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Objectives: In the surgical treatment of colorectal carcinoma (CRC), 1 in 10 patients has a peritumorous adhesion or tumor infiltration in the adjacent tissue or organs. Accordingly, multivisceral resection (MVR) must be performed in these patients. This prospective multicenter observational study aimed to analyze the possible differences between non-multivisceral resection (nMVR) and MVR in terms of early postoperative and long-term oncological treatment outcomes. We also aimed to determine the factors influencing overall survival., Methods: The data of 25,321 patients from 364 hospitals who had undergone surgery for CRC (the Union for International Cancer Control stages I-III) during a defined period were evaluated. MVR was defined as (partial) resection of the tumor-bearing organ along with resection of the adherent and adjacent organs or tissues. In addition to the patients' personal, diagnosis (tumor findings), and therapy data, demographic data were also recorded and the early postoperative outcome was determined. Furthermore, the long-term survival of each patient was investigated, and a "matched-pair" analysis was performed., Results: From 2008 to 2015, the MVR rates were 9.9 % (n=1,551) for colon cancer (colon CA) and 10.6 % (n=1,027) for rectal cancer (rectal CA). CRC was more common in men (colon CA: 53.4 %; rectal CA: 62.0 %) than in women; all MVR groups had high proportions of women (53.6 % vs. 55.2 %; pairs of values in previously mentioned order). Resection of another organ frequently occurred (75.6 % vs. 63.7 %). The MVR group had a high prevalence of intraoperative (5.8 %; 12.1 %) and postoperative surgical complications (30.8 % vs. 36.4 %; each p<0.001). Wound infections (colon CA: 7.1 %) and anastomotic insufficiencies (rectal CA: 8.3 %) frequently occurred after MVR. The morbidity rates of the MVR groups were also determined (43.7 % vs. 47.2 %). The hospital mortality rates were 4.9 % in the colon CA-related MVR group and 3.8 % in the rectal CA-related MVR group and were significantly increased compared with those of the nMVR group (both p<0.001). Results of the matched-pair analysis showed that the morbidity rates in both MVR groups (colon CA: 42.9 % vs. 34.3 %; rectal CA: 46.3 % vs. 37.2 %; each p<0.001) were significantly increased. The hospital lethality rate tended to increase in the colon CA-related MVR group (4.8 % vs. 3.7 %; p=0.084), while it significantly increased in the rectal CA-related MVR group (3.4 % vs. 3.0 %; p=0.005). Moreover, the 5-year (yr) overall survival rates were 53.9 % (nMVR: 69.5 %; p<0.001) in the colon CA group and 56.8 % (nMVR: 69.4 %; p<0.001) in the rectal CA group. Comparison of individual T stages (MVR vs. nMVR) showed no significant differences in the survival outcomes (p<0.05); however, according to the matched-pair analysis, a significant difference was observed in the survival outcomes of those with pT4 colon CA (40.6 % vs. 50.2 %; p=0.017). By contrast, the local recurrence rates after MVR were not significantly different (7.0 % vs. 5.8 %; both p>0.05). The risk factors common to both tumor types were advanced age (>79 yr), pT stage, sex, and morbidity (each hazard ratio: >1; p<0.05)., Conclusions: MVR allows curation by R0 resection with adequate long-term survival. For colon or rectal CA, MVR tended to be associated with reduced 5-year overall survival rates (significant only for pT4 colon CA based on the MPA results), as well as, with a significant increase in morbidity rates in both tumor entities. In the overall data, MVR was associated with significant increases in hospital lethality rates, as indicated by the matched-pair analysis (significant only for rectal CA)., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: To investigate the influence of anastomosis on the early postoperative and long-term oncological outcomes of patients with primary colon carcinoma (CA)., Methods: All consecutive patients with the histologically diagnosed primary colon CA (design, prospective multicenter observational study) were registered with regard to patient-, diagnostic-, tumor (Tu) finding-, and treatment-related aspects using a computer-based registry with 60 items to characterize early postoperative and long-term oncological outcome., Results: Basic data : From 2010 to 2016, data from a total of 14,466 patients were documented (mean age, 72.8 [range, 22-96] years; sex ratio, m:f=7,696:6,770). - 717/14,466 patients (4.96 %) were included in a matched-pair analysis. The majority of these patients underwent elective surgery ( n =12,620 patients; 87.2 %) regardless of whether a bowel anastomosis or an ostomy was created. In emergency surgery, a bowel anastomosis was possible in a large proportion ( n =1,332 patients [72.1 %]). In contrast, in 514 patients (27.9 %) who underwent emergency surgery, an ostomy was created. Interestingly, ostomy had to be created even less frequently in patients who had undergone planned surgery ( n =366 [2.5 %]). - Early postoperative outcome : Cases of postoperative mortality were mainly due to general complications. Especially among the patients treated in an emergency situation without intestinal anastomosis, a high proportion died of their pre-existing condition (17.0 %). Patients who underwent ostomy creation or emergency surgery had a worse risk profile (incl. arterial hypertension, diabetes mellitus, and secondary cardiac or renal diseases) which led to the decision to operate without anastomosis. Furthermore, data show no matter which technique had been used, patients that had undergone surgical intervention without anastomosis were more likely to develop complications. - Long-term oncosurgical outcome : The most important factors influencing long-term survival were age, resection status, and tumor stage (according to TNM and UICC). The more advanced the tumor growth, the lower the long-term survival. Patients categorized with the same tumor stage, age, and risk factors had a better chance of survival, if they underwent elective surgical intervention and with intestinal anastomosis. Interestingly, the multivariable analysis showed that older patients and such with distant metastasis benefit from a discontinuity resection., Conclusions: The association of intraoperative and postoperative complications with increased postoperative mortality, as well as preexisting risk factors and perioperative complications is in line with findings of current studies. Furthermore, current studies also agree that older patients and such with reduced general condition benefit from discontinuity resection., Competing Interests: Competing interests: Authors state no conflict of interest., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: For years, many efforts have been invested to prepare patients, in particular, those with reduced physical and psychic status, much better to provide and finally achieve better outocme if there is time available to provide several beneficial measures., Methods: Therefore, the objective was to illustrate the concept and various single elements of a complex prehabilitation concept based on (i) selective references from the medical literature and (ii) own clinical experiences from clinical practice in general and abdominal surgery., Results: Prehabiliation can be considered the solution of the efforts to improve preoperative status for patients in a disadvantageous status for almost all types of surgery and all other operative and/or interventional procedures. It is the targeted process to improve individual functionality and organ function before a planned (elective) surgical intervention; P. comprises basically nutritional, physical and psychological measures; P. focusses especially onto the elderly, frail and malnourished patients before a planned surgical intervention; the overall aim is to significantly improve final outcome characterized by shorter length of stay, lower complication rate and mortality as well as cost efficiency; P. is especially important in cancer surgery, in which the beneficial effects can be particularly implemented; P. programs and/or "Standard Operating Protocols" (SOP) may help to establish and materialize its single aspects and enhanced recovery after surgery (ERAS). There is still further potential to reliably establish and to utilize the options of prehabilitation measures as listed above., Conclusions: Prehabiliation is an indispensable aspect in today's preparation for elective surgery, which needs to become obligatory part of the preparation measures to planned surgical interventions, which can further contribute to a better final outcome and ERAS as well as, in addtion, needs to be further developed and accomplished., Competing Interests: Competing interests: No conflict of interest., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

