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Accumulating evidence suggests that metabolic demands of the regenerating liver are met via lipid metabolism and critical regulators of this process. As such, glucagon-like peptide-1 (GLP-1) and glucagon-like peptide-2 (GLP-2) critically affect hepatic regeneration in rodent models. The present study aimed to evaluate potential alterations and dynamics of circulating GLP-1 and GLP-2 in patients undergoing liver resections, focusing on post-hepatectomy liver failure (PHLF). GLP-1, GLP-2, Interleukin-6 (IL-6) and parameters of lipid metabolism were determined perioperatively in fasting plasma of 46 patients, who underwent liver resection. GLP-1 and GLP-2 demonstrated a rapid and consistently inverse time course during hepatic regeneration with a significant decrease of GLP-1 and increase of GLP-2 on POD1. Importantly, these postoperative dynamics were significantly more pronounced when PHLF occurred. Of note, the extent of resection or development of complications were not associated with these alterations. IL-6 mirrored the time course of GLP-2. Assessing the main degradation protein dipeptidyl peptidase 4 (DPP4) no significant association with either GLP-1 or -2 could be found. Additionally, in PHLF distinct postoperative declines in plasma lipid parameters were present and correlated with GLP-2 dynamics. Our data suggest dynamic inverse regulation of GLP-1 and GLP-2 during liver regeneration, rather caused by an increase in expression/release than by changes in degradation capacity and might be associated with inflammatory responses. Their close association with circulating markers of lipid metabolism and insufficient hepatic regeneration after liver surgery suggest a critical involvement during these processes in humans.

Myositis is a rare (<1%) but potentially severe immune‐related adverse event (irAE) of immune checkpoint inhibitors (ICIs), with a 40%–50% fatality rate. Its incidence and pathology in curative, neoadjuvant settings, particularly with chemoradiotherapy (CRT), remain poorly defined. Given the severity, stringent diagnostic and therapeutic approaches may be warranted in curative patients. In the CHINOREC trial, 50 rectal cancer (RC) patients receiving neoadjuvant CRT with ipilimumab (IPI) and nivolumab (NIVO) were prospectively monitored for myotoxicity biomarkers, including creatine kinase (CK) and cardiac troponins (cTnT, cTnI). Patients with CK and cTnT levels above the upper limit normal with or without overt clinical symptoms underwent muscle biopsy and guideline‐adapted treatment (glucocorticoids, immunoglobulin, infliximab, plasma exchange). Six patients (12%) developed biopsy‐confirmed myositis. Elevated cTnT, but not cTnI, distinguished skeletal from cardiac involvement, aligning with normal cardiac magnetic resonance imaging (CMR) findings. Immunohistochemistry showed a predominant CD8+ T cell infiltrate and patchy human leukocyte antigen (HLA) Class I upregulation. Despite myositis, all patients underwent successful tumor resection with normalized CK levels and no residual cardiac dysfunction. ICI‐induced myositis may be more frequent in neoadjuvant‐treated RC patients receiving CRT+ICI than in palliative settings. Comprehensive biomarker monitoring and early T cell‐directed intervention are essential for mitigating life‐threatening irAEs while preserving oncologic outcomes. ICI‐induced myositis occurred at a higher‐than‐expected rate (12%) in neoadjuvant‐treated rectal cancer patients receiving CRT+ICI. Elevated cTnT, but not cTnI, differentiated skeletal from cardiac involvement. Immunopathology showed a predominant CD8+ T cell infiltrate, highlighting a T cell‐mediated mechanism that necessitates early detection and targeted immunomodulation.

Background: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. Methods: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. Results: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06–1.80, p = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00–1.75, p = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31–0.94, p = 0.020). Conclusions: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

Background Gastrointestinal stromal tumors (GISTs) are the main mesenchymal neoplasms in the gastrointestinal tract. Tumor size, mitotic rate, and location correlate with potential malignancy and recurrence rate. Results of surgical treatment of gastric GIST are analyzed with emphasis on recurrence of disease after intermediate follow-up. Methods From 1998 to 2006, a total of 63 patients (median age 62.1 ± 14.1) underwent gastric resection for GIST. Fifty-five patients (93.6%) returned for follow-up investigations, which included computed tomography in 45, gastroscopy in 32, and endosonography in 29. Positron emission tomography was done in five patients. Results Mean tumor size was 5.3 ± 3.8 cm. Open atypical gastric resection was done in 32, distal gastric resection in five, and remnant gastrectomy in four patients. Laparoscopic gastric resection was initiated in 22 patients; the conversion rate was four of 22 (18.2%). Overall, R0 resection was reached in 61/63 patients (96.8%). According to the Fletcher criteria, 33 tumors (52.4%) were classified as intermediate or high risk GIST. Six patients (9.5%) died of unrelated causes before follow-up. After a median follow-up of 2.5 years, overall recurrence rate was 7.0% after R0 resection. Conclusion Histologically proven complete resection is an effective treatment for gastric GIST. Laparoscopic procedures were carried out successfully in selected patients.

