Outcome of endoscopic vacuum therapy for duodenal perforation.

BACKGROUND: Duodenal defects are complex clinical situations, and their management is challenging and associated with high mortality. Besides surgery, endoscopic treatment options exist, but the size and location of the perforation can limit their application. We present a retrospective study, demonstrating a successful application of endoscopic vacuum therapy (EVT) for duodenal leaks. METHODS: We performed a retrospective study of all patients who underwent EVT for duodenal perforations between 2016 and 2021 at two tertiary centers. We analyzed demographic and clinical patient characteristics, surgical outcomes, leak characteristics, sponge-related complications, and success rate. RESULTS: Indications for treatment with EVT in the duodenum consisted of leak after duodenal suture of a perforated ulcer (n = 4), iatrogenic perforation after endoscopic resection (n = 2), iatrogenic perforation during surgery (n = 2), and anastomotic leak after upper gastrointestinal surgery (n = 2). EVT was used as a first-line treatment in seven patients and as a second-line treatment in three patients. EVT was successfully applied in all interventions (n = 10, 100%). Overall, EVT lead to definitive closure of the defects in eight out of ten patients (80%). No severe EVT-related adverse events occurred. CONCLUSION: EVT is safe and technically feasible, so it emerges as a promising endoscopic treatment option for duodenal leaks. However, multidisciplinary collaboration and management are important to reduce the occurrence of postoperative complications, and to improve recovery rates.

Assessment of predictors of early postoperative complications after primary robotically assisted Roux-en-Y gastric bypass: a multicenter, retrospective cohort study.

BACKGROUND: Robotic Roux-en-Y gastric bypass (RRYGB) is performed in an increasing number of bariatric centers worldwide. Previous studies have identified a number of demographic and clinical variables as predictors of postoperative complications after laparoscopic Roux-en-Y gastric bypass (LRYGB). Some authors have suggested better early postoperative outcomes after RRYGB compared to LRYGB. The objective of the present study was to assess potential predictors of early postoperative complications after RRYGB. METHODS: A retrospective analysis of two prospective databases containing patients who underwent RRYGB between 2006 and 2019 at two high volumes, accredited bariatric centers was performed. Primary outcome was rate of 30 day postoperative complications. Relevant demographic, clinical and biological variables were entered in a multivariate, logistic regression analysis to identify potential predictors. RESULTS: Data of 1276 patients were analyzed, including 958 female and 318 male patients. Rates of overall and severe 30 day complications were 12.5% (160/1276) and 3.9% (50/1276), respectively. Rate of 30 day reoperations was 1.6% (21/1276). The overall gastrointestinal leak rate was 0.2% (3/1276). Among various demographic, clinical and biological variables, male sex and ASA score >2 were significantly correlated with an increased risk of 30 day complication rates on multivariate analysis (OR 1.68 and 1.67, p=0.005 and 0.005, respectively). CONCLUSION: This study identified male sex and ASA score >2 as independent predictors of early postoperative complications after RRYGB. These data suggest a potentially different risk profile in terms of early postoperative complications after RRYGB compared to LYRGB. The robotic approach might have a benefit for patients traditionally considered to be at higher risk of complications after LRYGB, such as those with BMI >50. The present study was however not designed to assess this hypothesis and larger, prospective studies are necessary to confirm these results.

Implementation and validation of a competency assessment tool for laparoscopic cholecystectomy.