Objectives: Patients with different diseases may show signs of malnutrition both before and during the hospital stay. The presence of malnutrition may impact the recovery and length of stay and consequently the costs. Early identification of malnutrition is thus a critical factor. The objective of this multicenter study is to determine the prevalence of malnutrition in colorectal cancer centers. Another objective is to investigate possible consequences, such as complications or length of stay. In addition, the study aims to demonstrate the relevance of nutrition management in colorectal cancer centers. At the same time, relevant requirements clearly demanded by the Certification Commission for Certified Colorectal Cancer Centers are met through implementation of the study., Methods: Between 2019 and 2021, patients in colorectal cancer centers were examined in the preoperative phase. In addition to questions about patients' state of health and nutrition, the validated screening forms-Subjective Global Assessment (SGA) and Nutritional Risk Screening Tool 2002 (NRS 2002)-were used to assess malnutrition. The data were processed by univariate analysis., Results: In total, data records of 3,102 patients were evaluated. The mean age of the participants was 68.5 ± 11.9 years, and their average body mass index (BMI) was 26.8 ± 5.3 kg/m 2 . The SGA questionnaire indicated that 23 % of the participants suffered from malnutrition and 38 % were at risk of malnutrition (NRS≥3). Malnutrition was found more frequently in patients with colorectal carcinomas than in patients with rectal carcinomas (53.1 vs. 32.1 %). The length of stay in hospital and the rate of complications were significantly higher when malnutrition was identified., Conclusions: Approximately one in three to four patients with a colorectal carcinoma has an increased risk of malnutrition. The two screening methods calculated a different prevalence (23 and 38 %). Any malnutrition that is present demonstrably has a significant impact both on the rate of complications and the length of stay and may therefore have a decisive influence on the costs. The results of this multicenter study underscore the need for systematic screening for malnutrition and at the same time should increase clinics awareness of the importance of establishing a nutrition management policy., Competing Interests: Competing interests: The survey was supported by Wisswerk, as a Department of PubliCare GmbH, Cologne. Karsten Ridwelski received honoraria from B.Braun AG and the German Society of Surgery. Carl Meißner received honoraria from B.Braun AG, Nutricia, Fresenius, and PubliCare GmbH., (© 2023 the author(s), published by De Gruyter, Berlin/Boston.)

