Search

Abstract Background Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib. Case presentation A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases. Conclusion We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.

Background: Cholangiocarcinomas (CCA) are a group of aggressive malignancies with poor prognosis. The distinct subtypes are related to different etiologies and genetic aberrations that are subject to targeted therapies. Mouse double minute 2 homolog (MDM2) is a potent inhibitor of tumor suppressor p53 and is proven to be altered in certain carcinomas. Novel targeted drugs, such as the MDM2-p53 antagonist Brigimadlin, have shown promising results for therapeutic efficacy in patients with MDM2 amplification and wild-type TP53 ., Objectives: This study therefore aimed to characterize CCAs regarding their MDM2 status, compare the concordance between fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) methods, and elucidate the role of MDM2 amplification in prognosis and other clinicopathological characteristics., Design: Retrospective cohort study., Methods: All patients ( n  = 52) were diagnosed with CCA and received surgical resection with curative intention at the University Hospital of Cologne. Samples were analyzed retrospectively for MDM2 amplification with FISH and IHC. We correlated results with pre-existing molecular as well as clinical data., Results: We included 52 patients with primary CCA, three of which showed positive MDM2 amplification (5.8%). MDM2 amplification was present only in the intrahepatic CCA type and all patients with positive MDM2 amplification exhibited normal p53 status. Among the large-duct subtypes of intrahepatic CCAs, patients with positive MDM2 amplification demonstrated better survival than patients with negative MDM2 amplification ( p  = 0.041). Of the patients with MDM2 amplification, two underwent adjuvant therapy post-surgery (66.7%). There was a strong correlation between MDM2 amplification and positive protein expression in IHC. There were no identifiable molecular co-alterations of MDM2 with FGFR2 or SWI/SNF complex alterations., Conclusion: Real-world evidence in our Caucasian patient population confirmed that a significant number of intrahepatic CCAs showcase MDM2 amplification, qualifying for a personalized therapy option with Brigimadlin. MDM2 amplification must therefore be considered in the context of personalized molecular testing in CCA., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Purpose: First-line therapy options in advanced cholangiocarcinoma (CCA) are based on the ABC-02 trial regimen (gemcitabine/cisplatin [G/C]). The NIFE trial examined nanoliposomal irinotecan/fluorouracil/leucovorin (nal-IRI/FU/LV) as alternative first-line therapy in advanced CCA., Methods: NIFE is a prospective, open-label, randomized, multicenter phase II study that aimed at detecting efficacy comparable with the standard treatment. Patients with advanced CCA were randomly assigned (1:1) to receive nal-IRI/FU/LV (arm A) or G/C (arm B). Stratification parameters were intrahepatic versus extrahepatic CCA, sex, and Eastern Cooperative Oncology Group (ECOG; 0/1). Arm A was designed as a Simon's optimal two-stage design and arm B served as a randomized control group. The primary goal was to exclude an inferior progression-free survival (PFS) at 4 months of only 40%, while assuming a rate of 60% on G/C population., Results: Between 2018 and 2020, overall 91 patients were randomly assigned to receive nal-IRI/FU/LV (n = 49) or G/C (n = 42). The NIFE trial formally met its primary end point with a 4-month PFS rate of 51% in patients receiving nal-IRI/FU/LV. The median PFS was 6 months (2.4-9.6) in arm A and 6.9 months (2.5-7.9) in arm B. Median overall survival (OS) was 15.9 months (10.6-20.3) in arm A and 13.6 months (6.5-17.7) in arm B. The exploratory comparison of study arms suggested a numerical but statistically not significant advantage for nal-IRI/FU/LV (hazard ratio for PFS, 0.85 [95% CI, 0.53 to 1.38] and for OS, 0.94 [95% CI, 0.58 to 1.50]). Analysis for stratification parameters revealed no differences for sex and ECOG, but for tumor localization. The objective response rate was 24.5% with nal-IRI/FU/LV and 11.9% with G/C. No unexpected toxicities occurred. AEs related to nal-IRI/FU/LV were mainly GI and to G/C hematologic., Conclusion: Treatment of advanced CCA with nal-IRI/FU/LV demonstrated efficacy in first-line therapy without new safety findings and merits further validation.

Purpose: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis, wherefore targeted therapies have experienced increasing interest. Zolbetuximab is a novel targeted therapy under investigation in patients with PDAC and targets Claudin 18.2 (CLDN18.2), which is a component of tight junctions and is of significance in various solid tumors. As its role in PDAC is not definitively elucidated, this study aims to clarify the significance of CLDN18.2 expression in PDAC in a real-world setting., Methods: All patients (n = 309) were recruited at one of the PANCALYZE study centers and received pancreatic resection with curative intention. Paraffin samples were analyzed using an antibody against CLDN18.2, which is known to be comparable to the antibody used by the SPOTLIGHT and GLOW studies., Results: 94 PDACs are positive for CLDN18.2 (30.4 %). Positive CLDN 18.2 expression was associated with significantly better cancer differentiation (p < 0.001). Patients with positive CLDN18.2 expression showed significantly better overall survival when compared to patients with negative expression (median OS: 30 versus 18 months, p = 0.003). Additionally, in multivariable analyses, CLDN18.2 expression was identified as an independent factor for better survival in patients with PDAC (HR = 0.686, 95 %CI = 0.492-0.956, p = 0.026)., Conclusion: Significant improvement in survival could be demonstrated by adding Zolbetuximab to known chemotherapy regimes in patients with gastro-esophageal junction adenocarcinoma with at least 75 % CLDN18.2 positive cancer cells. Our findings demonstrate, that 30.4 % of the included patients with PDAC would potentially be eligible for therapy with Zolbetuximab in a real-world patient cohort. Results of trials targeting Claudin 18.2 are pending in patients with PDAC., Competing Interests: Declaration of competing interest The authors have no relevant financial or non-financial interests to disclose., (Copyright © 2024. Published by Elsevier Inc.)