BACKGROUND: Achieving proficiency in a surgical procedure is a milestone in the career of a trainee. We introduced a competency assessment tool for laparoscopic cholecystectomy in our residency program. Our aim was to assess the inter-rater reliability of this tool. METHODS: We included all laparoscopic cholecystectomies performed by residents under the supervision of board certified surgeons. All residents were assessed at the end of the procedure by the supervising surgeon (live reviewer) using our competency assessment tool. Video records of the same procedure were analyzed by two independent reviewers (reviewer A and B), who were blinded to the performing trainee's. The assessment had three parts: a laparoscopic cholecystectomy-specific assessment tool (LCAT), the objective structured assessment of technical skills (OSATS) and a 5-item visual analogue scale (VAS) to address the surgeon's autonomy in each part of the cholecystectomy. We compared the assessment scores of the live supervising surgeon and the video reviewers. RESULTS: We included 15 junior residents who performed 42 laparoscopic cholecystectomies. Scoring results from live and video reviewer were comparable except for the OSATS and VAS part. The score for OSATS by the live reviewer and reviewer B were 3.68 vs. 4.26 respectively (p = 0.04) and for VAS (5.17 vs. 4.63 respectively (p = 0.03). The same difference was found between reviewers A and B with OSATS score (3.75 vs. 4.26 respectively (p = 0.001)) and VAS (5.56 vs. 4.63 respectively; p = 0.004)). CONCLUSION: Our competency assessment tool for the evaluation of surgical skills specific to laparoscopic cholecystectomy has been shown to be objective and comparable in-between raters during live procedure or on video material.

Multimodal treatment in oligometastatic gastric cancer.

Gastric cancer is generally diagnosed at an advanced stage, especially in countries without screening programs. Previously, the metastatic stage was synonymous with palliative management, and surgical indications were only for symptomatic relief. However, this therapeutic option is associated with poor prognosis. A subgroup of patients with limited metastatic disease could benefit from intensive treatment. A combination of chemotherapy, immunotherapy, and targeted therapy could help either maintain a resectable state for oligometastatic disease or diminish the metastasis size to obtain a complete resection configuration. This latter strategy is known as conversion therapy and has growing evidence with favorable outcomes. Oncosurgical approach of metastatic disease could prolong survival in selected patients. The challenge for the surgeon and oncologist is to identify these specific patients to offer the best multimodal management. We review in this article the actual evidence for the treatment of oligometastatic gastric cancer with curative intent.

Preventive HIPEC in combination with perioperative FLOT versus FLOT alone for resectable diffuse type gastric and gastroesophageal junction type II/III adenocarcinoma - the phase III "PREVENT"- (FLOT9) trial of the AIO /CAOGI /ACO.

BACKGROUND: The main reason for treatment failure after curative surgical resection of gastric cancer is intra-abdominal spread, with 40-50% peritoneal seeding as primary localization of recurrence. Peritoneal relapse is seen in 60-70% of tumors of diffuse type, compared to only 20-30% of intestinal type. Hyperthermic IntraPEritoneal Chemoperfusion (HIPEC) is an increasingly used therapy method for patients with peritoneal metastases. The preventive use of HIPEC could represent an elegant approach for patients (pts) before macroscopic peritoneal seeding, since pts. with operable disease are fit and may have potential risk of microscopic involvement, thus having a theoretical chance of cure with HIPEC even without the need for cytoreduction. No results from a PCRT from the Western hemisphere have yet been published. METHODS: This is a multicenter, randomized, controlled, open-label study including a total of 200 pts. with localized and locally advanced diffuse or mixed type (Laurens's classification) adenocarcinoma of the stomach and Type II/III GEJ. All enrolled pts. will have received 3-6 pre-operative cycles of biweekly FLOT (Docetaxel 50 mg/m2; Oxaliplatin 85 mg/m2; Leucovorin 200 mg/m2; 5-FU 2600 mg/m2, q2wk). Pts will be randomized 1:1 to receive surgery only and postoperative FLOT (control arm) or surgery + intraoperative HIPEC (cisplatin 75 mg/m2 solution administered at a temperature of 42 °C for 90 min) and postoperative FLOT (experimental arm). Surgery is carried out as gastrectomy or transhiatal extended gastrectomy. Primary endpoint is PFS/DFS, major secondary endpoints are OS, rate of pts. with peritoneal relapse at 2 and 3 years, perioperative morbidity/mortality and quality of life. The trial starts with a safety run-in phase. After 20 pts. had curatively intended resection in Arm B, an interim safety analysis is performed. Recruitment has already started and first patient in was on January 18th, 2021. DISCUSSION: If the PREVENT concept proves to be effective, this could potentially lead to a new standard of therapy. On the contrary, if the outcome is negative, pts. with gastric cancer and no peritoneal involvement will not be treated with HIPEC during surgery. TRIAL REGISTRATION: The study is registered on June 25th, 2020 under ClinicalTrials.gov Identifier: NCT04447352 ; EudraCT: 2017-003832-35 .