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)., Competing Interests: Declaration of interests MDR reports consulting fees from Roche Diagnostics and Medtronic; leadership or fiduciary role in the European Society of Gastrointestinal Endoscopy (ESGE) and World Endoscopy Organization (WEO). All other authors report no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Introduction: With 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 Analysis: A 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 Dissemination: This 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 Number: DRKS00029682., Competing Interests: Competing interests: CL, PMC and GR are employees of Johnson & Johnson. JL, KB, AH, RSC, KR, CK and MK report no competing interests related to the manuscript., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

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., (© 2022. The Author(s).)

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.

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 × 10 -04 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10 -09 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10 -11 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 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 × 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., (© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Aims: Adjuvant chemotherapy for resected rectal cancer is widely used. However, studies on adjuvant treatment following neoadjuvant chemoradiotherapy (CRT) and total mesorectal excision (TME) have yielded conflicting results. Recent studies have focused on adding oxaliplatin to both preoperative and postoperative therapy, making it difficult to assess the impact of adjuvant oxaliplatin alone. This study was aimed at determining the impact of (i) any adjuvant treatment and (ii) oxaliplatin-containing adjuvant treatment on disease-free survival in CRT-pretreated, R0-resected rectal cancer patients., Method: Patients undergoing R0 TME following 5-fluorouracil (5FU)-only-based CRT between January 1, 2008, and December 31, 2010, were selected from a nationwide registry. After propensity score matching (PSM), comparison of disease-free survival (DFS) using Kaplan-Meier analysis and log-rank test was performed in (i) patients receiving no vs. any adjuvant treatment and (ii) patients treated with adjuvant 5FU/capecitabine without vs. with oxaliplatin., Results: Out of 1497 patients, 520 matched pairs were generated for analysis of no vs. any adjuvant treatment. Mean DFS was significantly prolonged with adjuvant treatment (81.8 ± 2.06 vs. 70.1 ± 3.02 months, p < 0.001). One hundred forty-eight matched pairs were available for analysis of adjuvant therapy with or without oxaliplatin, showing no improvement in DFS in patients receiving oxaliplatin (76.9 ± 4.12 vs. 79.3 ± 4.44 months, p = 0.254). Local recurrence rate was not significantly different between groups in either analysis., Conclusion: In this cohort of rectal cancer patients treated with neoadjuvant CRT and TME surgery under routine conditions, adjuvant chemotherapy significantly improved DFS. No benefit was observed for the addition of oxaliplatin to adjuvant chemotherapy in this setting.

