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Background: Gastric cancer (GC) is clinically heterogenous according to location (cardia/non-cardia) and histopathology (diffuse/intestinal). We aimed to characterize the genetic risk architecture of GC according to its subtypes. Another aim was to examine whether cardia GC and oesophageal adenocarcinoma (OAC) and its precursor lesion Barrett's oesophagus (BO), which are all located at the gastro-oesophageal junction (GOJ), share polygenic risk architecture. Methods: We did a meta-analysis of ten European genome-wide association studies (GWAS) of GC and its subtypes. All patients had a histopathologically confirmed diagnosis of gastric adenocarcinoma. For the identification of risk genes among GWAS loci we did a transcriptome-wide association study (TWAS) and expression quantitative trait locus (eQTL) study from gastric corpus and antrum mucosa. To test whether cardia GC and OAC/BO share genetic aetiology we also used a European GWAS sample with OAC/BO. Findings: Our GWAS consisting of 5816 patients and 10,999 controls highlights the genetic heterogeneity of GC according to its subtypes. We newly identified two and replicated five GC risk loci, all of them with subtype-specific association. The gastric transcriptome data consisting of 361 corpus and 342 antrum mucosa samples revealed that an upregulated expression of MUC1, ANKRD50, PTGER4, and PSCA are plausible GC-pathomechanisms at four GWAS loci. At another risk locus, we found that the blood-group 0 exerts protective effects for non-cardia and diffuse GC, while blood-group A increases risk for both GC subtypes. Furthermore, our GWAS on cardia GC and OAC/BO (10,279 patients, 16,527 controls) showed that both cancer entities share genetic aetiology at the polygenic level and identified two new risk loci on the single-marker level. Interpretation: Our findings show that the pathophysiology of GC is genetically heterogenous according to location and histopathology. Moreover, our findings point to common molecular mechanisms underlying cardia GC and OAC/BO. Funding: German Research Foundation (DFG).

IntroductionWith growing emphasis on surgical safety, it appears fundamental to assess the safety of colorectal resection involving primary stapled anastomosis. Surgical stapling devices can considerably foster patient safety in colorectal surgery, but their misuse or malfunction encompass a unique risk of postoperative complications. The Digital Device Briefing Tool (DDBT) is a digital cognitive aid developed to enhance safe use of the Ethicon circular stapling device during colorectal resection. The purpose of this study is to evaluate how a digital operative workflow, including DDBT, compared with routine surgical care, affects morbidity and mortality in patients undergoing left-sided colorectal resection with primary stapled colorectal anastomosis for colorectal cancer or benign disease.Methods and analysisA multicentre, prospective cohort study will be conducted at five certified academic colorectal centres in Germany. It compares a non-digital with a Johnson & Johnson digital solution (Surgical Process Institute Deutschland (SPI))-guided operative workflow in patients undergoing left hemicolectomy, sigmoidectomy, anterior rectal resection and Hartmann reversal procedure. The sample size is set at 528 cases in total, divided into 3 groups (a non-digital and two SPI-guided workflow cohorts, with and without DDBT) in a ratio of 1:1:1, with 176 patients each. The primary endpoint is a composite outcome comprising the overall rate of surgical complications, including death, during hospitalisation and within the first 30 days after colorectal resection. Secondary endpoints include operating time, length of hospital stay and 30-day hospital readmission rate.Ethics and disseminationThis study will be performed in line with the Declaration of Helsinki. The ethics committee of the Charité—University Medicine Berlin, Germany, approved the study (No: 22-0277-EA2/060/22). Study Investigators will obtain written informed consent from each patient before a patient may participate in this study. The study results will be submitted to an international peer-reviewed journal.Trial registration numberDRKS00029682.

Objectives Patients with autoimmune gastritis (AIG) are reported to have an increased risk of developing gastric cancer (GC). In this study, we assess the characteristics and outcomes of GC patients with AIG in a multicenter case-control study. Methods Between April 2013 and May 2017, patients with GC, including cancers of the esophagogastric junction (EGJ) Siewert type II and III, were recruited. Patients with histological characteristics of AIG were identified and matched in a 1:2 fashion for age and gender to GC patients with no AIG. Presenting symptoms were documented using a self-administered questionnaire. Results Histological assessment of gastric mucosa was available for 572/759 GC patients. Overall, 28 (4.9%) of GC patients had AIG (67 ± 9 years, female-to-male ratio 1.3:1). In patients with AIG, GC was more likely to be localized in the proximal (i.e. EGJ, fundus, corpus) stomach (odds ratio (OR) 2.7, 95% confidence interval (CI) 1.0–7.1). In GC patients with AIG, pernicious anemia was the leading clinical sign (OR 22.0, 95% CI 2.6–187.2), and the most common indication for esophagogastroduodenoscopy (OR 29.0, 95% CI 7.2–116.4). GC patients with AIG were more likely to present without distant metastases (OR 6.2, 95% CI 1.3–28.8) and to be treated with curative intention (OR 3.0, 95% CI 1.0–9.0). The five-year survival rates with 95% CI in GC patients with and with no AIG were 84.7% (83.8–85.6) and 53.5% (50.9–56.1), respectively (OR 0.25, 95% CI 0.08–0.75, p = 0.001). Conclusions Pernicious anemia leads to earlier diagnosis of GC in AIG patients and contributes significantly to a better clinical outcome.