Current surgical treatment standards for esophageal and esophagogastric junction cancer.

A number of different surgical techniques for the treatment of cancer of the esophagus and the esophagogastric junction have been proposed. Guidelines generally recommend a transthoracic approach for esophageal cancer, including Siewert type I tumors. In tumors of the proximal esophageal third, transthoracic esophagectomy may be extended to a three-field approach, including resection of cervical lymph nodes. However, the choice between transthoracic esophagectomy with intrathoracic anastomosis (Ivor Lewis esophagectomy) and the three-incision approach with cervical esophago-gastrostomy (McKeown esophagectomy) remains controversial, with guidelines varying among different countries. Furthermore, it is commonly accepted that Siewert type III tumors should be treated by extended total gastrectomy with transhiatal resection of the lower esophagus, whereas currently no consensus exists regarding the optimal surgical approach for the treatment of Siewert type II adenocarcinoma. Likewise, there is a major controversy regarding palliative and potentially curative treatment modalities in oligometastatic disease. This review deals with current surgical treatment standards for cancer of the esophagus and the eosphagogastric junction, including discussion of ongoing trials.

Minimal length of proximal resection margin in adenocarcinoma of the esophagogastric junction: a systematic review of the literature.

The minimal length of proximal margin (PM) in esophagogastric junction cancer has not been established yet and its impact on patient survival remains unclear. Pubmed, Embase and Scopus databases were searched for "adenocarcinoma of the esophagogastric junction", "adenocarcinoma of the gastroesophageal junction" and "cardia cancer", each combined with "proximal margin". English written studies that specified PM length in AEG were included. Survival data in relation to PM were extracted. 13 studies, that were all retrospective case series, with a total number of 2648 patients met inclusion criteria and were analyzed. While 93% of 230 patients with Siewert type I had esophagectomy, 69% of 1270 patients with Siewert type II and 93% of 872 patients with Siewert type III had transhiatal extended gastrectomy. Minimal PM length was treated by five studies and ranged between 2 and 6 cm. While three studies defined minimal PM by the necessary length to obtain R0 resection, two studies found minimal PM length significantly associated with survival. Multivariate analyses revealed in two studies an independent impact of PM on survival, whereas one study did not found any significant relation between PM and survival. One study showed that PM length was significantly associated with survival in T2-4N0-2 tumors, but not in T1 or N3 tumors. In conclusion, available retrospective studies did not allow a conclusion for a minimal length of PM and showed no clear evidence for an impact of PM length on survival. Taking into consideration available data and the shrinkage phenomen, a PM > 2 cm might be necessary to obtain a sufficient PM.

Neoadjuvant chemoradiation for patients with advanced oesophageal cancer - which response grading system best impacts prognostic discrimination?