Background: 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., Methods: 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 <62 %) within 30 days after surgery in patients who received at least the first catumaxomab dose., Results: Of 64 patients treated with neoadjuvant chemotherapy, 58 underwent surgery and 54 received at least the first catumaxomab dose. Postoperative complications were reported in 18 of 54 evaluable patients (complication rate 33 %; 95 % confidence interval: 21-48 %); thus, the primary endpoint was met. The most frequent complications were pulmonary infection (17 %) and anastomosis insufficiency requiring surgery (11 %). The most common catumaxomab-related adverse events were pyrexia (67 %), leucocytosis (19 %), abdominal pain (17 %) and chills (17 %). The 4-year disease-free and overall survival rates were 38 and 50 %., Conclusion: Intra- and postoperative administration of catumaxomab as part of a multimodal treatment approach was feasible and tolerable in patients with advanced gastric cancer and should be further investigated in a randomised trial.

Background: Development 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., Methods: Twelve 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 <50%., Results: 157 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%)., Conclusion: In 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.

Background: The prognostic impact of isolated lymphovascular invasion (LVI) after radical resection of rectal cancer is controversially discussed. However, it could be relevant to decide for an adjuvant treatment., Aim: The aim of the analysis was, based on the data of an observational study, to determine the prognostic relevance of the isolated LVI., Materials and Methods: Patients after radical resection of rectal cancer with no hemangioinvasion were subdivided in three groups: I-no LVI, no lymph node metastases (LNM); II-positive LVI, no LNM; III-positive LNM. Five-year local recurrence rate, distant metastases-free and disease-free survival were determined uni- and multivariate., Results: Patients, n = 846, were studied (I, n = 471; II, n = 75; III, n = 300). The univariate comparison between the groups revealed the following 5-year results: local recurrence rate: 9.4 vs 10.0 vs 14.0%; distant metastases-free survival: 84.1 vs 82.5 vs 49.3%; disease-free survival: 83.2 vs 80.7 vs 45.5%. The differences between groups I and III were significant, but not between groups I and II. The determined higher disease-free survival rate in group II vs group III was significant (P = 0.041), but the differences in local recurrence rate and rate of distant metastases did not reach statistical significance. The multivariate analysis revealed no impact of the isolated LVI on the oncological outcome., Conclusion: The isolated LVI has no independent prognostic impact on the local recurrence rate and long-term survival after radical resection of rectal cancer. Based on this finding, no indication for an adjuvant treatment in these patients can be derived.