Background: The gut microbiome modulates the liver immune microenvironment and is deeply integrated into the pathophysiology of metabolic dysfunction-associated steatotic liver disease (MASLD). Appendectomies, which are performed in almost all patients diagnosed with appendicitis, cause long-term alterations to the gut microbiome, providing a potential link with the development of MASLD. We therefore investigated a potential link between appendicitis and the presence of MASLD in a large cohort of outpatients in Germany., Methods: The present study included 26,717 individuals with and 26,717 without appendicitis. Univariable Cox-regression analyses were conducted to assess the association between appendicitis and MASLD., Results: During the long-term follow-up, 4.8% of patients with appendicitis and 3.4% of those in the non-appendicitis group were diagnosed with MASLD ( p < 0.001), corresponding to an incidence of 5.4 (appendicitis cohort) versus 3.5 (non-appendicitis cohort) cases per 1000 patient years. These findings were confirmed in regression analysis, revealing a strong and statistically significant association between appendicitis and the development of MASLD (HR: 1.57; 95% CI: 1.39-1.78). This link was observed for all age groups and was independent of patients' sex., Conclusion: We provide evidence from a large cohort of outpatients in Germany suggesting a link between appendicitis and MASLD. This might help to better stratify patients according to their individual risk for the development of chronic liver diseases.

Background: Data on perioperative chemotherapy in resectable pancreatic ductal adenocarcinoma (rPDAC) are limited. NEONAX examined perioperative or adjuvant chemotherapy with gemcitabine plus nab-paclitaxel in rPDAC (National Comprehensive Cancer Network criteria)., Patients and Methods: NEONAX is a prospective, randomized phase II trial with two independent experimental arms. One hundred twenty-seven rPDAC patients in 22 German centers were randomized 1 : 1 to perioperative (two pre-operative and four post-operative cycles, arm A) or adjuvant (six cycles, arm B) gemcitabine (1000 mg/m 2 ) and nab-paclitaxel (125 mg/m 2 ) on days 1, 8 and 15 of a 28-day cycle., Results: The primary endpoint was disease-free survival (DFS) at 18 months in the modified intention-to-treat (ITT) population [R0/R1-resected patients who started neoadjuvant chemotherapy (CTX) (A) or adjuvant CTX (B)]. The pre-defined DFS rate of 55% at 18 months was not reached in both arms [A: 33.3% (95% confidence interval [CI] 18.5% to 48.1%), B: 41.4% (95% CI 20.7% to 62.0%)]. Ninety percent of patients in arm A completed neoadjuvant treatment, and 42% of patients in arm B started adjuvant chemotherapy. R0 resection rate was 88% (arm A) and 67% (arm B), respectively. Median overall survival (mOS) (ITT population) as a secondary endpoint was 25.5 months (95% CI 19.7-29.7 months) in arm A and 16.7 months (95% CI 11.6-22.2 months) in the upfront surgery arm. This difference corresponds to a median DFS (mDFS) (ITT) of 11.5 months (95% CI 8.8-14.5 months) in arm A and 5.9 months (95% CI 3.6-11.5 months) in arm B. Treatment was safe and well tolerable in both arms., Conclusions: The primary endpoint, DFS rate of 55% at 18 months (mITT population), was not reached in either arm of the trial and numerically favored the upfront surgery arm B. mOS (ITT population), a secondary endpoint, numerically favored the neoadjuvant arm A [25.5 months (95% CI 19.7-29.7months); arm B 16.7 months (95% CI 11.6-22.2 months)]. There was a difference in chemotherapy exposure with 90% of patients in arm A completing pre-operative chemotherapy and 58% of patients starting adjuvant chemotherapy in arm B. Neoadjuvant/perioperative treatment is a novel option for patients with resectable PDAC. However, the optimal treatment regimen has yet to be defined. The trial is registered with ClinicalTrials.gov (NCT02047513) and the European Clinical Trials Database (EudraCT 2013-005559-34)., Competing Interests: Disclosure Reported grants and personal fees: TS: Amgen, AstraZeneca, Bayer, BMS, Falk Foundation, Pierre Fabre, Servier, Boehringer Ingelheim, Cantargia AB, Sanofi, Merck Serono; Roche; HA: AstraZeneca, MSD, Servier, Seattle Genetics, Chugai Pharma; HF: Bayer, Merck, Pfizer, Mylan; AK: Ipsen, Pierre Fabre, Roche, CCS: Merck; MG: Amgen, Lilly, Merck; DW: AstraZeneca, Bayer, BMS, Eisai, Falk Pharma, Incyte, Roche, Ipsen; AT: Amgen, Falk Pharma, Merck, Pfizer; LP: AstraZeneca, Servier; MT: CPRIT, Novartis, Abbvie, Advance Medical/Teladoc Health, AstraZeneca, BMS, EcoR1 Capital, Eisai, Elicio Therapeutics, FibroGen, GlaxoSmithKline, Immunovia, Ipsen, Karyopharm Therapeutics, Merck, Pharmacyclics, Swedish Orphan Biovitrum, Ono Pharmaceutical, BIOPHARM, GlaxoSmithKline, Pharmacyte Biotech, Tocagen; ACR: Amgen, AstraZeneca, BMS, MCI Group, Merck Serono, MSD, Roche, Pierre Fabre, Roche, Alexion Pharmaceuticals, BioNTech, Rafael Pharmaceuticals, Servier; TJE: AstraZeneca, Bayer, BMS, Daiichi Sankyo, Eisai, Incyte, Ipsen, Lilly, Merck Serono, MSD, Pierre Fabre, Roche, Sanofi, Servier. All other authors have declared no conflicts of interest., (Copyright © 2022 European Society for Medical Oncology. All rights reserved.)