AIMS: Neoadjuvant chemoradiation reduces tumour volume and improves the R0 resection rate, followed by extended survival for patients with advanced oesophageal cancer. The degree of tumour regression has high prognostic relevance. To date, there is still no generally accepted tumour regression grading system. The aim of this study was to compare the prognostic discrimination power of different histological regression grading systems: (i) the fibrosis/tumour ratio within the primary tumour (Mandard classification), (ii) the percentage of residual vital tumour cells (VTC) compared to the original primary tumour (Cologne Regression) and (iii) the ypT category, in patients with cT3 carcinoma of the oesophagus after neoadjuvant chemoradiation. METHODS AND RESULTS: This study included 216 patients with oesophageal cancer clinically staged as cT3NxM0 and treated from 2009 to 2012 with standardised chemoradiation followed by oesophagectomy [median age 62 years, 176 (81%) male and 138 (64%) adenocarcinoma patients]. The subgroup frequencies of the three classification systems were ypT category: ypT0 = 18%, ypT1 = 14%, ypT2 = 23%, ypT3 = 44%, ypT4 = 1%; Mandard classification: TRG1 = 18%, TRG2 = 26%, TRG3 = 24%, TRG4 = 30%, TRG5 = 2%; and Cologne Regression Scale: no tumour = 18%, 1-10% VTC = 27%, 10-50% VTC = 26% and >50% VTC = 29%. The Mandard and Cologne Regression classifications showed better prognostic differentiation for the subgroups than the ypT category. The four-tiered Cologne Regression system had a good prognostic relevance. Comparing results of the re-evaluated Cologne Regression classification with the classification by routine pathological report showed very good inter-rater agreement, with kappa value 0.891. CONCLUSION: Compared to the original primary tumour, the tumour regression grading system using the percentage of residual vital tumour has prognostic relevance.

The presence of an asymptomatic aberrant right subclavian artery: A potential risk factor in esophageal surgery?

Bleeding of an aberrant right subclavian artery following transthoracic en bloc esophagectomy and intrathoracic gastric reconstruction is a rare but severe complication in esophageal surgery. Preoperative diagnosis can be achieved by computed tomography or magnetic resonance angiography (MRA). Various treatment options are available; thus, the treatment can be challenging and should be adjusted to the severity of the symptoms. Bleeding of an aberrant right subclavian artery can result from perioperative vascular injury or various postoperative complications. We report about a case of a patient with esophageal cancer and an asymptomatic, simultaneously existing aberrant right subclavian artery. The patient underwent a successful conventional Ivor-Lewis esophageal resection without any life-threatening bleeding. Early detection and intraoperative identification was of major importance for successful surgery.

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) in combination with standard of care chemotherapy in primarily untreated chemo naïve upper gi-adenocarcinomas with peritoneal seeding - a phase II/III trial of the AIO/CAOGI/ACO.

BACKGROUND: Peritoneal metastasis is a common and dismal evolution of several gastrointestinal (GI) tumors, including gastric, colorectal, hepatobiliary, pancreatic, and other cancers. The therapy of peritoneal metastasis is largely palliative; with the aim of prolonging life and preserving its quality. In the meantime, a significant pharmacological advantage of intraperitoneal chemotherapy was documented in the preclinical model, and numerous clinical studies have delivered promising clinical results. METHODS: This is a prospective, open, randomized multicenter phase III clinical study with two arms that aims to evaluate the effects of pressurized intraperitoneal aerosol chemotherapy (PIPAC) combined with systemic chemotherapy vs. intravenous systemic chemotherapy alone on patients with metastatic upper GI tumors with a peritoneal seeding. Upper GI-adenocarcinomas originated from biliary tract, pancreas and stomach, or esophago- gastric junction are eligible. Patients in the study are treated with standard of care systemic palliative chemotherapy (mFOLFOX6) vs. PIPAC with intravenous (i.v.) chemotherapy (mFOLFOX6). Patients in first line with first diagnosed peritoneal seeding are eligible. Primary outcome is progression free survival (PFS). CONCLUSIONS: PIPAC-procedure is explicit a palliative method but it delivers cytotoxic therapy like in hyperthermic intraperitoneal chemotherapy (HIPEC)-procedure directly to the tumor in a minimally invasive technique, without the need for consideration of the peritoneal-plasma barrier. The technique of PIPAC is minimally invasive and very gentle and the complete procedure takes only round about 45 min and, therefore, optimal in a clearly palliative situation where cure is not the goal. It is also ideal for using this approach in a first line situation, where deepest response should be achieved. The symbiosis of systemic therapy and potentially effective surgery has to be well-planned without deterioration of the patient due to aggressive way of surgery like in cytoreductive surgery (CRS)+HIPEC. TRIAL REGISTRATION: EudraCT: 2018-001035-40.