Background: Locoregional intra-arterial (i.a.) chemotherapy may provide high levels of cytostatic concentrations within the tumour and, simultaneously, a low rate of systemic side effects compared with systemic administration of anti-neoplastic drugs. In addition, this may lead to an increase of tumour response rate and prolongation of survival time. The aim of the study was (1) to evaluate the benefit of an i.a. infusion of cytostatic drugs via the coeliac trunk on tumour response rate and survival time, (2) to elucidate problems and risks, and finally (3) to achieve an improvement of overall therapeutic management in pancreatic carcinoma., Patients and Methods: In 22 patients (12 female; 10 male; mean age 57.1 years) with locally advanced pancreatic carcinoma, which was confirmed by histopathology, i.a. chemotherapy was administered. Through a catheter, which was inserted via the femoral artery by the Seldinger technique and placed with the tip in the coeliac trunk, two different drug combinations were given. Group A ( n=12) were given a bolus injection of a mixture (chemo-occlusion) consisting of amilomer (Spherex) and epirubicin (Farmorubicin) followed by short-time infusion of folic acid and 24-h infusion of 5-FU. Group B ( n=10) were given treatment over 5 days: mitoxantrone (Novantrone, day [d] 1), 5-FU and folic acid (Haemato-folin, d 2-4), and cisplatin (d 5). Treatment was repeated in both groups every 4 weeks. Tumour response was assessed by computed tomography every 8 weeks., Results: In group A, there was one complete and one partial remission, resulting in a remission rate of 16.6%. Two patients showed stable disease, while in two-thirds of the patients ( n=8), progressive disease was found. Median survival time was 3 months; 1-year survival rate was 33.3% (4 of 12 patients). In group B, again, one complete and one partial remission were observed (remission rate 20%). In three cases, stable disease, and in 50% of patients ( n=5), progressive disease, were documented. Median survival was 7.0 months; 1-year survival rate was 20% (2 of 10 patients). If both groups were compared, there was no difference in survival. In addition, no prolongation of survival time was found in comparison with patients of a historical study group treated with established systemic chemotherapy using gemcitabine monotherapy ( n=28; median survival time 9 months). Though a tendency for poorer outcome of i.a. chemotherapy was seen when the Kaplan-Meier curves of survival were compared, this difference was not statistically significant (log rank test, P=0.08)., Conclusion: Despite conceptual and pharmacokinetic advantages of locoregional i.a. chemotherapy, better outcome with regard to tumour response rate and survival time could not be found. I.a. chemotherapy is, therefore, still an experimental treatment option in pancreatic carcinoma and can, currently, not be recommended for routine use.

Purpose: Neoadjuvant chemotherapy in locally advanced gastric cancer is effective, but is often associated with severe side effects, including fatal outcome. This study evaluates a combination of cisplatin, folinic acid and 5-fluorouracil (PLF) in terms of efficacy (R-0 resection rate) and toxicity., Methods: Twenty-five patients with locally advanced gastric cancer who after extensive staging were deemed not suitable for curative resection underwent neoadjuvant chemotherapy. Three or four cycles of cisplatin (50 mg/m(2) days 1 and 15), folinic acid (200 mg/m(2) days 1, 8, 15 and 22), and 5-fluorouracil (2,000 mg/m(2 ) days 1, 8, 15 and 22) were administered. Cases with progressive disease were taken off the study. Two weeks after finishing chemotherapy resection was performed and all patients were enrolled in a structured follow-up., Results: Of the patients, 22/25 finished chemotherapy and 20 of those underwent laparotomy. In 13/25 patients (52%) a R-0 resection and in three cases a R-1 resection were achieved. Four patients stayed irresectable. During 76 completed cycles of chemotherapy we observed five cases of WHO grade-III toxicity and no grade-IV toxicity., Conclusions: The presented PLF protocol yields R-0 resection rates comparable to protocols like EAP (etoposide, adriamycin, platinum), but with a better safety profile allowing administration in an outpatient setting. Our study supports PLF as a reference neoadjuvant treatment for gastric cancer even outside of clinical studies.

Background and Aims: We compared the effectiveness and side effects of various cytostatic agents for use in perioperative intraperitoneal irrigation to prevent peritoneal carcinomatosis., Methods: The adenocarcinoma cell line CC-531 was implanted during laparotomy at the mesenterial trunk of anesthetized male WAG rats. Direct perioperative intraperitoneal chemotherapy was performed after 5 min with either 5-fluorouracil, cisplatin, or mitomycin; controls received only tumor cells. The animals were inspected daily over 30 days for side effects. They were then killed, and the greater omentum and mesentery were resected, the tumor mass was examined for the presence of peritoneal carcinomatosis, and tumor nodules in the greater omentum and mesentery were counted., Results: All the animals in the control group developed histologically confirmed peritoneal carcinomatosis. Animals receiving cisplatin or mitomycin by direct intraperitoneal perioperative chemotherapy showed no macroscopic or histological evidence of tumor growth. Two animals in the fluorouracil group had macroscopically and histologically manifest tumor growth; another animal showed only histological evidence of malignancy. Substantial side effects were noted in the cisplatin group, with all animals experiencing bleeding in the peritoneum and toxic necrotic reactions of the colon; two animals died of these side effects., Conclusion: Direct intraperitoneal chemotherapy with cisplatin or mitomycin prevents peritoneal carcinomatosis in experimental investigations.