Background: The prognostic and predictive value of carbohydrate antigen 19-9 (CA 19-9) in locally advanced pancreatic cancer (LAPC) has not yet been defined from prospective randomized controlled trials (RCTs)., Patients and Methods: A total of 165 LAPC patients were treated within the NEOLAP RCT for 16 weeks with multiagent induction chemotherapy [ICT; either nab-paclitaxel/gemcitabine alone or nab-paclitaxel/gemcitabine followed by FOLFIRINOX (combination of fluorouracil, leucovorin, irinotecan, and oxaliplatin)] followed by surgical exploration of all patients without evidence of disease progression. CA 19-9 was determined at baseline and after ICT and correlated with overall survival (OS) and secondary R0 resection rate., Results: From the NEOLAP study population (N = 165) 133 patients (81%) were evaluable for CA 19-9 at baseline and 81/88 patients (92%) for post-ICT CA 19-9 response. Median OS (mOS) in the CA 19-9 cohort (n = 133) was 16.2 months [95% confidence interval (CI) 13.0-19.4] and R0 resection (n = 31; 23%) was associated with a significant survival benefit [40.8 months (95% CI 21.7-59.8)], while R1 resected patients (n = 14; 11%) had no survival benefit [14.0 (95% CI 11.7-16.3) months, hazard ratio (HR) 0.27; P = 0.001]. After ICT most patients showed a CA 19-9 response (median change from baseline: -82%; relative decrease ≥55%: 83%; absolute decrease to ≤50 U/ml: 43%). Robust CA 19-9 response (decrease to ≤50U/ml) was significantly associated with mOS [27.8 (95% CI 18.4-37.2) versus 16.5 (95% CI 11.7-21.2) months, HR 0.49; P = 0.013], whereas CA 19-9 baseline levels were not prognostic for OS. Multivariate analysis demonstrated that a robust CA 19-9 response was an independent predictive factor for R0 resection. Using a CA 19-9 decrease to ≤61 U/ml as optimal cut-off (by receiver operating characteristic analysis) yielded 72% sensitivity and 62% specificity for successful R0 resection, whereas CA 19-9 nonresponders (<20% decrease or increase) had no chance for successful R0 resection., Conclusions: CA 19-9 response after multiagent ICT provides relevant prognostic and predictive information and is useful in selecting LAPC patients for explorative surgery., Clinical Trial Number: ClinicalTrials.govNCT02125136; https://clinicaltrials.gov/ct2/show/NCT02125136; EudraCT 2013-004796-12; https://www.clinicaltrialsregister.eu/ctr-search/trial/2013-004796-12/results., Competing Interests: Disclosure IH reports honoraria from Celgene/BMS and Roche. JTS reports honoraria from AstraZeneca, Bayer, Celgene/BMS, MorphoSys, Roche, and Shire. EG reports honoraria from AstraZeneca, Celgene/BMS, MSD, Sanofi, and Servier. GS reports grants and honoraria from AstraZeneca, AURIKAMED, BeiGene, Eisai, Celgene/BMS, Deutsche Röntgengesellschaft, Isofol Medical, Janssen-Cilag, Lilly, Medizinwelten-Services GmbH, MOLOGEN, Novartis, Nutricia, Roche, Sanofi, Servier, and Shire. UMM reports honoraria from Amgen, Celgene/BMS, Lilly, Pierre-Fabre, Roche, and Sanofi. DW reports grants and honoraria from AstraZeneca, Bayer, Celgene/BMS, Eisai, Falk, Incyte, Ipsen, Novartis, Roche, Servier, Shire, and Sirtex. MF reports honoraria from Celgene/BMS, Falk, MSD, Roche and Servier. FK reports grants and honoraria from Celgene/BMS. SB reports grants and honoraria from Astra-Zeneca, Celgene/BMS, Fresenius, Incyte, Janssen-Cilag and Servier. TJE reports honoraria from Astra-Zeneca, Bayer, Celgene/BMS, Ipsen, Lilly, MSD, Roche, and Servier. RK reports employment by AIO-Studien-gGmbH. FA reports grants from the Interdisciplinary Center for Clinical Research (IZKF) Würzburg, Germany. AS reports grants from Deutsche Krebsgesellschaft (DKG). VH reports grants, honoraria, and nonfinancial support from Amgen, Astra-Zeneca, Baxalta, Boehringer-Ingelheim, Celgene/BMS, Halozyme, Lilly, Merck, MSD, Novartis, OncoSil, Pierre-Fabre, Roche, Sanofi, Servier, Shire, Sirtex, Taiho, and Terumo. VK reports grants and honoraria from Amgen, Astra-Zeneca, Celgene/BMS, MSD, and Servier. All remaining authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

The combination of the anti-PD-L1 antibody atezolizumab and the anti-VEGF bevacizumab is the first approved immunotherapeutic regimen for first-line therapy in patients with unresectable hepatocellular carcinoma (HCC), currently approved in more than 80 countries. The efficacy and tolerability of this regimen suggest that the use of atezolizumab + bevacizumab could be extended to the treatment of patients with intermediate-stage HCC in combination with transarterial chemoembolization (TACE). The authors describe the rationale and design of the DEMAND study. This investigator-initiated, multicenter, randomized phase II study is the first trial to evaluate the safety and efficacy of atezolizumab + bevacizumab prior to or in combination with TACE in patients with intermediate-stage HCC. The primary end point is the 24-month survival rate; secondary end points include objective response rate, progression-free survival, safety and quality of life. Clinical Trial Registration: NCT04224636 (ClinicalTrials.gov).

Biliary tract cancers (BTC) are rare but aggressive. Due to limited anti-tumor effects of current second- and later-line treatment regimens, novel treatment options are required. Nanoliposomal irinotecan in combination with leucovorin and 5-fluorouracil (FOLFnal-IRI) achieved promising results as a second-line treatment in patients with pancreatic cancer, warranting further investigation in BTC. In the present study, a retrospective analysis of patients receiving FOLFnal-IRI after initial platinum-based chemotherapy for advanced BTC between January 2016 and August 2020 at the University Hospital Cologne (Cologne, Germany) was performed. A total of 11 patients were identified who met the inclusion criteria. A total of 4 patients (36.4%) were female and the median age was 54 years. The proportion of patients suffering from gallbladder carcinoma, intrahepatic and extrahepatic cholangiocarcinoma was 18.2, 63.6 and 9.1%, respectively. Furthermore, 7 patients (63.6%) received FOLFnal-IRI as their second-, 3 (27.3%) as third- and one (9.1%) as their fourth-line therapy. The disease control rate was 54.5% and 3 grade III toxicities were recorded. Progression-free survival and overall survival (OS) after initiation of FOLFnal-IRI was 5.1 and 12.4 months, respectively. OS after initial diagnosis was 24.7 months. FOLFnal-IRI demonstrated promising antitumor potential with an acceptable safety profile as a subsequent therapy regimen in advanced biliary tract malignancies. Further randomized controlled trials of its value as a treatment option for BTC appear justified., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Allo et al.)