Current and future treatment options for esophageal cancer in the elderly.

INTRODUCTION: Esophageal cancer is the eighth most common cancer globally and has the sixth worst prognosis because of its aggressiveness and poor survival. Data regarding cancer treatment in older patients is limited because the elderly have been under-represented in clinical trials. Therefore, we reviewed the existing literature regarding treatment results for elderly patients (70+ years). Areas covered: We used pubmed to analyze the actual literature according to elderly esophageal cancer patients with subheading of incidence, esophagectomy, chemoradiation or chemotherapy. The main points of interest were treatment options for patients with Barrett's esophagus or early carcinoma, advanced tumor stages, and inoperable cancer. Expert opinion: The incidence of esophageal cancer has been increasing over the past thirty years, with a rapid increase of esophageal adenocarcinoma in Western industrialized nations. Patients aged over 60 years have been particularly affected. In this review, we have shown that elderly patients with esophageal cancer have various alternatives for adequate treatment. Clinical evaluation of comorbidity is necessary to make treatment decisions. Therapeutic options for early carcinomas are endoscopic or surgical resection. For elderly patients with advanced carcinomas, preoperative chemoradiation or chemotherapy should be discussed.

Immune checkpoints programmed death 1 ligand 1 and cytotoxic T lymphocyte associated molecule 4 in gastric adenocarcinoma.

Remarkable efficacy of immune checkpoint inhibition has been reported for several types of solid tumors and early studies in gastric adenocarcinoma are promising. A detailed knowledge about the natural biology of immune checkpoints in gastric adenocarcinoma is essential for clinical and translational evaluation of these drugs. This study is a comprehensive analysis of cytotoxic T lymphocyte associated molecule 4 (CTLA-4) and programmed death 1 ligand 1 (PD-L1) expression in gastric adenocarcinoma. PD-L1 and CTLA-4 were stained on tumor sections of 127 Caucasian patients with gastric adenocarcinoma by immunohistochemistry (IHC) and somatic mutation profiling was performed using targeted next-generation sequencing. Expression of PD-L1 and CTLA-4 on lymphocytes in tumor sections, tumor-draining lymph nodes (TDLN) and peripheral blood were studied by flow-cytometry and immune-fluorescence microscopy in an additional cohort. PD-L1 and CTLA-4 were expressed in 44.9% (57/127) and 86.6% (110/127) of the analyzed gastric adenocarcinoma samples, respectively. Positive tumor cell staining for PD-L1 or CTLA-4 was associated with inferior overall survival. Somatic mutational analysis did not reveal a correlation to expression of PD-L1 or CTLA-4 on tumor cells. Expression of PD-1 (52.2%), PD-L1 (42.2%) and CTLA-4 (1.6%) on tumor infiltrating T cells was significantly elevated compared to peripheral blood. Of note, PD-1 and PD-L1 were expressed far higher by tumor-infiltrating lymphocytes than CTLA-4. In conclusion, specific immune checkpoint-inhibitors should be evaluated in this disease and the combination with molecular targeted therapies might be of benefit. An extensive immune monitoring should accompany these studies to better understand their mode of action in the tumor microenvironment.

International comparison of the German evidence-based S3-guidelines on the diagnosis and multimodal treatment of early and locally advanced gastric cancer, including adenocarcinoma of the lower esophagus.