In 2007, the ASSO-LM1 trial, a multicenter prospective study, was initiated to investigate the resectability (R0) rate following preoperative combination therapy with XELOX and bevacizumab in patients with potentially resectable colorectal liver metastases. Six cycles of systemic therapy were administered preoperatively, although the sixth cycle did not include bevacizumab, resulting in 5 weeks between the last bevacizumab dose and surgery. Treatment with bevacizumab plus XELOX was restarted for another six cycles postoperatively. In total, 43 patients were enrolled in the ASSO-LM1 trial. Eight patients were ineligible for resection due to protocol violation and progression in two patients. The resectability of operated patients was 97% with 34 R0 resections and one R1 resection. Postoperative morbidity occurred in 22% of patients, of which three operative revisions were related to the primary tumor resection. Efficacy results for response in 38 eligible patients confirmed an ORR of 66%, 31% SD and 3% PD according to RECIST. Preoperative grade 3/4 adverse events were 17% diarrhea, 5% HFS and 5% thromboembolic events. Overall survival significantly differed depending upon the fulfillment of adjuvant treatment in curative resected patients (59.1 mo vs. 30.8 mo). In conclusion, the ASSO-LM1 trial is a hypothesis-generating study confirming the prognostic benefits of perioperative therapy with XELOX and bevacizumab in patients with metastatic colorectal cancer confined to the liver.

Immune checkpoint inhibitors (ICIs) show efficacy in treatment of several solid tumors, but microsatellite-stable rectal cancer is largely resistant. Radiotherapy may enhance tumor immunogenicity and thus may make the combination of radiotherapy and ICIs a promising strategy to treat rectal cancer. While anti-programmed cell death protein 1 antibodies in neoadjuvant regimens have been linked to higher complete response rates, the added benefit of including a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) inhibitor remains unclear. To evaluate the safety and feasibility of combining ipilimumab and nivolumab with neoadjuvant chemoradiotherapy (CRT) for rectal cancer. The CHINOREC trial was a prospective, randomized, open-label, multicenter phase 2 clinical trial conducted from June 2, 2020, to March 15, 2024, across multiple academic and tertiary medical centers in Austria. Analysis was based on intention to treat. Neoadjuvant CRT consisted of 50 Gy in 2-Gy fractions with concurrent capecitabine (1650 mg/m2/d). The experimental arm received additional intravenous ipilimumab (1 mg/kg on day 7) and nivolumab (3 mg/kg every 2 weeks starting on day 14) (CRT plus ipilimumab and nivolumab group). Surgical resection was performed 10 to 12 weeks after CRT. The primary outcome was the safety and feasibility of combining CRT with sequential ipilimumab and nivolumab, assessed by surgical complications and reoperation rates. Secondary outcomes included clinical and pathological response rates. Of the 145 patients assessed, 80 were randomized to receive either CRT alone (CRT group) (n = 30) or to the CRT plus ipilimumab and nivolumab group (n = 50) (49 male [61%]; median age, 60 [range, 36-83] years). Differences in surgical complication rates were not statistically significant between the CRT and CRT plus ipilimumab and nivolumab groups (any grade, 20 of 26 patients [77%] vs 33 of 43 [77%]; P > .99), as were reoperation rates (2 of 26 [8%] vs 3 of 43 [7%]; P > .99). Major pathological response (10 of 26 [38%] vs 16 of 43 [37%]; P > .99) and complete response (9 of 30 [30%] vs 11 of 50 [22%]; P = .44) rates were overall high in both groups. In this randomized clinical trial of patients with rectal cancer, integrating ipilimumab and nivolumab into neoadjuvant CRT was safe and feasible, with no increase in surgical complications. Although complete response rates did not significantly improve, the dual ICI regimen demonstrated promising clinical activity. These findings support further translational research to optimize timing, dosing, and fractionation of radiotherapy and ICI therapy and to guide patient selection. ClinicalTrials.gov Identifier: NCT04124601.

