was detected at 16q22.1 containing E-cadherin locus. Three cases (6%) showed the identical missense mutation, A592T. This mutation is not likely to contribute strongly to the carcinogenesis of gastric cancer, because a low frequency (1.6%) of this mutation was also found in 187 normal individuals. We also detected a low frequency (0.36%, 0%) of this mutation in 280 breast tumours and 444 other tumours, including colon and rectum, lung, endometrium, ovary, testis, kidney, thyroid carcinomas and sarcomas, respectively. We also analyzed the aberrant E-cadherin mRNAs in the gastric tumours and found that 7 tumours (18%) had aberrant mRNAs in addition to the normal mRNA. These aberrant mRNAs may produce abnormal E-cadherin molecules, resulting in weak cell-cell adhesion and invasive behaviour of carcinoma cells. Reduced expression of E-cadherin and β-catenin was identified at the frequency of 42% and 28%, respectively. Specially, 11 tumours (22%) exhibited positive cytoplasmic staining for β-catenin IHC. An association was found between reduced expression of E-cadherin and β-catenin. Moreover, an association was detected between reduced expression of E-cadherin and diffuse histotype. CONCLUSION: Our results support the hypothesis that alterations of E-cadherin and β-catenin play a role in the initiation and progression of gastric cancer

Worldwide Esophageal Cancer Collaboration : clinical staging data

Peer reviewe

Neoadjuvant chemoradiation followed by surgery versus surgery alone for patients with adenocarcinoma or squamous cell carcinoma of the esophagus (CROSS)

textabstractBackground. A surgical resection is currently the preferred treatment for esophageal cancer if the tumor is considered to be resectable without evidence of distant metastases (cT1-3 N0-1 M0). A high percentage of irradical resections is reported in studies using neoadjuvant chemotherapy followed by surgery versus surgery alone and in trials in which patients are treated with surgery alone. Improvement of locoregional control by using neoadjuvant chemoradiotherapy might therefore improve the prognosis in these patients. We previously reported that after neoadjuvant chemoradiotherapy with weekly administrations of Carboplatin and Paclitaxel combined with concurrent radiotherapy nearly always a complete R0-resection could be performed. The concept that this neoadjuvant chemoradiotherapy regimen improves overall survival has, however, to be proven in a randomized phase III trial. Methods/design. The CROSS trial is a multicenter, randomized phase III, clinical trial. The study compares neoadjuvant chemoradiotherapy followed by surgery with surgery alone in patients with potentially curable esophageal cancer, with inclusion of 175 patients per arm. The objectives of the CROSS trial are to compare median survival rates and quality of life (before, during and after treatment), pathological responses, progression free survival, the number of R0 resections, treatment toxicity and costs between patients treated with neoadjuvant chemoradiotherapy followed by surgery with surgery alone for surgically resectable esophageal adenocarcinoma or squamous cell carcinoma. Over a 5 week period concurrent chemoradiotherapy will be applied on an outpatient basis. Paclitaxel (50 mg/m2) and Carboplatin (Area-Under-Curve = 2) are administered by i.v. infusion on days 1, 8, 15, 22, and 29. External beam radiation with a total dose of 41.4 Gy is given in 23 fractions of 1.8 Gy, 5 fractions a week. After completion of the protocol, patients will be followed up every 3 months for the first year, every 6 months for the second year, and then at the end of each year until 5 years after treatment. Quality of life questionnaires will be filled out during the first year of follow-up. Discussion. This study will contribute to the evidence on any benefits of neoadjuvant treatment in esophageal cancer patients using a promising chemoradiotherapy regimen. Trial registration. ISRCTN80832026

The yield of diagnostic laparoscopy with peritoneal lavage in gastric adenocarcinoma: A retrospective cohort study

\ua9 2024 The AuthorsIntroduction: Diagnostic laparoscopy (DL) with peritoneal lavage has been adopted as a standard staging procedure for patients with gastric cancer (GC). Evaluation of the value of DL is important given ongoing improvements in diagnostic imaging and treatment. As contemporary data from European centres are sparse, this retrospective cohort study aimed to assess the yield of DL in patients with potentially curable gastric cancer, and to identify predictive factors for peritoneal metastases. Methods: Patients with adenocarcinoma of the stomach, treated between January 2016 and December 2018, were identified from institutional databases of two high volume European Upper-GI centres. Patients who underwent a DL with peritoneal lavage for potentially curable disease after clinical staging with imaging (cT1-4N0-3M0) were included. The primary outcome was the proportion of patients with a positive DL, defined as macroscopic metastatic disease, positive peritoneal cytology washings (PC+) or locally irresectable disease. Results: Some 80 of 327 included patients (24.5%) had a positive DL, excluding these patients from neoadjuvant treatment (66 of 327; 20.2%) and/or surgical resection (76 of 327; 23.2%). In 34 of 327 patients (10.3%), macroscopic metastatic disease was seen, with peritoneal deposits in 30 of these patients. Only 16 of 30 patients with peritoneal disease had positive cytology. Some 41 of 327 patients (12.5%) that underwent DL had PC+ in the absence of macroscopic metastases and five patients (1.5%) had an irresectable primary tumour. Diffuse type carcinoma had the highest risk of peritoneal dissemination, irrespective of cT and cN categories. Conclusion: The diagnostic yield of staging laparoscopy is high, changing the management in approximately one quarter of patients. DL should be considered in patients with diffuse type carcinoma irrespective of cT and cN categories