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. Non-haematological 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.

A 59-year-old woman presented with epigastric pain and weight loss. Ultrasound, computed tomography, and magnetic resonance imaging scans of the abdomen showed a tumor in segments 6 and 7 of the right liver lobe, measuring 8 cm in greatest diameter. The tumor was subsequently resected, and histopathology showed a poorly differentiated adenocarcinoma immunoreactive for CA 19-9 and cytokeratin 19. In the absence of any other clinically detectable primary tumor, the lesion was diagnosed as a peripheral intrahepatic cholangiocarcinoma. In addition, multiple bile duct hamartomas were found in the surrounding parenchyma. The tumor was unrelated to Caroli disease, primary sclerosing cholangitis, ulcerative colitis, or nonbiliary cirrhosis, as demonstrated by further clinical and histopathologic investigations, but probably was associated with the presence of multiple bile duct hamartomas. To our knowledge, this is the eighth reported case of a cholangiocarcinoma associated with multiple bile duct hamartomas.

Transforming growth factors beta (TGF-beta) 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-beta1 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-beta1 using the reverse transcriptase polymerase chain reaction (RT-PCR) and immunohistochemistry. Fifteen of 19 patients with gastric cancer expressed TGF-beta1 in the tumour. In 11 of these 15 cases TGF-beta1 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-beta1 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-beta1 in the stomach (P< 0.0001). TGF-beta1 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-beta1 only in one of 19 cases, the induction of TGF-beta1 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.

In a prospective clinical trial we treated 27 patients with metastatic colorectal carcinoma a continuous 24-h high-dose regimen of 2.6 g/m2 5-fluoroucil and 500 mg/m2 folinic acid per week for 6 weeks. To evaluate the effect of amifostine, a selective cyto- and radioprotector, in reducing chemotherapy-related mucositis, 740 mg/m2 amifostine was administered before chemotherapy, and the results were compared to 15 patients without amifostine treatment. In the amifostine group the dose was reduced or treatment was stopped because of mucositis observed in 6 of the 12 patients, while 13 of the 15 control patients could not be treated according to the treatment plan. The incidence of gastrointestinal side effects of WHO grade III or higher was reduced in the amifostine group, with no mucositis of this severity, versus 3 of 15 in the control group. The response rate was identical in the two treatment arms (33.3%).

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., Summary 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/m2 per day for 5 days as a continuous 24-hour infusion) plus folinic acid (200 mg/m2 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.

A phase II pilot study of bendamustine as salvage treatment in patients with advanced breast cancer was performed to determine the objective response rates and make further observations on the toxicity of this drug. A group of 37 patients, pretreated with chemotherapy for advanced disease, entered the trial. Treatment consisted of 150 mg/m2 bendamustine on days 1 and 2 of a 4-week treatment course. Patients continued to receive treatment until complete remission and then two further courses, until tumour progression or unacceptable toxicity ensued. A total of 36 patients received at least one treatment course and were assessable for toxicity; 33 patients were evaluable for treatment results. Dose-limiting grade 3 and 4 WHO toxicity occurred in 5 and 3 patients respectively; 27% of patients entered complete or partial tumour remission. The median time to tumour progression was 2 months with a range of 1-14 months. The efficacy of bendamustine was apparently independent of pretreatment with anthracyclines, suggesting a lack of cross-resistance between bendamustine and anthracyclines. It can be concluded that bendamustine in the dose and application schedule used here is active in the salvage therapy of women with advanced breast cancer. The toxicity was acceptable. Future studies have to confirm the data of this pilot trial and to define the role of bendamustine in the combination chemotherapy of metastatic breast cancer that has been suggested by previous trials.

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-fluorouracil (5-FU) administered as a five-day continuous infusion modulated 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 effectiveness 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 chemotherapy 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.