Background: According to current guidelines, treatment of patients with hepatic oligometastasis in pancreatic cancer is not reflected and systemic chemotherapy is recommended in those patients. Retrospective data suggest beneficial outcomes in patients with hepatic oligometastasis, though prospective data from clinical trials addressing this particular patient group is not available., Methods: In this single arm, phase-2 trial, survival data from patients receiving neoadjuvant chemotherapy followed by R0/R1 resection will be compared to historic data from patients with oligometastatic adenocarcinoma of the pancreas. The clinical trial will focus on a well-defined patient collective with metastatic load limited to the liver as target organ with a maximum of five metastases. The combination of liposomal irinotecan (nal-IRI), oxaliplatin (OX) and 5-fluouracil (5-FU)/folinic acid (FA) (nal-IRI + OX+ 5-FU/FA, NAPOX) was chosen as neoadjuvant chemotherapy; the choice was based on an ongoing clinical study in which NAPOX appeared manageable, with promising anti-tumor activity in first-line treatment of patients with metastatic pancreatic adenocarcinoma. In total 150 patients will be enrolled for this trial with an aim of 55 patients receiving a complete macroscopic synchronous tumor and metastatic resection., Discussion: This is the first clinical study to prospectively evaluate the value of multimodality therapy concepts in oligometastatic pancreatic cancer., Trial Registration Numbers: EudraCT 2019-002734-37 ; NCT04617457 ., (© 2021. The Author(s).)

Thermal ablative therapies are standard treatments for localized hepatocellular carcinoma (HCC). In addition to local tumor destruction, ablation leads to abscopal effects in distant lesions most likely mediated by an anti-tumor immune response. Although microwave ablation (MWA) is increasingly substituting other ablative techniques, its systemic immunostimulatory effects are poorly studied. We analyzed tumor-specific immune responses in peripheral blood of HCC patients after thermal ablation with regard to T cell responses and disease outcome. While comprehensive flow cytometric analyses in sequential samples of a prospective patient cohort (n = 23) demonstrated only moderate effects of MWA on circulating immune cell subsets, fluorospot analyses of specific T cell responses against seven tumor-associated antigens (TTAs) revealed de-novo or enhanced tumor-specific immune responses in 30% of patients. This anti-tumor immune response was related to tumor control as Interferon-y and Interleukin-5 T cell responses against TAAs were more frequent in patients with a long-time remission (> 1 year) after MWA (7/16) compared to patients suffering from an early relapse (0/13 patients) and presence of tumor-specific T cell response (IFN-y and/or IL-5) was associated to longer progression-free survival (27.5 vs. 10.0 months). Digital image analysis of immunohistochemically stained archival HCC samples (n = 18) of patients receiving combined MWA and resection revealed a superior disease-free survival of patients with high T cell abundance at the time of thermal ablation (37.4 vs. 13.1 months). Our data demonstrates remarkable immune-related effects of MWA in HCC patients and provides additional evidence for a combination of local ablation and immunotherapy in this challenging disease.

Background: The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer., Methods: In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m 2 plus gemcitabine 1000 mg/m 2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , irinotecan 180 mg/m 2 , fluorouracil 400 mg/m 2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m 2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136., Findings: Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase., Interpretation: Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival., Funding: Celgene., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Objectives: The interferon-induced protein with multiple tetratricopeptide repeats 3 (IFIT3) seems to be associated with the prognosis in pancreatic cancer. Here we clarify whether the heterogeneity of IFIT3 expression affects previous IFIT3 analysis., Methods: This retrospective study analyzes pancreatic cancer tissue samples retrieved by surgery from 2 independent patient cohorts. Patients underwent either primary surgery (n = 72) or received neoadjuvant chemotherapy (n = 12). Immunohistochemistry assessed IFIT3 expression and its heterogeneity. Complementarily, we analyzed publicly available transcriptomic data (n = 903)., Results: Of the primarily resected tumors, 16.4% were heterogeneous. Patients with IFIT3-negative tumors did not survive longer compared with patients with IFIT3-positive tumors. An analysis of publicly available data confirmed this result. Patients developing lung metastases had the best prognosis (4.8 years) with significantly lower IFIT3 expression compared with liver metastasis (P = 0.0117). Patients receiving neoadjuvant therapy who are IFIT3 negative had a longer disease-free survival (1.2 vs 0.3 years, P = 0.0081)., Conclusions: Low IFIT3 expression is not associated with longer survival. Divergent results from tissue microarray analyses could be explained with tumor heterogeneity. As a single biomarker, IFIT3 is not suitable for predicting disease prognosis. Recurrence of lung metastases and response to neoadjuvant chemotherapy are associated with low IFIT3 expression.

Background: CONKO-006 was designed for patients with pancreatic adenocarcinoma with postsurgical R1 residual status to evaluate the efficacy and safety of the combination of gemcitabine and sorafenib (GemSorafenib) compared with those of gemcitabine + placebo (GemP) for 12 cycles., Patients and Methods: This randomised, double-blind, placebo-controlled, multicenter study was planned to detect an improvement in recurrence-free survival (RFS) from 42% to 60% after 18 months. Secondary objectives were overall survival (OS), safety and duration of treatment., Results: 122 patients were included between 02/2008 and 09/2013; 57 were randomised to GemSorafenib and 65 to GemP. Patient characteristics were wellbalanced (GemSorafenib/GemP) in terms of median age (63/63 years), tumour size (T3/T4: 97/97%), and nodal positivity (86/85%). Grade 3/4 toxicities comprised diarrhoea (GemSorafenib: 12%; GemP: 2%), elevated gamma-glutamyl transferase (GGT) (19%; 9%), fatigue (5%; 2%) and hypertension (5%; 2%), as well as neutropenia (18%; 25%) and thrombocytopenia (9%; 2%). By August 2017, 118 (97%) RFS event had occurred. There were no difference in RFS (median GemSorafenib: 8.5 versus GemP: 9.4 months; p = 0.730) nor OS (median GemSorafenib: 17.6 versus GemP: 17.5 months; p = 0.481). Landmark analyses suggest that patients who received more than six cycles of postoperative chemotherapy had significantly longer OS (p = 0.021)., Conclusion: CONKO-006 is the first randomised clinical trial to include exclusively patients with PDAC with postsurgical R1 status thus far. Sorafenib added to gemcitabine did neither improve RFS nor OS. However, postoperative treatment exceeding six months seemed to prolong survival and should be further investigated in these high-risk patients., Clinical Trial Information: German Tumor Study Registry (Deutsches Krebsstudienregister), DRKS00000242., (Copyright © 2020. Published by Elsevier Ltd.)