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin:A systematic review and meta-analysis

Background:Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Catheter-based intraperitoneal (IP) chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs, compared to intravenous administration. We reviewed the effectiveness of palliative intraperitoneal chemotherapy for patients with peritoneal metastases of gastric origin.Methods:Embase, MEDLINE, Web of Science, and Cochrane were searched for articles on chemotherapy with palliative intent in patients with peritoneal metastases of gastric origin published up to April 2023. The primary outcome was overall survival. Secondary outcomes included toxicity and clinicopathological outcomes in patients that underwent conversion surgery. A Bayesian random effect model was used to calculate the pooled median overall survival (mOS).Results:21 studies including 904 patients were retrieved, categorized in 3 treatment groups (IP docetaxel, IP paclitaxel and PIPAC). The pooled mOS for all intraperitoneal chemotherapy treatments was 14.2 months (95% CI: 10.8 – 17.7 months). The pooled hazard ratio of IP paclitaxel and docetaxel favored the combination of IP and systemic chemotherapy compared to systemic chemotherapy only (0.64, 95% CI: 0.47 – 0.86). mOS of IP paclitaxel, IP docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.3 months (95% CI: 14.0 – 22.7 months), 13.2 months (95% CI: 3.6 – 25.1 months) and 9.0 months (95% CI: 2.3 – 16.5 months). All treatment methods had a relatively safe toxicity profile. Conversion surgery was performed in 14% of the patients and a radical resection was achieved in 69%, with a mOS ranging from 24 to 33 months.Conclusions:Patients with peritoneal metastases of gastric origin treated with intraperitoneal chemotherapy had a pooled median overall survival of 14.2 months and a pooled hazard ratio of 0.64 compared to systemic chemotherapy. Intraperitoneal chemotherapy, regardless of method of administration, is a safe treatment and conversion surgery is possible in a selected subset of patients

Intraperitoneal chemotherapy for peritoneal metastases of gastric origin:A systematic review and meta-analysis

Background:Gastric cancer with peritoneal metastases is associated with a dismal prognosis. Catheter-based intraperitoneal (IP) chemotherapy and pressurized intraperitoneal aerosol chemotherapy (PIPAC) are methods to deliver chemotherapy intraperitoneally leading to higher intraperitoneal concentrations of cytotoxic drugs, compared to intravenous administration. We reviewed the effectiveness of palliative intraperitoneal chemotherapy for patients with peritoneal metastases of gastric origin.Methods:Embase, MEDLINE, Web of Science, and Cochrane were searched for articles on chemotherapy with palliative intent in patients with peritoneal metastases of gastric origin published up to April 2023. The primary outcome was overall survival. Secondary outcomes included toxicity and clinicopathological outcomes in patients that underwent conversion surgery. A Bayesian random effect model was used to calculate the pooled median overall survival (mOS).Results:21 studies including 904 patients were retrieved, categorized in 3 treatment groups (IP docetaxel, IP paclitaxel and PIPAC). The pooled mOS for all intraperitoneal chemotherapy treatments was 14.2 months (95% CI: 10.8 – 17.7 months). The pooled hazard ratio of IP paclitaxel and docetaxel favored the combination of IP and systemic chemotherapy compared to systemic chemotherapy only (0.64, 95% CI: 0.47 – 0.86). mOS of IP paclitaxel, IP docetaxel and PIPAC with cisplatin and doxorubicin were respectively 18.3 months (95% CI: 14.0 – 22.7 months), 13.2 months (95% CI: 3.6 – 25.1 months) and 9.0 months (95% CI: 2.3 – 16.5 months). All treatment methods had a relatively safe toxicity profile. Conversion surgery was performed in 14% of the patients and a radical resection was achieved in 69%, with a mOS ranging from 24 to 33 months.Conclusions:Patients with peritoneal metastases of gastric origin treated with intraperitoneal chemotherapy had a pooled median overall survival of 14.2 months and a pooled hazard ratio of 0.64 compared to systemic chemotherapy. Intraperitoneal chemotherapy, regardless of method of administration, is a safe treatment and conversion surgery is possible in a selected subset of patients