Purpose In a post hoc analysis of the MAGIC trial, patients with curatively resected gastric cancer (GC) and mismatch repair (MMR) deficiency (MMRd) had better median overall survival (OS) when treated with surgery alone but worse median OS when treated with additional chemotherapy. Further data are required to corroborate these findings. Methods Between April 2013 and December 2018, 458 patients with curatively resected GC, including cancers of the esophagogastric junction Siewert type II and III, were identified in the German centers of the staR consortium. Tumor sections were assessed for expression of MLH1, MSH2, MSH6 and PMS2 by immunohistochemistry. The association between MMR status and survival was assessed. Similar studies published up to January 2021 were then identified in a MEDLINE search for a meta-analysis. Results MMR-status and survival data were available for 223 patients (median age 66 years, 62.8% male), 23 patients were MMRd (10.3%). After matching for baseline clinical characteristics, median OS was not reached in any subgroup. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd and MMRp had a HR of 0.67 (95% CI 0.13–3.37, P = 0.63) and 1.44 (95% CI 0.66–3.13, P = 0.36), respectively. The meta-analysis included pooled data from 385 patients. Compared to perioperative chemotherapy, patients receiving surgery alone with MMRd had an improved OS with a HR of 0.36 (95% CI 0.14–0.91, P = 0.03), whereas those with MMRp had a HR of 1.18 (95% CI 0.89–1.58, P = 0.26). Conclusion Our data support a positive prognostic effect for MMRd in GC patients treated with surgery only and a differentially negative prognostic effect in patients treated with perioperative chemotherapy. MMR status determined by preoperative biopsies may be used as a predictive biomarker to select patients for perioperative chemotherapy in curatively resectable GC.

Background and Aims: Symptoms of patients with gastric cancer (GC) are often unspecific and differences in symptoms between patients with cardia and non-cardia GC have been poorly investigated. We aimed to characterize symptoms of patients with cardia and non-cardia GC. Methods: Patients with cardia (Siewert type II and III) and non-cardia GC were recruited in the German multicenter cohort of the Gastric Cancer Research (staR) study between 2013 and 2017. Alarm, dyspeptic and reflux symptoms at the time of presentation were documented using a self-administered questionnaire. Results: A completed self-administered questionnaire was available for 568/759 recruited patients (132 cardia GC, 436 non-cardia GC, male 61%, mean age 64 years). Dyspeptic symptoms were more common in patients with non-cardia GC (69.0 vs. 54.5%, p=0.0024). Cardia GC patients reported more frequently alarm symptoms (69.7 vs. 44.7%, p

Purpose To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer. Methods This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2‑year overall survival (OS). Arm A was considered insufficiently active if 2‑year OS was ≤40% (null hypothesis = H0), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable. Results Two-year OS was 71% in arm A (95% CI: 55–87%) vs. 53% in arm B (95% CI: 36–71%); H0 was rejected. Median OS was 49.1 vs. 24.1 months (p = 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30–1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25–1.04) for progression, 0.43 (0.13–1.40) for locoregional failure, and 0.43 (0.17–1.05) for distant metastasis. Overall response was 81% vs. 69% (p = 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 (p = 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, p = 0.044). Conclusion Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 x 10(-04)) and on chromosome 8q24 at rs2585176 (P = 1.09 x 10(-09)). On chromosome 5p13 we found cis-eQTL effects with an up-regulation of PTGER4 expression in GC risk allele carrier (P = 9.27 x 10(-11)). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 x 10(-47)). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 x 10(-09)). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.