BackgroundMyotoxicities (myositis, myocarditis or rhabdomyolysis) are rare (incidence 0.21%) but potentially life-threatening immune-mediated adverse reactions (IMARs) of immune checkpoint inhibitors (ICI), such as ipilimumab (IPI) or nivolumab (NIVO), with a case fatality rate (CFR) of up to 40%. The true incidence is likely to be underestimated and may not be representative for neoadjuvant treatment approaches in gastrointestinal (GI) cancers, especially in combination with chemoradiotherapy (CRT). Currently the summary of product characteristics (SmPC) does not suggest any pre-emptive screening and surveillance for myotoxicities.MethodsThe CHINOREC study (NCT04124601) is an ongoing prospective, randomized, open-label, multicenter, phase II investigator-initiated trial (IIT). Patients with locally advanced rectal cancer (LARC) receive either neoadjuvant CRT (50 Gy + capecitabine 1650 mg/m2/d PO) alone or in combination with a single dose of IPI 1 mg/kg IV and 3 cycles of NIVO 3 mg/kg IV Q2W, with subsequent surgical resection in a curative intend. Patients are continuously screened at baseline and throughout the whole study period for cardio/myotoxicity biomarkers, such as creatine kinase (CK), creatine kinase muscle-brain (CK-MB), myoglobin (MB), troponin T (TnT) and N-terminal prohormone brain natriuretic peptide (NT-proBNP).ResultsFrom 06/2020-03/2022, 24 patients were randomized to the CRT+IPI/NIVO arm. Out of these, 4 patients (16%) developed a biopsy-proven myositis, of whom 2 (8%) were symptomatic (1 patient with a grade 4 SAE). All patients were promptly initiated with medical interventions in a step-up approach, starting at the first time of elevated cardio/myotoxicity biomarkers (regardless of symptoms). Patients received prednisolone 1-2 mg/kg with concomitant intravenous immunoglobulin (IVIG) 2 g/kg. If myotoxicity biomarkers did not improve, patients received plasma exchange (PLEX) and if further ineffective, infliximab 5 mg/kg IV. To this date all patients have resolved back to normal CK and MB levels. Although all myositis patients had strikingly elevated TnT (median peak 330 ng/L, 95% CI 39-3097) and NT-proBNP levels (median peak 655 pg/mL, 95% CI 507-1161) myocardial involvement/overlap could not be proven by cardiac magnetic resonance imaging (MRI), transthoracic echocardiogram (TTE), electrocardiography (ECG) and/or coronary computed tomography angiography (CTA). However, myocardial biopsies were not performed due to safety concerns.ConclusionsPatients receiving neoadjuvant ICI with CRT should be closely monitored by myotoxicity biomarkers for potentially severe ICI-induced myositis to initiate early counter treatment in a step-up approach. Highly elevated TnT values were observed despite the lack of myocarditis in cardiac diagnostic work-up. As treatment for ICI-induced myositis will concomitantly treat potential cardiotoxicity, myocardial biopsy may be debatable.AcknowledgementsThis is an investigator-initiated trial (IIT), which received a research grant and the study medications from Bristol-Myers Squibb (BMS).Trial RegistrationNCT04124601Ethics ApprovalThe study protocol was verified by the ”Ethics Committee of the Medical University of Vienna” (EC No. 2040/2019).ConsentWritten informed consent was obtained from the patient for publication of this abstract. A copy of the written consent is available for review by the Editor of this journal.

Background Despite significant improvements in perioperative mortality as well as response rates to multimodality treatment, results after surgical resection of pancreatic adenocarcinoma with respect to long-term outcomes remain disappointing. Patient recruitment for prospective international trials on adjuvant and neoadjuvant regimens is challenging for various reasons. We set out to assess the preconditions and potential to perform perioperative trials for pancreatic cancer within a well-established Austrian nationwide network of surgical and medical oncologists (Austrian Breast & Colorectal Cancer Study Group). Methods From 2005 to 2010 five high-volume centers and one medium-volume center completed standardized data entry forms with 33 parameters (history and patient related data, preoperative clinical staging and work-up, surgical details and intraoperative findings, postoperative complications, reinterventions, reoperations, 30-day mortality, histology, and timing of multimodality treatment). Outside of the study group, in Austria pancreatic resections are performed in three “high-volume” centers (>10 pancreatic resections per year), three “medium-volume” centers (5–10 pancreatic resections per year), and the rest in various low-volume centers (<5 pancreatic resections per year) in Austria. Nationwide data for prevalence of and surgical resections for pancreatic adenocarcinoma were contributed by the National Cancer Registry of Statistics of Austria and the Austrian Health Institute. Results In total, 492 consecutive patients underwent pancreatic resection for ductal adenocarcinoma. All postoperative complications leading to hospital readmission were treated at the primary surgical department and documented in the database. Overall morbidity and pancreatic fistula rate were 45.5 % and 10.1 %, respectively. Within the entire cohort there were 9.8 % radiological reinterventions and 10.4 % reoperations. Length of stay was 16 days in median (0–209); 12 of 492 patients died within 30 days after operation, resulting in a 30-day mortality rate of 2.4 %. Seven of the total 19 deaths (36.8 %) occurred after 30 days, during hospitalization at the surgical department, resulting in a hospital mortality rate of 3.9 % (19/492). With a standardized histopathological protocol, there were 70 % (21/30) R0 resections, 30 % (9/30) R1 resections, and no R2 resections in Vienna and 62.7 % (32/51) R0 resections, 35.3 % (18/51) R1 resections, and 2 % (1/51) R2 resections in Salzburg. Resection margin status with nonstandardized protocols was classified as R0 in 82 % (339/411), R1 in 16 % (16/411), and R2 in 1.2 % (5/411). Perioperative chemotherapy was administered in 81.1 % of patients (8.3 % neoadjuvant; 68.5 % adjuvant; 4.3 % palliative); chemoradiotherapy (1.6 % neoadjuvant; 3 % adjuvant; 0.2 % palliative), in 4.9 % of patients. The six centers that contributed to this registry initiative provided surgical treatment to 40 % of all Austrian patients, resulting in a median annual recruitment of 85 (51–104) patients for the entire ABCSG-group and a median of 11.8 (0–38) surgeries for each individual department. Conclusions Surgical quality data of the ABCSG core pancreatic group are in line with international standards. With continuing centralization the essential potential to perform prospective clinical trials for pancreatic adenocarcinoma is given in Austria. Several protocol proposals aiming at surgical and multimodality research questions are currently being discussed.