BACKGROUND: Clinical guidelines are essential in implementing and maintaining nationwide stage-specific diagnostic and therapeutic standards. In 2011, the first German expert consensus guideline defined the evidence for diagnosis and treatment of early and locally advanced esophagogastric cancers. Here, we compare this guideline with other national guidelines as well as current literature. METHODS: The German S3-guideline used an approved development process with de novo literature research, international guideline adaptation, or good clinical practice. Other recent evidence-based national guidelines and current references were compared with German recommendations. RESULTS: In the German S3 and other Western guidelines, adenocarcinomas of the esophagogastric junction (AEG) are classified according to formerly defined AEG I-III subgroups due to the high surgical impact. To stage local disease, computed tomography of the chest and abdomen and endosonography are reinforced. In contrast, laparoscopy is optional for staging. Mucosal cancers (T1a) should be endoscopically resected "en-bloc" to allow complete histological evaluation of lateral and basal margins. For locally advanced cancers of the stomach or esophagogastric junction (≥T3N+), preferred treatment is preoperative and postoperative chemotherapy. Preoperative radiochemotherapy is an evidence-based alternative for large AEG type I-II tumors (≥T3N+). Additionally, some experts recommend treating T2 tumors with a similar approach, mainly because pretherapeutic staging is often considered to be unreliable. CONCLUSIONS: The German S3 guideline represents an up-to-date European position with regard to diagnosis, staging, and treatment recommendations for patients with locally advanced esophagogastric cancer. Effects of perioperative chemotherapy versus chemoradiotherapy are still to be investigated for adenocarcinoma of the cardia and the lower esophagus.

Homozygous GNAS 393C-allele carriers with locally advanced esophageal cancer fail to benefit from platinum-based preoperative chemoradiotherapy.

BACKGROUND: Currently, patients with locally advanced esophageal cancer receive neoadjuvant chemoradiotherapy but only about half of these patients benefit from this treatment. GNAS T393C has been shown to predict the postoperative course in solid tumors and may therefore be useful for treatment stratification. The aim of the present study was to determine if the single-nucleotide polymorphism GNAS T393C can be used for treatment stratification in esophageal cancer patients. METHODS: A total of 596 patients underwent surgical resection for esophageal carcinoma from 1996 to 2008; 279 patients received chemoradiotherapy prior to surgery (RTX-SURG group). All patients and a reference group of 820 healthy White individuals were genotyped for GNAS T393C. RESULTS: The 5-year-survival rate for the 317 patients who underwent esophagectomy as initial treatment (SURG group) was 57 % for homozygous C-allele carriers (n = 99) and 43 % for T-allele carriers (n = 218; log- rank test p = 0.025). Multivariate analysis revealed the GNAS T393C genotype (p = 0.034), pT (p < 0.001), pN (p < 0.001) and age (p < 0.001) as prognostic of survival. Homozygous C-allele carriers with a locally advanced tumor stage (cT3/T4, n = 129) in the SURG group had a 5-year survival rate of 37 %, which, remarkably, exceeded the 5-year survival rate of 30 % for the entire RTX-SURG group (n = 279). In the RTX-SURG group, the GNAS T393C genotype did not show any prognostic significance. CONCLUSIONS: Patients with a locally advanced esophageal cancer and an homozygous GNAS 393C genotype do not benefit from platinum-based neoadjuvant chemoradiotherapy, indicating that these patients should be treated by alternative treatment strategies.

Validation of 2-mm tissue microarray technology in gastric cancer. Agreement of 2-mm TMAs and full sections for Glut-1 and Hif-1 alpha.

BACKGROUND/AIM: Tissue Microarray (TMA) is a widely used method to perform high-throughput immunohistochemical analyses on different tissues by arraying small sample cores from paraffin-fixed tissues into a single paraffin block. TMA-technology has been validated on numerous cancer tissues and also for gastric cancer studies, although it has not been validated for this tumor tissue so far. The objective of this study was to assess, whether the 2-mm TMA-technology is able to provide representative samples of gastric cancer tissue. MATERIALS AND METHODS: TMA paraffin blocks were constructed by means of 220 formalin-fixed and paraffin-embedded gastric cancer samples with a sample diameter of 2 mm. The agreement of immunohistochemical stainings of Glut-1 and Hif-1 alpha in TMA sections and the original full sections was calculated using kappa statistics and direct adjustment. RESULTS: The congruence was substantial for Glut-1 (kappa 0.64) and Hif-1 alpha (kappa 0.70), but with an agreement of only 71% and 52% within the marker-positive cases of the full-section slides. CONCLUSION: Due to tumor heterogeneity primarily, the TMA technology with a 2-mm sample core shows relevant limitations in gastric cancer tissue. Although being helpful for tissue screening purposes, the 2-mm TMA technology cannot be recommended as a method equal to full-section investigations in gastric cancer.