Metastatic pancreatic cancer has the worst prognosis of all cancers. With nab-Paclitaxel/gemcitabine, FOLFIRINOX, and gemcitabine/erlotinib, several treatment options are available which improve the patient's overall survival. Especially for patients who develop rash under erlotinib treatment can benefit from gemcitabine/erlotinib combination therapy. This non-interventional study (NIS ML21284) investigated the effectiveness and tolerability of gemcitabine/erlotinib therapy in the treatment routine of metastatic pancreatic cancer, in particular, in the context of the occurrence of a rash.Between 2007 and 2010, the treatment data of 433 patients in 98 centres were documented. All parameters recorded were assessed descriptively.Treatment with gemcitabine/erlotinib resulted in both a significant increased median overall survival of the patient subgroup with rash grade ≥ 1 (9.90; 95 % confidence interval [CI], 8.19 to 11.05 vs. 6.48 months; 95 % CI, 5.66 to 7.40, p = 0.0010) and median progression-free survival (5.43, 95 % CI, 4.90 to 6.12 vs. 3.98 months, 95 % CI, 3.52 to 5.03, p = 0.0131). The overall response rate of patients treated with gemcitabine/erlotinib, who had developed rash grade ≥ 1, was 5.9 % higher compared to patients without rash (31.7 % vs. 25.8 %).In conclusion, these results from the daily treatment routine of metastatic pancreatic cancer underline the importance of combined gemcitabine/erlotinib therapy for a subgroup of patients who develop a rash in the course of erlotinib treatment., Competing Interests: CBW erhält persönliche Honorare von Roche, Zuschüsse von Roche, persönliche Honorare von Celgene, RedHill und Ipsen außerhalb der eingereichten Arbeit.VH erhält Honorare von Roche, Merck, Amgen, Celgene, Boehringer; Beratertätigkeiten und Advisory Board von Roche, Merck, Celgene, Boehringer, BAXALTA, MSD, BMS, Halozyme; Forschungsgelder (Institution) von Roche, Celgene, Boehringer, Servier.HWT hat keinen Interessenkonflikt.MG hat ein Anstellungsverhältnis oder Führungsposition (Praxisinhaber Hämatologisch-Onkologische Praxis Stolberg; Leiter des onkologischen Zentrum am Bethlehem Stolberg); Kongress- und Reisekostenunterstützung: Roche Pharma, Celegene, Ipsen, Onkovis; Beratungs- bzw. Gutachtertätigkeit: Roche Phama, BMS, Novartis, Pfizer; Honorare: Roche Pharma, BMS, Novartis, Pfizer, Amgen, Merck, Celegene; Finanzierung wissenschaftlicher Untersuchungen: Roche Pharma, BMS, Novartis, Pfizer, ioMedico, Pierre Fabre, Chugai, Onkovis, Celegene, Amgen, Astra Zeneca, Sanofi, Eisai, Medac, Octapharma, Gilead, Teva, Merck.HGH hat keinen Interessenkonflikt.NB hat eine leitende Funktion bei iOMEDICO im Angestelltenverhältnis, erhält einen Travel Grant von Roche Pharma AG und ist Mitglied eines von der Roche Pharma AG organisierten Advisory Boards.MS hat keinen Interessenkonflikt.AB ist Mitarbeiter der F. Hoffmann-La Roche AG, Schweiz.WD gibt folgende Beratertätigkeiten an: Bayer Health Pharma, BMS, Celgene, Eisai, Ipsen, Novartis, Roche Pharma AG, Shire Baxelta, Sirtex. Vortragstätigkeit: Bayer Health Pharma, BMS, Celgene, Novartis, Shire Baxelta, Sirtex. Forschungsgelder: Roche Pharma AG., (© Georg Thieme Verlag KG Stuttgart · New York.)

Background: To date, patients with metastasized pancreatic ductal adenocarcinoma (PDAC M1) are regarded as a uniform collective. We hypothesize the existence of oligometastatic disease (OMD): a state of PDAC M1 disease with better tumor biology, limited metastasis, and increased survival., Methods: Data of 128 PDAC M1 patients treated at the University of Cologne between 2008 and 2018 was reviewed. Interdependence between clinical parameter was calculated using the Mann-Whitney U-Test. Survival curves were generated using the Kaplan-Meier method and analyzed using the log-rank test., Results: Eighty-one (63%) patients had metastases confined to one organ (single organ metastasis, SOG) whereas the remaining 47 (37%) showed multiple metastatic sites (multi-organ metastasis, MOG). Survival analysis revealed a median overall survival (OS) of 12.2 months for SOG vs 4.5 months for MOG (95% CI 5.7-9.8; p < 0.001). We defined limited disease by the presence of ≤4 metastases in liver or lung. Limited disease together with CA 19-9 baseline < 1000 U/ml and response or stable disease after first-line chemotherapy defined OMD. We identified 8 patients with hepatic metastases and 2 with pulmonary metastases matching all OMD criteria. This group of 10 (7.8%) had a median overall survival of 19.4 vs 7.2 months compared to the remaining patients (95% CI 5.7-9.8; p = 0.009)., Conclusion: We propose a definition of oligometastatic disease in PDAC including anatomical criteria and biological criteria reflecting better tumor biology. The 10 OMD patients (7.8%) survived significantly longer and might even benefit from surgical resection in the future.