The primary tumor side is emerging as a prognostic factor for patients with liver metastatic colorectal cancer (mCRC). In a combined analysis of data from 2 randomized studies, the addition of selective internal radiation therapy to first-line chemotherapy in patients with mCRC was associated with statistically and clinically significant overall survival gains for patients with a right-sided primary tumor. Background: The primary tumor side is emerging as a major prognostic factor for patients with metastatic colorectal cancer (mCRC). We examined the survival data from 2 randomized studies to determine whether the outcomes differ between patients with mCRC with right-sided primary (RSP) tumors and those with left-sided primary (LSP) tumors after selective internal radiation therapy (SIRT) plus mFOLFOX6 (folinic acid [leucovorin], 5-fluorouracil, oxaliplatin) chemotherapy, versus chemotherapy alone. Patients and Methods: Separate and combined analyses were performed on the data from the SIRFLOX and FOXFIRE global trials, which compared chemotherapy plus SIRT with chemotherapy alone for patients with mCRC liver metastases. The primary tumor side data were prospectively collected. The principal outcome measure was overall survival (OS) stratified by treatment and primary tumor side. Results: In the combined analysis of all 739 patients enrolled, SIRT had no effect on OS (median OS, 24.3 vs. 24.6 months; hazard ratio [HR], 1.021; P = .810). For the 179 patients (24.2%) with a RSP tumor, OS was improved with the addition of SIRT (median, 22.0 vs. 17.1 months HR, 0.641; P = .008). The addition of SIRT was not associated with a significant difference in OS among the 540 patients with a LSP tumor (median, 24.6 vs. 26.6 months; HR, 1.120; P = .264). A test of treatment interaction by primary tumor side was statistically significant for RSP and SIRT (P = .002). Conclusion: The addition of SIRT for patients with RSP tumors, but not for those with LSP tumors, was associated with a statistically and clinically significant OS gain. (C) 2018 Elsevier Inc. All rights reserved.

To advance preclinical testing of novel targeted drugs in colorectal cancer (CRC) we established a panel of 133 mouse xenograft models from fresh tumor specimens of 239 patients with CRC of all four UICC stages. A subgroup of 67 xenograft models was treated with cetuximab, bevacizumab and oxaliplatin as single agents. Mutation status of KRAS (G12, G13, A146T), BRAF (V600E) and PIK3CA (E542K, E545K, H1047R) was assessed in all xenografts by allelespecific real-time PCR. KRAS codon 61 was assessed by conventional sequencing. AREG and EREG expression levels were analyzed by real-time PCR expression assays. In the treatment experiment we observed response rates of 27% (18/67) for cetuximab, 3% (2/67) for bevacizumab, and 6% (4/67) for oxaliplatin. Classification based on KRAS, BRAF and PIK3CA mutation status identified 15 of the responders (sensitivity 83%, confidence interval at p = 0.05 (CI): 59% - 96%), and 38 nonresponders (specificity 78%, CI: 63% - 88%). If any mutation except in KRAS codon 13 were considered, the classifier reached sensitivity of 94% and specificity of 69%. We improved specificity of the classifiers to 90% and 86% respectively by adding AREG and EREG RNA expression thresholds retrospectively. In patient-derived xenograft models, we found a predictive classifier for response to cetuximab that is more accurate than established biomarkers. We confirmed its potential performance in primary human tumors. For patients, the classifier’s sensitivity promises increased response rates and its specificity limits unnecessary toxicity. Given the scope of our xenograft models across all UICC stages, this applies not only to mCRC but also to the adjuvant setting of earlier stages. The xenograft collection allows to mimic randomized phase II trials and to test novel drugs effectively as single agents or in combinations. It also enables the development of highly accurate companion diagnostics as demonstrated by us for cetuximab.

Die kontrastverstärkte Mehrschicht-Computertomographie (MSCT) hat sich als das Standard-Schnittbildverfahren sowohl zur Diagnostik als auch zur Therapiekontrolle von Leberläsionen durchgesetzt. Zur Abklärung der lokalen Verhältnisse vor einer Leberteilresektion kann die diffusionsgewichtete Magnetresonanztomographie (DWI-MRT) wichtige zusätzliche Befunde liefern. Um das Kriterium der R0-Resektion zu erfüllen, erscheint ein Sicherheitsabstand von 0,5 mm ausreichend. Eine neoadjuvante Chemotherapie mit dem Ziel, die Tumorgröße zu verringern, kann parallel zur Pfortaderembolisation durchgeführt werden, ohne dass die perioperative Morbidität und Mortalität beeinträchtigt wird. Bezüglich des Managements primär resektabler Lebermetastasen besteht dringender Studienbedarf. Trotz der eher geringen Evidenz wird die adjuvante Chemotherapie in Deutschland derzeit breiter befürwortet als die perioperative Chemotherapie. Auch bezüglich der präoperativen Therapie bei Patienten mit (noch) nicht resektablen Lebermetastasen besteht erheblicher Studienbedarf. Bei KRAS-Wildtyp-Tumoren werden mit einer Cetuximab/Chemotherapie-Kombination hohe Ansprechraten (im Sinne einer metrischen Verkleinerung der Metastasen) erzielt. Bevacizumab/Chemotherapie-Kombinationen führen zu hohen pathohistologischen Komplett- und Partialremissionen. Welches der beste Parameter zur Erfolgsbeurteilung einer präoperativen Therapie ist, ist derzeit noch unbekannt, weshalb Vergleichsstudien mit dem Überleben als hartem Endpunkt durchgeführt werden müssen.