Extracapsular lymph node spread as a negative prognostic factor of adenocarcinoma of the pancreas and cancer of the papilla of vater.

OBJECTIVE: The aim of this study was to analyze the incidence and impact of extracapsular lymph node spread (ELNS) in pancreatic cancer (PC) and cancer of the papilla of Vater (CPV). METHODS: Between 2004 and 2009, 148 patients underwent surgical therapy for PC (n = 112) and CPV (n = 36). The resected lymph nodes (LNs) were further analyzed for ELNS. RESULTS: In 95 (64.2%) patients, LN metastasis was present. In 45 (47.3%) of these patients, an ELNS was present on histopathology. The patients' survival was negatively affected by ELNS. For PC, the 5-year survival rate was 37% for patients with no LN metastasis compared with 4% and 0% for patients with LN metastasis (pN1) but without extracapsular LN involvement and patients with pN1 disease with extracapsular LN involvement of at least 1 LN, respectively (P < 0.001). In patients with CPV, the 5-year survival rate was 56% for patients with no LN metastasis and 44% and 0% for patients with pN1 disease but without extracapsular LN involvement and patients with pN1 disease with extracapsular LN involvement of at least 1 LN, respectively (P = 0.006). Multivariate analysis revealed ELNS as an independent prognostic factor of survival for both tumor types. CONCLUSIONS: Extracapsular LN spread is an independent negative prognostic factor in PC and CPV. In future staging systems, ELNS should be included.

Neoadjuvant radiochemotherapy in adenocarcinoma of the esophagus: ERCC1 gene polymorphisms for prediction of response and prognosis.

INTRODUCTION: Neoadjuvant radiochemotherapy (RT/CTx) regimens were primarily designed for treatment of squamous cell carcinoma of the esophagus. Own preliminary results demonstrate that also patients with locally advanced adenocarcinoma of the esophagus may achieve a major response in 30% with a 3-year survival rate of 80%. To identify these patients, ERCC1 (rs11615) gene polymorphisms were analyzed. ERCC1 is a key enzyme of the nucleotide excision and repair (NER) complex to prevent DNA inter- and intra-strand crosslinks. PATIENTS AND METHODS: Genomic DNA from 217 patients with cT3/4 adenocarcinoma of the esophagus was extracted from paraffin-embedded tissues. Of these patients, 153 underwent neoadjuvant RT/CTx (CDDP, 5-FU, 36 Gy). For analysis of ERCC1 single nucleotide polymorphisms (SNPs), allelic discrimination was performed by quantitative real-time PCR. Two allele-specific TaqMan probes in competition were used for amplification of ERCC1 (rs11615). Allelic genotyping was correlated with histomorphologic tumor regression after neoadjuvant RT/CTx and survival. Major response (MaHR) was defined as <10% vital residual tumor cells (VRTC). RESULTS: Analysis of tumor regression revealed a MaHR in 56/153 (36.6%) patients with a 5-year survival rate (5-YSR) of 74% (p < 0.001). ERCC1 gene polymorphisms for all patients showed the following expression pattern: ERCC1 polymorphism (rs11615) CC: n = 27 (12.4%), TT: n = 98 (45.2%), C/T: n = 92 (42.4%). ERCC1 polymorphism CT was identified as a predictor for response to the neoadjuvant RT/CTx (p < 0.001). The 5-YSR for patients with C/T genotype was 51%. Contrary to this, the 5-YSR for the group of patients with a CC/TT polymorphism decreased to 34%. CONCLUSION: Analysis of ERCC1 (rs11615) gene polymorphisms reveals a significant correlation with response and survival in patients with adenocarcinoma of the esophagus treated with a neoadjuvant radiochemotherapy. Single nucleotide polymorphisms of ERCC1 (rs11615) could therefore be applied to further individualize therapy in esophageal cancer.