Background: Carcinomas of the small bowel are rare tumors usually with dismal prognosis. Most recently, some potentially treatable molecular alterations were described. We emphasize the growing evidence of individualized treatment options in small bowel carcinoma., Methods: We performed a DNA- based multi-gene panel using ultra-deep sequencing analysis (including 14 genes with up to 452 amplicons in total; KRAS, NRAS, HRAS, BRAF, DDR2, ERBB2, KEAP1, NFE2L2, PIK3CA, PTEN, RHOA, BRCA1, BRCA2 and TP53) as well as an RNA-based gene fusion panel including ALK, BRAF, FGFR1, FGFR2, FGFR3, MET, NRG1, NTRK1, NTRK2, NTRK3, RET and ROS1 on eleven formalin fixed and paraffin embedded small bowel carcinomas. Additionally, mismatch-repair-deficiency was analyzed by checking the microsatellite status using the five different mononucleotide markers BAT25, BAT26, NR-21, NR-22 and NR-27 and loss of mismatch repair proteins using four different markers (MLH1, MSH6, MSH2, PMS2)., Results: In five out of eleven small bowel carcinomas we found potentially treatable genetic alterations. Three patients demonstrated pathogenic (class 5) BRCA1 or BRCA2 mutations - one germline-related in a mixed neuroendocrine-non neuroendocrine neoplasm (MiNEN). Two additional patients revealed an activating ERBB2 mutation or PIK3CA mutation. Furthermore two tumors were highly microsatellite-instable (MSI-high), in one case associated to Lynch-syndrome. We did not find any gene fusions., Conclusion: Our results underscore, in particular, the relevance of potentially treatable molecular alterations (like ERBB2, BRCA and MSI) in small bowel carcinomas. Further studies are needed to proof the efficacy of these targeted therapies in small bowel carcinomas.

Background: Adenocarcinomas or combined adeno-neuroendocrine carcinomas (MANEC) of small bowel usually have a dismal prognosis with limited systemic therapy options. This is the first description of a patient showing a germline-related BRCA1 mutated MANEC of his ileum. The tumor presented a susceptibility to a combined chemotherapy and the PARP1-inhibitor olaparib., Case Presentation: A 74-year old male patient presented with a metastasized MANEC of his ileum. Due to clinical symptoms his ileum-tumor and the single brain metastasis were removed. We verified the same pathogenic (class 5) BRCA1 mutation in different tumor locations. There was no known personal history of a previous malignant tumor. Nevertheless we identified his BRCA1 mutation as germline-related. A systemic treatment was started including Gemcitabine followed by selective internal radiotherapy (SIRT) to treat liver metastases and in the further course Capecitabine but this treatment finally failed after 9 months and all liver metastases showed progression. The treatment failure was the reason to induce an individualized therapeutic approach using combined chemotherapy of carboplatin, paclitaxel and the Poly (ADP-ribose) polymerase- (PARP)-inhibitor olaparib analogous to the treatment protocol of Oza et al. All liver metastases demonstrated with significant tumor regression after 3 months and could be removed. In his most current follow up from December 2017 (25 months after his primary diagnosis) the patient is in a very good general condition without evidence for further metastases., Conclusion: We present first evidence of a therapy susceptible germline-related BRCA1 mutation in small bowel adeno-neuroendocrine carcinoma (MANEC). Our findings offer a personalized treatment option. The germline background was unexpected in a 74-year old man with no previously known tumor burden. We should be aware of the familiar background in tumors of older patients as well.

Background: Combination chemotherapy has shown benefit in the treatment of biliary cancer and further improvements might be achieved by the addition of a biological agent. We report here the effect of chemotherapy with the monoclonal EGFR antibody panitumumab as therapy for KRAS wild-type biliary cancer., Patients and Methods: Patients with advanced biliary tract cancer were randomised (2:1) to receive cisplatin 25 mg/m 2 and gemcitabine 1000 mg/m 2 on day 1 and day 8/q3w with (arm A) or without panitumumab (arm B; 9 mg/kg BW, i.v q3w). The primary end-point was the evaluation of progression-free survival (PFS) at 6 months. Secondary end-points included objective response rate (ORR), overall survival (OS), and toxicity. In addition, a post hoc assessment of genetic alterations was performed. Finally, we performed a meta-analysis of trials with chemotherapy with and without EGFR antibodies., Results: Sixty-two patients were randomised in arm A and 28 patients in arm B. Patients received 7 treatment cycles in median (1-35) with a median treatment duration of 4.7 months (141 days, 8-765). PFS rate at 6 months was 54% in patients treated with cisplatin/gemcitabine and panitumumab but was 73% in patients treated with cisplatin/gemcitabine without antibody, respectively. Secondary end-points were an ORR of 45% in treatment arm A compared with 39% receiving treatment B and a median OS of 12.8 months (arm A) and of 20.1 months (arm B), respectively. In contrast to the p53-status, genetic alterations in IDH1/2 were linked to a high response after chemotherapy and prolonged survival. In accordance with our results, the meta-analysis of 12 trials did not reveal a survival advantage for patients treated with EGFR antibodies compared with chemotherapy alone., Conclusions: Panitumumab in combination with chemotherapy does not improve ORR, PFS and OS in patients with KRAS wild-type, advanced biliary cancer. Genetic profiling should be included in CCA trials to identify and validate predictive and prognostic biomarkers., Clinical Trials Number: The trial was registered with NCT01320254., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Purpose Gemcitabine is standard of care in the adjuvant treatment of resectable pancreatic ductal adenocarcinoma (PDAC). The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with gemcitabine has shown efficacy in the treatment of advanced PDAC and was considered to improve survival in patients with primarily resectable PDAC after R0 resection. Patients and Methods In an open-label, multicenter trial, patients were randomly assigned to one of two study arms: gemcitabine 1,000 mg/m 2 days 1, 8, 15, every 4 weeks plus erlotinib 100 mg once per day (GemErlo) or gemcitabine (Gem) alone for six cycles. The primary end point of the study was to improve disease-free survival (DFS) from 14 to 18 months by adding erlotinib to gemcitabine. Results In all, 436 patients were randomly assigned at 57 study centers between April 2008 and July 2013. A total of 361 instances (83%) of disease recurrence were observed after a median follow-up of 54 months. Median treatment duration was 22 weeks in both arms. There was no difference in median DFS (GemErlo 11.4 months; Gem 11.4 months) or median overall survival (GemErlo 24.5 months; Gem 26.5 months). There was a trend toward long-term survival in favor of GemErlo (estimated survival after 1, 2, and 5 years for GemErlo was 77%, 53%, and 25% v 79%, 54%, and 20% for Gem, respectively). The occurrence or the grade of rash was not associated with a better survival in the GemErlo arm. Conclusion To the best of our knowledge, CONKO-005 is the first study to investigate the combination of chemotherapy and a targeted therapy in the adjuvant treatment of PDAC. GemErlo for 24 weeks did not improve DFS or overall survival over Gem.