Das Kolonkarzinom gehort zu den haufigsten Tumorentitaten und wird bei der Mehrheit der Patienten im lokalisierten Stadium diagnostiziert. Das Rezidivrisiko schwankt je nach Stadium zwischen 10 und 80%, kann aber bei Risikopatienten mit einer postoperativen Chemotherapie in relevantem Mase gesenkt werden. Im Stadium III ist die adjuvante Chemotherapie eindeutig indiziert, sofern keine Kontraindikationen vorliegen. Im Stadium II hat die Chemotherapie einen nur marginalen Effekt auf das rezidivfreie Uberleben und wird daher nicht routinemasig empfohlen. Bei Vorliegen von Risikofaktoren wie Perforation, unzureichender Anzahl untersuchter Lymphknoten etc. kann die Chemotherapie jedoch auch im Stadium II eine relevante Verbesserung bringen und sollte individuell mit den Patienten diskutiert werden. Es wird die Kombination aus Oxaliplatin plus 5-FU/Folinsaure (FOLFOX) empfohlen. Alternativ konnen auch orale Fluoropyrimidine als Monotherapie gegeben werden.

Postoperative relapse rate after gastrectomy and perioperative chemotherapy remain high in patients with advanced gastric cancer due to the spread of disseminated tumour cells in the peritoneal cavity. Perioperative administration of catumaxomab could potentially eliminate residual tumour cells after intended curative resection of the primary tumour. This open-label, phase II study investigated the safety and efficacy of catumaxomab following neoadjuvant chemotherapy and subsequent surgery in patients with resectable (T2–4, N+, M0) gastric adenocarcinoma. Patients received catumaxomab intra- (single 10 μg dose) and postoperatively (10, 20, 50 and 150 μg on days 7, 10, 13 and 16, respectively). The primary endpoint was the postoperative complication rate (maximum rate defined as

Summary Background Poor treatment results obtained with palliative chemotherapy for advanced gastric cancer indicate the need for new effective and well-tolerated regimens Patients and methods Forty-three patients with locally advanced or metastatic gastric cancer were enrolled in a phase II study to evaluate the efficacy and safety of combination chemotherapy with doxetacel 75 mg/m2 and cisplatin 75 mg/m2 given every three weeks Results Thirty-nine patients were evaluable for response Four achieved a complete response and twelve a partial response, for an overall response rate of 37.2% (16 of 43 patients; 95% confidence interval (CI) 22 98–53 72) Median time to progression was 6 1 months and median overall survival 10 4 months Forty-two percent of all patients were still alive at one year and twelve percent at two years The major toxicity was leukopenia which reached grade 3–4 in 18.6% (n = 8) of the patients However, no febrile neutropenia occurred Nonhaematological toxicities were usually mild to moderate Grade 3 toxicities included diarrhea (9% of the patients), nausea and vomiting (7%), and alopecia (7%). Severe ototoxicity with or without peripheral neuropathy developed after completion of chemotherapy in two patients. Conclusions These results suggest that the combination of docetaxel and cisplatin has moderate toxicity and is an effective regimen for the treatment of advanced gastric cancer, both with regard to response rate and survival.

Objective To determine the impact of adjuvant hepatic arterial infusion (HAI) on survival relative to resection alone in patients with radical resection of colorectal liver metastases. Background Data Nearly 40% to 50% of all patients with colorectal carcinoma develop liver metastases. Curative resection results in a 5-year survival rate of 25% to 30%. Intrahepatic recurrence occurs after a median of 9 to 12 months in up to 60% of patients. The authors hypothesized that adjuvant intraarterial infusion of 5-fluorouracil (5-FU) might decrease the rate of intrahepatic recurrence and improve survival in patients with radical resection of colorectal liver metastases. Methods Between April 5, 1991, and December 31, 1996, patients with colorectal liver metastases from 26 hospitals were stratified by the number of metastases and the site of the primary tumor and randomized to resection of the liver metastases followed by adjuvant HAI of 5-FU (1000 mg/m 2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m 2 per day for 5 days as a short infusion), or liver resection only. Results The first planned intention-to-treat interim analysis after inclusion of 226 patients and 91 events (deaths) showed a median survival of 34.5 months for patients with adjuvant therapy versus 40.8 months for control patients. The median time to progression was 14.2 months for the chemotherapy group versus 13.7 months for the control group. Grade 3 and 4 toxicities (World Health Organization), mainly stomatitis (57.6%) and nausea (55.4%), occurred in 25.6% of cycles and 62.9% of patients. Conclusion According to this planned interim analysis, adjuvant HAI, when used in this dose and schedule in patients with resection of colorectal liver metastases, reduced the risk of death at best by 15%, but at worst the risk of death was doubled. Thus, the chance of detecting an expected 50% improvement in survival by the use of HAI was only 5%. Patient accrual was therefore terminated.