Background: The pretreatment De Ritis ratio [aspartate transaminase (AST)/alanine transaminase (ALT)] has been shown to be an adverse prognostic marker in various cancer entities. However, its relevance to advanced pancreatic ductal adenocarcinoma (PDAC) has not yet been studied. In the present study we investigated the AST/ALT ratio as a possible predictor of treatment response and disease outcome in patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel. Methods: A post hoc analysis of a prospective, multicenter, noninterventional study was performed. A total of 202 patients with advanced PDAC treated with first-line gemcitabine/nab-paclitaxel for whom the AST/ALT ratio was measured were included in this analysis. Results: Median and 1-year progression-free survival estimates were 4.8 months and 5.1%, respectively in patients with an AST/ALT ratio above the 75th percentile of its distribution, and 6.0 months and 18.7%, respectively in patients with an AST/ALT ratio less than or equal to this cutoff, respectively (log-rank p  = 0.004). In univariable Cox regression, a doubling of the AST/ALT ratio was associated with a 1.4-fold higher relative risk of progression or death [hazard ratio = 1.38, 95% confidence interval (CI): 1.06–1.80, p  = 0.017]. The prognostic association was also found in multivariable analysis adjusting for Eastern Cooperative Oncology Group performance status and lung metastases (hazard ratio per AST/ALT ratio doubling = 1.32, 95% CI: 1.00–1.75, p  = 0.047). In treatment response analysis, a doubling of the AST/ALT ratio was associated with a 0.5-fold lower odds of objective response (odds ratio = 0.54, 95% CI: 0.31–0.94, p  = 0.020). Conclusions: The pretreatment serum AST/ALT ratio predicts poor disease outcome and response rate in patients with advanced PDAC treated with gemcitabine/nab-paclitaxel and might represent a novel and inexpensive marker for individual risk assessment in the treatment of pancreatic cancer.

Objective ‘Fast-track' rehabilitation is able to accelerate recovery, reduce general morbidity, and decrease hospital stay. This is widely accepted for colonic resections. Despite recent evidence that fast track concepts are safe and feasible in rectal resection, there is no information on the acceptance and utilization of these concepts among Austrian and German surgeons. Method A questionnaire concerning perioperative routines in elective, open rectal resection was sent to the chief surgeons of 1,270 German and 120 Austrian surgical centers. Results The response rate was 63% in Austria (76 centers) and 30% in Germany (385 centers). Mechanical bowel preparation is only abandoned by 2% of the Germany and 7% of the Austrian surgeons. Nasogastric decompression tubes are rarely used; four of five of the questioned surgeons in both countries use intra-abdominal drains. Half of the surgical centers allow the intake of clear fluids on the day of surgery. Mobilization starts in half of the centers on the day of surgery. Epidural analgesia is used in three-fourths of the institutions. Institutions which have implemented fast track rehabilitation for rectal resections discharge the patients earlier then hospitals that adhere to traditional care. Conclusion In many perioperative procedures, Austrian and German Surgeons rely on their traditional approaches. Recent evidence-based adaptations of perioperative routines in rectal resections are only slowly introduced into daily routine; therefore, further efforts have to be done to optimizing patients' care.