Esophageal cancer is the eighth most common malignant tumor worldwide, and the number of incidences of esophageal adenocarcinoma is increasing in the Western world. Despite improvements in perioperative treatment, the overall survival rate of patients with esophageal adenocarcinoma remains poor. Breast cancer type 1 susceptibility protein (BRCA1)-associated protein (BAP1) is located on chromosome 3p21, and it is an enzyme with ubiquitin carboxyl hydrolase activity that regulates cell growth. It interacts with BRCA1, and the nuclear localization of BAP1 is required for its tumor suppressor function. BAP1 is frequently mutated in uveal melanomas, malignant mesothelioma and several carcinomas, including a subtype of renal cell carcinoma, intrahepatic cholangiocarcinoma and squamous cell carcinoma of the esophagus. Furthermore, several germline-associated mutations of tumors have been described (BAP1 hereditary cancer syndrome). However, the importance and frequency of BAP1 alterations in adenocarcinoma of the esophagus remain to be elucidated. In the present study, tissue microarrays of 332 resected adenocarcinomas (including a few cases of concomitant Barrett dysplasia) of the esophagus were constructed. The tumor tissue was analyzed using immunohistochemistry to investigate the levels of BAP1 expression. Fibroblasts or inflammatory cells served as an internal positive control. Three adenocarcinomas revealed nuclear loss of BAP1 (0.9%). One case with concomitant Barrett dysplasia also exhibited a loss of BAP1. Of the resected adenocarcinomas, 329 of them exhibited an intact and uniform strong nuclear staining pattern. To the best of our knowledge, this is the first description of BAP1 deficiency in adenocarcinomas of the esophagus. Furthermore, it has been demonstrated that BAP1 loss is possibly an early event in esophageal adenocarcinoma. These results warrant further functional and clinical evaluation.

Adenocarcinoma of the pancreas has a poor prognosis. At present, no relevant personalized targets have been identified. Sequencing studies have implicated gene alterations of disruptor of telomeric silencing 1 like histone lysine methyltransferase (DOT1L) in pancreatic adenocarcinoma. DOT1L is part of the histone modification system and catalyzes methylation of H3K79, which is crucial in cell signaling and DNA damage repair. DOT1L is considered to be a target of therapy in mixed lineage leukemia gene-deficient leukemia cases and a potential target in breast carcinoma. The frequencies and importance of DOT1L copy-number variations and their specific correlation with protein expression in adenocarcinoma of the pancreas have yet to be investigated. In the present study, tissue microarrays of 230 resected pancreatic adenocarcinoma cases were constructed. The tumor tissue was analyzed using fluorescence in situ hybridization (FISH) and immunohistochemistry. In total, 10/225 carcinoma cases (4.4%) analyzed by immunohistochemistry demonstrated intense nuclear protein expression of DOT1L and in 9/224 tumors analyzed using FISH (4.0%), copy-number variations (CNV) were detectable. No DOT1L amplification was detected in the carcinoma cohort. To the best of our knowledge, the present study describes for the first time the frequency of CNV of DOT1L using the gold standard fluorescence in situ hybridization (FISH) and their specific correlation to the protein expression in adenocarcinomas of the pancreas. Although the positive cases by immunohistochemistry and copy-number variations by FISH were not congruent with each other, the data suggest a potential role for DOT1L in a small subset of pancreatic cancer cases. The significance of the two analysis methods concerning their druggability in pancreatic adenocarcinoma requires further studies.

Background: Drug-induced skin toxicity may correlate with treatment efficacy in cancer patients receiving chemotherapy or biological agents. The correlation of the capecitabine-associated hand-foot skin reaction (HFS) on outcome parameters in pancreatic cancer (PC) has not yet been investigated., Methods: Within the multicentre phase III AIO-PK0104 trial, patients with confirmed advanced PC were randomly assigned to first-line treatment with either capecitabine plus erlotinib (150 mg/day, arm A) or gemcitabine plus erlotinib (150 mg/day, arm B). A cross-over to either gemcitabine (arm A) or capecitabine (arm B) was performed after failure of the first-line regimen. Data on skin toxicity were correlated with efficacy study endpoints using uni- and multivariate analyses. To control for guarantee-time bias (GTB), we focused on subgroup analyses of patients who had completed two and three or more treatment cycles., Results: Of 281 randomised patients, skin toxicity data were available for 255 patients. Median time to capecitabine-attributed HFS was two cycles, 36 of 47 (77%) HFS events had been observed by the end of treatment cycle three. Considering HFS during first-line treatment in 101 patients treated with capecitabine for at least two cycles within the capecitabine plus erlotinib arm, time to treatment failure after first- and second-line therapy (TTF2) and overall survival (OS) both were significantly prolonged for the 44 patients (44%) with HFS compared to 57 patients without HFS (56%) (TTF2: 7.8 vs. 3.8 months, HR 0.50, p = 0.001; OS: 10.4 vs. 5.9 months, HR 0.55, p = 0.005). A subgroup analysis of 70 patients on treatment with capecitabine for at least three cycles showed similar results (TTF2: 8.3 vs. 4.4 months, HR 0.53, p = 0.010; OS: 10.4 vs. 6.7 months, HR 0.62, p = 0.056)., Conclusion: The present subgroup analysis from AIO-PK0104 suggests that HFS may serve as an independent clinical predictor for treatment outcome in capecitabine-treated patients with advanced PC.