The prognosis for patients with pancreatic cancer is poor, even after resection with curative intent. Gemcitabine-based chemotherapy is standard treatment for advanced pancreatic cancer, but its effect on survival in the adjuvant setting has not been demonstrated.To analyze whether previously reported improvement in disease-free survival with adjuvant gemcitabine therapy translates into improved overall survival.CONKO-001 (Charité Onkologie 001), a multicenter, open-label, phase 3 randomized trial to evaluate the efficacy and toxicity of gemcitabine in patients with pancreatic cancer after complete tumor resection. Patients with macroscopically completely removed pancreatic cancer entered the study between July 1998 and December 2004 in 88 hospitals in Germany and Austria. Follow-up ended in September 2012.After stratification for tumor stage, nodal status, and resection status, patients were randomly assigned to either adjuvant gemcitabine treatment (1g/m2 d 1, 8, 15, q 4 weeks) for 6 months or to observation alone.The primary end point was disease-free survival. Secondary end points included treatment safety and overall survival, with overall survival defined as the time from date of randomization to death. Patients lost to follow-up were censored on the date of their last follow-up.A total of 368 patients were randomized, and 354 were eligible for intention-to-treat-analysis. By September 2012, 308 patients (87.0% [95% CI, 83.1%-90.1%]) had relapsed and 316 patients (89.3% [95% CI, 85.6%-92.1%]) had died. The median follow-up time was 136 months. The median disease-free survival was 13.4 (95% CI, 11.6-15.3) months in the treatment group compared with 6.7 (95% CI, 6.0-7.5) months in the observation group (hazard ratio, 0.55 [95% CI, 0.44-0.69]; P .001). Patients randomized to adjuvant gemcitabine treatment had prolonged overall survival compared with those randomized to observation alone (hazard ratio, 0.76 [95% CI, 0.61-0.95]; P = .01), with 5-year overall survival of 20.7% (95% CI, 14.7%-26.6%) vs 10.4% (95% CI, 5.9%-15.0%), respectively, and 10-year overall survival of 12.2% (95% CI, 7.3%-17.2%) vs 7.7% (95% CI, 3.6%-11.8%).Among patients with macroscopic complete removal of pancreatic cancer, the use of adjuvant gemcitabine for 6 months compared with observation alone resulted in increased overall survival as well as disease-free survival. These findings provide strong support for the use of gemcitabine in this setting.isrctn.org Identifier: ISRCTN34802808.

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The goal of improving adjuvant treatment can be reached in two ways: firstly, by developing more effective drugs and protocols and, secondly, by selecting suitable patients on the basis of clinical and molecular factors. In UICC (Union internationale contre le cancer) stage II, microsatellite instability (MSI) is a strong prognostic factor. Whether it can also be used as a predictive marker is currently a matter of controversy because the available data are contradictory. The question whether or not the MSI status should be checked before treatment decisions are made in stage II patients can therefore not be clearly answered at present. For adjuvant treatment in stage III, with capecitabine/oxaliplatin (XELOX) there is now a new protocol available that is based on the orally administered prodrug capecitabine. With regard to the question of how much older patients in this stage may also benefit from a combination chemotherapy, new--and contradictory--data have emerged recently: firstly, preliminary results of two new studies have given rise to safety concerns and, secondly, an analysis by the 'ACCENT Collaborative Group' indicated lower efficacy of the 'newer' adjuvant protocols in older people. These findings, however, have now been called into question as a result of a new subgroup analysis from the XELOXA study. The expert group therefore recommended that the decision whether to treat patients older than 70 years with an (oral) fluoropyrimidine alone or in combination with oxaliplatin should be based on clinical parameters such as biological age and comorbidities.