Prognostic significance of a new grading system of lymph node morphology after neoadjuvant radiochemotherapy for esophageal cancer.

BACKGROUND: Along with primary tumor response, lymph node (LN) status after radiochemotherapy is one of the most important prognostic factors for advanced esophageal carcinoma. We investigated the influence of neoadjuvant radiochemotherapy on histomorphologic parameters of LNs. METHODS: One hundred ninety-two patients with esophageal carcinoma underwent surgery after preoperative radiochemotherapy. Response of primary tumor was graded as "minor" or "major." Two matched subgroups were chosen: 20 patients with minor response and 20 patients with major response. Histomorphologic criteria of LNs underwent univariate and multivariate analyses and correlated with tumor response and prognosis statistics. RESULTS: The LNs from 40 patients (N = 1276) were examined (median number of LNs per patient, 31). Of patients with minor response, 65% showed LN metastasis; of those with major response, 20% did so (p = 0.011). Major responders had significantly lower rates of capsular and central fibrosis and vascular transformation and had more sarcoidlike lesions. Logistic regression analysis did not distinguish these parameters between major and minor responders. The 5-year survival rate was 55% for major responders and 10% for minor responders (p = 0.025), 47% for patients with LN metastasis (LNM) and 18% for patients with LNM (p = 0.041). An optimal prognostic factor, LN morphologic grading, was defined as follows: low risk, no LNM and less than 3 LNs with central fibrosis; medium risk, no LNM and central fibrosis in 3 or more LNs or LNM with an LN ratio of less than 0.05; high risk, all other cases. The 5-year survival rate was 56%, 25%, and 0% for patients considered to have low, medium, and high risk, respectively, according to LN morphologic grading (p < 0.003). With the inclusion of this classification in the Cox regression analysis, no other factors showed prognostic relevance. CONCLUSIONS: Grading of LN morphology after neoadjuvant radiochemotherapy is the most important prognostic factor for patients with esophageal cancer.

Altered levels of the onco-microRNA 21 and the tumor-supressor microRNAs 143 and 145 in advanced rectal cancer indicate successful neoadjuvant chemoradiotherapy.

microRNAs (miRNAs) are small non-coding RNAs with important post-transcriptional regulatory functions. miRNA-21 (miR-21) is upregulated and miR-143 and miR-145 are downregulated in colorectal carcinoma. The aim of our study was to determine if these miRNAs change their expression levels in response to neoadjuvant chemoradiotherapy in advanced rectal cancer. Forty patients with advanced rectal cancer (clinical uT3/T4 Nx) were included. All patients underwent neoadjuvant chemoradiotherapy and surgical resection. Expression of miR-21, -143 and -145 was examined in macrodissected tumor tissue before and after chemoradiotherapy and normal rectal tissue from the resection specimen. RNA was extracted from formalin-fixed and paraffin-embedded tissue by TRIzol method, polyadenylated, reverse transcribed and analyzed by real-time PCR. Therapy response was assessed according to pathological tumor regression. miR-21 was more highly expressed in tumor tissue than in non-tumorous tissue. However, there was a moderately lower expression in post-therapeutic tumor tissue compared to pre-therapeutic tumor tissue. There was a significant upregulation of miR-143 and miR-145 in post-therapeutic tumor tissue compared to pre-therapeutic tumor tissue. According to the predictive and prognostic value of the analyzed miRNAs, a significant correlation between miR-145 expression and tumor regression was seen. Patients with a low intratumoral post-therapeutic expression had significantly more often a worse response to neoadjuvant therapy compared to patients with a high expression of miR145. The present results support the hypothesis that chemoradiotherapy can profoundly alter miRNA expression profiles. miRNAs might play important roles as molecular biomarkers in the prediction of response to treatment and prognosis.