Purpose: We studied a cohort of adult patients with chronic hepatitis B (CHB) infection, followed at a tertiary referral liver center in Germany over 12.5 years to analyze the clinical features and impact of management on disease progression and survival of CHB patients in general and of those with CHB and HCC in particular., Methods: We retrospectively evaluated the medical records of 242 adult (age ≥ 18 years) patients. CHB was defined as positive hepatitis B surface antigen (HBsAg) and/or HBV-DNA levels >10 IU/mL for at least 6 months. Patient demographics, HBV markers, antiviral treatment, laboratory parameters, liver imaging and histology were recorded for each visit. HCC patients were divided into two groups and separately analyzed (group 1: n = 24, HCC at first visit and group 2: n = 11, HCC during surveillance)., Results: The mean age was 44 years in CHB patients without HCC (63% male) and about 59 years in patients with HCC (77% male). Antiviral therapy was given to 59% of patients without HCC compared to only 25% in group 1 and 18% in group 2 with comparable median HBV DNA levels of approximately 36,000 IU/mL. There was no statistically significant difference concerning the HCC stages (Milan, UCSF, BCLC) at first diagnosis. Five-year survival was 19% in group 1 vs. 64% in group 2 (p = 0.019), with LTx performed in 12 vs. 45%, respectively., Conclusion: Surveillance of CHB patients did not result in early stage detection of HCC but in a higher likelihood to receive potentially curative treatments.

Background: Patients with ileostomies regularly suffer from short bowel syndrome or high volume output associated with loss of absorptive surface and subsequent impairment of absorption for drugs and different nutrients resulting in electrolyte and fluid balance disorders as well as renal insufficiency. Adaptation of these fundamental functions of the gut with adequate fluid uptake, absorption of sufficient different nutrients and vitamins represents a major challenge to rehabilitate these patients shortly after surgery. Patients with ileostomy often develop metabolic acidosis with normal anion gap. In our retrospective study we would like to draw attention to these metabolic disorders in patients with ileostomy in comparison to patients with colostomy and patients undergoing gastrectomy for gastric cancer., Methods: In the period from 2005 to 2012 we examined 164 patients with ileostomy in our rehabilitation clinic, 109 patients with colostomy and 193 patients after surgery for gastric cancer of the possible presence of metabolic acidosis by using capillary blood gas analysis (metabolic acidosis was anticipated, if base excess was ≤- 3,0 mmol/l). Patients are treated as inpatients both in early stage and for follow-up rehabilitation. The length of time in our rehabilitation clinic lies in between 24-28 days. On the basis of random samples we tested blood samples in 19 patients with ileostomy in succession for ferritin, folic acid, zinc, selenium and vitamin B12. Statistical analysis comprised the classical intervals (mean and standard deviation, range and T-test for dependent and independent samples)., Results: In total we tested 164 inpatients with ileostomy in our rehabilitation clinic (median age 67.4 years, range 19-79 years). Surgery for ileostomy took place about 1.4 months on average ago (range ¼-56 months). 60 (36.5%) inpatients suffered from metabolic acidosis often combined with renal insufficiency. Supportive therapy intravenously administered in 10 patients and sodium bicarbonate given by mouth in 40 patients significantly improved metabolic acid (base excess improved on average from -7.2 to -3.2 mmol/l, p<0.00138) and renal function calculated on the basis of serum creatinine (serum creatinine decreased from 1.49 on average to 1.34 mg/dl, p<0.04039). Body weight remained constant over the whole period on average with 74 kg. Diuretics did not show any influence on the base excess. In 19 patients with ileostomy who did not take any kind of supplements, among the parameters tested were a high percentage of zinc (9 of 19 patients, 47%) and selenium deficiency (13 of 19 patients, 68%). 50 patients with ileostomy were younger than 65 years of age and thus in the working age population. In the group of patients after gastrectomy because of gastric cancer (n=193, median age 69.1 years, range 36-82 years), surgery for gastrectomy took place about 1.8 months on average ago and in this group only 14 patients (7%) showed metabolic acidosis. In the group of patients with colostomy (n=109, median age 69.5 years, range 39-82 years), surgery for colostomy took place about 2.1 months on average ago and in this group only 6 patients (5.5%) suffered from metabolic acidosis., Conclusion: Medical rehabilitation is indicated for patients with enterostoma. Acceptance of the enterostoma by the patient himself, psychological stabilization, achievement of self-sufficiency in stoma care, improvement of physical abilities and finally being fit for full or limited employment are the most important objectives in rehabilitation medicine. Metabolic acidosis was often found in patients with ileostomy and was an important clinical appearance. Blood gas analysis is recommended to verify metabolic acidosis and if confirmed sodium bicarbonate and in cases of high volume output salt-depleting ileostomy additionally intravenous fluid support should be offered controlling body weight in the follow-up. As could be shown by our analysis patients with ileostomy should also be tested for zinc and selenium deficiency., (© Georg Thieme Verlag KG Stuttgart · New York.)

Patients receiving treatment for acute myelogenous leukemia (AML) and recipients of allogeneic stem cell transplantation (aSCT) are at high risk of contracting Clostridium difficile infection (CDI), the most frequently observed nosocomial diarrhea and enterocolitis. Data were retrieved from the prospective Cologne Cohort of Neutropenic Patients. Patients hospitalized for aSCT as well as patients receiving treatment for AML were included in the analysis. Risk factor analysis for the occurrence of CDI was performed by backward-stepwise logistic regression (P < .1). During the period from January 2007 to August 2010, 310 hospitalizations of 152 patients with AML and 229 hospitalizations of 223 patients undergoing aSCT were eligible for analysis. Incidence rates for CDI per 10,000 patient days were 17.9 for AML patients and 27.4 for aSCT recipients. Among AML and aSCT patients, median time from initiation of chemotherapy to CDI was 10 days (range, -8 to 101 days) and 17 days (range, 6 to 79), respectively. Logistic regression identified carbapenem exposure to be associated with development of CDI in AML patients (odds ratio [OR], 2.2) and aSCT recipients (OR, 1.4). In both groups, previous exposure to carbapenems was significantly associated with development of CDI. A follow-up study, assessing the effect of an antibiotic stewardship intervention to decrease the administration of carbapenems in hematological high-risk patients, is warranted., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)