As far as the management of primary resectable liver metastases is concerned, three approaches are currently competing with each other: surgery alone, surgery with pre- and postoperative chemotherapy, and surgery with postoperative chemotherapy alone. The core of the argument for pre- and postoperative chemotherapy in these patients is the European Organisation for Research and Treatment of Cancer (EORTC) 40983 study, which concluded that, in comparison with surgery alone, perioperative chemotherapy improved the 3-year progression-free survival (PFS) by 7 months. In contrast to this, there are two smaller studies--at a somewhat lower strength of evidence-- indicating that adjuvant chemotherapy extends PFS by 9.1 months compared with surgery alone. In Germany, the adjuvant approach continues to be favored in many places; this can also be seen in the formulation of the S3 guideline. In patients with unresectable liver metastases--with the associated difficulty of classification due to the lack of clear and definitive criteria--preoperative systemic therapy to induce 'conversion' is indicated, in order to allow secondary resection. In KRAS wild-type tumors, high response rates (in terms of a reduction in size of the metastases, such as according to RECIST (Response Evaluation Criteria in Solid Tumors)) and a high conversion rate are achieved using a cetuximab/chemotherapy combination. Triple chemotherapy combinations with 5-fluorouracil (5-FU), oxaliplatin and irinotecan also produce high response rates. Bevacizumab/chemotherapy combinations have led to a high number of complete and partial pathohistological remissions in phase II studies; these seem to correlate with long survival times. In the absence of long-term survival data, it therefore seems to remain unclear as to what is the best parameter to use in order to assess the success of preoperative treatment. Lung metastases, too, or local peritoneal carcinomatosis can nowadays be operated on in selected patients with a good prospect of long-term remission or even cure. The surgery should, however, generally only be carried out in experienced centers, especially in the case of peritoneal carcinomatosis. For synchronous metastasization, the appropriate management depends on the size and extent of liver metastases and of the primary tumor. Small, peripherally lying and safely resectable liver metastases can be removed before or at the same time as the primary tumor, especially if a hemicolectomy is being carried out. If the metastases are unresectable and there is no bleeding or stenosis, the primary tumor can also be left in situ and systemic chemotherapy can be carried out first. However, it should be borne in mind that, according to current data, palliative resection of the primary tumor combined with systemic therapy leads to longer overall survival than does chemotherapy alone. Whether resection or chemotherapy should be done first therefore depends on the patient's clinical situation.

BackgroundDevelopment of incisional hernia after open abdominal surgery remains a major cause of post-operative morbidity. The aim of this study was to determine the current practice of surgeons in terms of access to and closure of the abdominal cavity in elective open surgery.MethodsTwelve surgical departments of the INSECT-Trial group documented the following variables for 50 consecutive patients undergoing abdominal surgery: fascial closure techniques, applied suture materials, application of subcutaneous sutures, subcutaneous drains, methods for skin closure. Descriptive analysis was performed and consensus of treatment variables was categorized into four levels: Strong consensus >95%, consensus 75–95%, overall agreement 50–75%, no consensus Results157 out of 599 patients were eligible for analysis (85 (54%) midline, 54 (35%) transverse incisions). After midline incisions the fascia was closed continuously in 55 patients (65%), using slowly absorbable (n = 47, 55%), braided (n = 32, 38%) sutures with a strength of 1 (n = 48, 57%). In the transverse setting the fascia was closed continuously in 39 patients (72%) with slowly absorbable (n = 22, 41%) braided sutures (n = 27, 50%) with a strength of 1 (n = 30, 56%).ConclusionIn the present evaluation midline incision was the most frequently applied access in elective open abdominal surgery. None of the treatments for abdominal wall closure (except skin closure in the midline group) is performed on a consensus level.

Introduction: Data obtained in multicenter studies on quality assurance can reflect the current situation in the treatment of gastric cancer. Adenocarcinoma of the gastroesophageal junction (AGJ) appears to be a separate tumor entity. Methods: Perioperative data on the diagnostic and therapeutic management in gastric cancer patients were collected by means of a prospective multicenter observational study "QCGC 2" from 01/01/2007 to 12/31/2009. Early postoperative treatment results and long-term oncological outcome in patients with AGJ with those of the stomach were compared. Results: 2,897 patients with gastric cancer out of 141 hospitals of each profile were enrolled in the study; out of them, 2,788 (96.2 %) underwent surgical intervention. With regard to tumor site, 544 cases with AGJ were operated within 108/141 hospitals (76.6 %) only. Patients with AGJ showed a significantly shorter median survival (25 months) depending on the tumor stage compared with subjects suffering from gastric cancer (38 months). Overall 5-year survival rate of AGJ patients ( 33.1 %) was significantly worse compared with that of individuals with gastric cancer (41.4 %) also depending on single tumor stages according to UICC classification (p

Background Perioperative chemotherapy (CT) has demonstrated as survival benefit in locally advanced gastric cancer (GC) in randomized trials. However, the overall cure rate is 30-40% and a significant number of patients are not able to receive the postoperative part of their CT regimen. In Europe, the trifunctional antibody catumaxomab is approved for the treatment of malignant ascites based on a pivotal trial which also included GC patients. A new multimodal approach combining neoadjuvant CT, followed by gastrectomy and intraperitoneal (i.p.) immunotherapy with catumaxomab was assessed in a single-arm multicenter phase II study. We here report 2-year follow-up data. Methods GC pts (T2/T3/T4, N + /–, M0) received 3 cycles of neoadjuvant fluoropyrimidin/platinum-based CT followed by ´en-bloc R0-gastrectomy. Catumaxomab was administered i.p. as intraoperative bolus (10 µg) followed by 4 consecutive 3-hour infusions of 10-150 µg. Primary safety endpoint was the rate of predefined postoperative complications observed during 30 days after surgery. Key efficacy endpoints included disease-free (DFS) and overall survival (OS). Results The original study data presented at the WCGC in 2011 (Schuhmacher et al., Ann Oncol (2011) 22(suppl. 5)) showed that the primary endpoint was met and the described application regimen is safe. At time of surgery, 27.8% of patients were stage I, 27,8% of patients were stage II, 22,3% of patients were stage III and 14,8% of patients were stage IV as assessed according to pTNM measures. At 24 months 39/54 (safety analysis set) patients were still alife,14/54 were dead, (one patient lost to follow-up), 24/37 had no progression, only 13/37 patients relapsed (for 2 patients disease status was not recorded). At the 2 year cut off DFS was 56.4% (95% CI: 41–69%), OS was 75% (95% CI: 60–85%). Conclusions Catumaxomab as part of a multimodal therapy in primarily resectable GC is a feasible option. The 2-year follow up efficacy results show promising data for DFS and OS in a cohort of locally advanced gastric cancer pts. Disclosure C. Bokemeyer: receiving finance of clinical studies, consultant for Fresenius Biotech GmbH. K. Ridwelski: receives finance for clinical studies from Fresenius Biotech. D. Atanackovic: receives financial support for clinical studies from Fresenius Biotech and is a consultant for Fresenius Biotech. D. Arnold: receives financial support for clinical studies from Fresenius Biotech. E. Woll: receives financial support for clinical studies from Fresenius Biotech. M. Buchler: receives financial support for clinical studies from Fresenius Biotech. C. Kruger: receives financial support for clinical studies from Fresenius Biotech. C. Schuhmacher: receives financial support for clinical studies from Fresenius Biotech

Transforming growth factors beta (TGF-β) constitute a family of polypeptide growth factors that control cell growth, cell differentiation and migration, as well as the formation of the extracellular matrix. Recent analyses revealed the overexpression of TGF-β1 in human gastric cancers and demonstrated increased cell proliferation in the stomach of patients with gastric cancer and their first-degree relatives. Using human gastric tissues obtained from patients with gastric cancer (n = 19), biopsies from healthy first-degree relatives of gastric cancer patients (n = 18) and healthy individuals (n = 19), we analysed the expression of TGF-β1 using the reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Fifteen of 19 patients with gastric cancer expressed TGF-β1 in the tumour. In 11 of these 15 cases TGF-β1 mRNA was also detectable in the non-tumourous stomach. Interestingly, all but two individuals with a first-degree relative diagnosed with gastric cancer exhibited TGF-β1 expression in either the antrum or corpus biopsy or both. In contrast, only one of 19 individuals without a family history of gastric cancer expressed TGF-β1 in the stomach (P< 0.0001). TGF-β1 expression is detectable in a large proportion of gastric cancers and in the stomach of healthy first-degree relatives of gastric cancer patients. Since individuals without gastric cancers in their family express TGF-β1 only in one of 19 cases, the induction of TGF-β1 expression in first-degree relatives of patients with gastric cancer points to the presence of specific molecular alterations in a subgroup of individuals with an increased risk of developing gastric cancer that may precede the development of gastric cancers. © 2000 Cancer Research Campaign

Summary Objective: A previous phase I trial in 14 pretreated patients with progressive advanced colorectal cancer demonstrated 750 mg/m2 to be the maximum tolerable dose of 5-fluorouraci l (5-FU) administered as a five-day continuous infusion modu- lated by short infusions of 100 mg/m2 folinic acid twice daily. The dose-limiting toxicities were hand-foot syndrome and severe mucositis. A response rate of 21% and 50% stable disease could be achieved. In order to determine the effective- ness and tolerability, we initiated a multicenter phase II trial applying a 650 mg/m2 recommended dose of 5-FU and 100 mg/m2 folinic acid twice daily every three weeks. Patients and methods: From January 1994 to July 1996, 88 advanced and progressive colorectal cancer patients either previously treated with a bolus schedule of 5-FU and folinic acid (34 patients) or without (54 patients) previous chemo- therapy were included in this trial. Results: In the group of previously treated patients, therapy led to 6% (2 of 34 patients) remissions while stable disease could be observed in 68% (23 of 34 patients) of the patients. The median survival time was 14 months. The main toxicity was mucositis grade 3 in 15% of the previously treated patients and 10% in the nonpretreated patients. In the population of nonpretreated patients, the overall response rate was 15% (eight of 54 patients) and stable disease could be induced in 67% (36 of 54 patients). The median survival time was 13.7 months. Conclusion: This regimen is an active second-line therapy in advanced colorectal cancer with minimal toxicity, thus preserving the quality of life during palliative chemotherapy. Antitumor activity in previously untreated patients does not seem superior to that obtained with weekly regimens applying 24- or 48-hour continuous infusions of 5-FU and folinic acid.

Accurate prediction of response to therapy is a prerequisite for individualized approaches to colorectal cancer treatment. Testing of various cancer drugs on the individual patient tumor can support selection of effective therapies. To this end, we have established 149 stably passageable NOD/SCID mouse tumor xenografts from patients of all four Dukes stages within the framework of the prospective multicenter clinical study. All patients gave written informed consent prior to surgery. In a pharmacological study, 75 xenograft tumor models underwent single-agent treatment with oxaliplatin (OX), cetuximab (CE), or bevacizumab (BE). Each of the 75 tumors was transplanted onto 20 mice (5 controls and 5 for each drug). Models with a treated-to-control tumor growth ratio of 20% or lower were defined as responders. This resulted in response rates of 7% for OX, 24% for CE, and 4% for BE. Mutation analysis was conducted on 71 xenografts by allele-specific RT-PCR for the following hotspots: KRAS: 34G>A, 34G>T, 34G>C, 35G>A, 35G>T, 35G>C, 38 G>A and 436 G>A; BRAF: 1799 T>A, and PIK3CA: 1624G>A, 1633G>A, 3140A>G. KRAS mutations were found in 46%, BRAF in 10%, and PIK3CA in 15% of the xenografts. 59% of the xenografts carry at least one mutation. KRAS mutations were never observed together with BRAF-mutations while it combined with PIK3CA in 8 cases (11%). The corresponding primary tumors showed the same mutation profile. We examined mutation status with response to therapy to CE and OX. 3/5 OX responders were KRAS wildtype (wt) (Sensitivity (S+) 66%) while 31/66 OX non-responders were KRAS mutated (Specificity (S-) 46%). If also mutations in BRAF and PIK3CA are considered 40/60 OX non-responders were identified (S-66%). Of the 18 CE responders, all are wt for BRAF and PIK3CA. Three show mutations of KRAS, two of them in codon 13, which seems to confirm a recently published clinical observation by De Roock et al. (JAMA 2010, 304:1812) that this mutation may be related to an improved response under CE treatment. Wt status in all three genes was observed in 83% of the responders. KRAS mutations were seen in 57% of the non-responders. If mutations in BRAF and PIK3CA are also considered, the fraction of recognized non-responders increases to 73%. We also investigated how well response can be predicted from the mutation data. A machine learning approach was used to estimate unbiased prospective prediction rates for response to CE based on the mutation profile. In each of a large number of bootstrap loops, a new predictor was trained on a new randomly selected subset of the tumors and applied to the remaining tumors. KRAS, BRAF and PIK3CAmutations achieve a S+ of 84% (95% CI: 59% and 96%) and a S- of 68% (95% CI: 54% and 80%). KRAS, BRAF, and PIK3CA mutation status combined has potential clinical utility higher than KRAS alone to individualize CE treatment, also in the adjuvant setting, for patients with Dukes B and Dukes C. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-317. doi:10.1158/1538-7445.AM2011-LB-317

ContextThe role of adjuvant therapy in resectable pancreatic cancer is still uncertain, and no recommended standard exists.ObjectiveTo test the hypothesis that adjuvant chemotherapy with gemcitabine administered after complete resection of pancreatic cancer improves disease-free survival by 6 months or more.Design, Setting, and PatientsOpen, multicenter, randomized controlled phase 3 trial with stratification for resection, tumor, and node status. Conducted from July 1998 to December 2004 in the outpatient setting at 88 academic and community-based oncology centers in Germany and Austria. A total of 368 patients with gross complete (R0 or R1) resection of pancreatic cancer and no prior radiation or chemotherapy were enrolled into 2 groups.InterventionPatients received adjuvant chemotherapy with 6 cycles of gemcitabine on days 1, 8, and 15 every 4 weeks (n = 179), or observation ([control] n = 175).Main Outcome MeasuresPrimary end point was disease-free survival, and secondary end points were overall survival, toxicity, and quality of life. Survival analysis was based on all eligible patients (intention-to-treat).ResultsMore than 80% of patients had R0 resection. The median number of chemotherapy cycles in the gemcitabine group was 6 (range, 0-6). Grade 3 or 4 toxicities rarely occurred with no difference in quality of life (by Spitzer index) between groups. During median follow-up of 53 months, 133 patients (74%) in the gemcitabine group and 161 patients (92%) in the control group developed recurrent disease. Median disease-free survival was 13.4 months in the gemcitabine group (95% confidence interval, 11.4-15.3) and 6.9 months in the control group (95% confidence interval, 6.1-7.8; P