Publications by authors named "Martin Schneider"

297 Publications

Targeted Plasma Metabolic Profiles and Risk of Recurrence in Stage II and III Colorectal Cancer Patients: Results from an International Cohort Consortium.

Metabolites 2021 Feb 24;11(3). Epub 2021 Feb 24.

Huntsman Cancer Institute Salt Lake City, Salt Lake City, UT 84112, USA.

The identification of patients at high-risk for colorectal cancer (CRC) recurrence remains an unmet clinical need. The aim of this study was to investigate associations of metabolites with risk of recurrence in stage II/III CRC patients. A targeted metabolomics assay (128 metabolites measured) was performed on pre-surgery collected EDTA plasma samples from n = 440 newly diagnosed stage II/III CRC patients. Patients have been recruited from four prospective cohort studies as part of an international consortium: Metabolomic profiles throughout the continuum of CRC (MetaboCCC). Cox proportional hazard models were computed to investigate associations of metabolites with recurrence, adjusted for age, sex, tumor stage, tumor site, body mass index, and cohort; false discovery rate (FDR) was used to account for multiple testing. Sixty-nine patients (15%) had a recurrence after a median follow-up time of 20 months. We identified 13 metabolites that were nominally associated with a reduced risk of recurrence. None of the associations were statistically significant after controlling for multiple testing. Pathway topology analyses did not reveal statistically significant associations between recurrence and alterations in metabolic pathways (e.g., sphingolipid metabolism = 0.04; p = 1.00). To conclude, we did not observe statistically significant associations between metabolites and CRC recurrence using a well-established metabolomics assay. The observed results require follow-up in larger studies.
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http://dx.doi.org/10.3390/metabo11030129DOI Listing
February 2021

Circulating B-vitamin biomarkers and B-vitamin supplement use in relation to quality of life in patients with colorectal cancer: results from the FOCUS consortium.

Am J Clin Nutr 2021 Mar 1. Epub 2021 Mar 1.

Department of Epidemiology, GROW School for Oncology and Developmental Biology, Maastricht University, Maastricht, The Netherlands.

Background: B vitamins have been associated with the risk and progression of colorectal cancer (CRC), given their central roles in nucleotide synthesis and methylation, yet their association with quality of life in established CRC is unclear.

Objectives: To investigate whether quality of life 6 months postdiagnosis is associated with: 1) circulating concentrations of B vitamins and related biomarkers 6 months postdiagnosis; 2) changes in these concentrations between diagnosis and 6 months postdiagnosis; 3) B-vitamin supplement use 6 months postdiagnosis; and 4) changes in B-vitamin supplement use between diagnosis and 6 months postdiagnosis.

Methods: We included 1676 newly diagnosed stage I-III CRC patients from 3 prospective European cohorts. Circulating concentrations of 9 biomarkers related to the B vitamins folate, riboflavin, vitamin B6, and cobalamin were measured at diagnosis and 6 months postdiagnosis. Information on dietary supplement use was collected at both time points. Health-related quality of life (global quality of life, functioning scales, and fatigue) was assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 6 months postdiagnosis. Confounder-adjusted linear regression analyses were performed, adjusted for multiple testing.

Results: Higher pyridoxal 5'-phosphate (PLP) was cross-sectionally associated with better physical, role, and social functioning, as well as reduced fatigue, 6 months postdiagnosis. Associations were observed for a doubling in the hydroxykynurenine ratio [3-hydroxykynurenine: (kynurenic acid + xanthurenic acid + 3-hydroxyanthranilic acid + anthranilic acid); an inverse marker of vitamin B6] and both reduced global quality of life (β = -3.62; 95% CI: -5.88, -1.36) and worse physical functioning (β = -5.01; 95% CI: -7.09, -2.94). Dose-response relations were observed for PLP and quality of life. No associations were observed for changes in biomarker concentrations between diagnosis and 6 months. Participants who stopped using B-vitamin supplements after diagnosis reported higher fatigue than nonusers.

Conclusions: Higher vitamin B6 status was associated with better quality of life, yet limited associations were observed for the use of B-vitamin supplements. Vitamin B6 needs further study to clarify its role in relation to quality of life.
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http://dx.doi.org/10.1093/ajcn/nqaa422DOI Listing
March 2021

Uptake Rates of Novel Therapies and Survival Among Privately Insured Versus Publicly Insured Patients With Colorectal Cancer in Germany.

J Natl Compr Canc Netw 2021 Feb 12:1-10. Epub 2021 Feb 12.

1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg.

Background: In the era of personalized medicine, cancer care is subject to major changes and innovations. It is unclear, however, to what extent implementation of such innovations and their impact on patient outcomes differ by health insurance type. This study compared provision of treatment and survival outcomes among patients with colorectal cancer (CRC) who had statutory health insurance (SHI) versus private health insurance (PHI) in Germany.

Methods: We analyzed patterns of CRC treatment (surgery, chemotherapy/radiotherapy, and targeted therapy) and survival in a large cohort of patients who were diagnosed with CRC in 2003 through 2014 and were observed for an average of 6 years. Associations of type of health insurance with treatment administration and with overall, CRC-specific, and recurrence-free survival were investigated using multivariable logistic and Cox proportional hazards models, respectively.

Results: Of 3,977 patients with CRC, 427 (11%) had PHI. Although type of health insurance was not associated with treatment administration in patients with stage I-III disease, those with stage IV disease with PHI more often received targeted therapy (65% vs 40%; odds ratio, 2.43; 95% CI, 1.20-4.91), with differences decreasing over time because of catch-up of uptake rates in patients with SHI. Median overall survival was longer in patients with PHI than in those with SHI (137.0 vs 114.9 months; P=.010), but survival advantages were explained to a large extent by differences in sociodemographic factors. In patients with stage IV disease, survival advantages of PHI were nonsignificant and were restricted to the early years after diagnosis.

Conclusions: We observed major differences in uptake of targeted therapy between patients with PHI and those with SHI but no differences in patient survival after adjusting for relevant sociodemographic, clinical, and tumor characteristics. Further studies are needed on factors associated with the uptake of therapeutic innovations and their impact on patient survival by health insurance type.
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http://dx.doi.org/10.6004/jnccn.2020.7636DOI Listing
February 2021

Postoperative acute pancreatitis is a serious but rare complication after distal pancreatectomy.

HPB (Oxford) 2021 Jan 13. Epub 2021 Jan 13.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: The clinical relevance of hyperamylasemia after distal pancreatectomy (DP) remains unclear and no internationally accepted definition of postoperative acute pancreatitis (POAP) exists. The aim of this study was to characterize POAP after DP and to assess the role of serum amylase (SA) in POAP.

Methods: Outcomes of 641 patients who had undergone DP between 2015 and 2019 were analyzed. Postoperative SA was determined in all patients. POAP was defined based on contrast-enhanced computed tomography (CT) or intraoperative findings during relaparotomy.

Results: An elevation of SA on postoperative day 1 (hyperamylasemia) was found in 398 patients (62.1%). Twelve patients (1.87%) were identified with POAP. Ten patients demonstrated radiologic criteria for POAP and in two patients POAP was diagnosed during relaparotomy. Outcome of POAP patients was worse than that of patients with hyperamylasemia alone and that with normal SA without POAP evidence (postoperative pancreatic fistula 50% vs 30.6% vs 18.5%; length of hospital stay 26 days vs 12 vs 11, respectively). The overall 90-day mortality of all 641 patients was 0.6%.

Conclusion: POAP is a serious but rare complication after DP. Hyperamylasemia is of prognostic relevance after DP, but it seems not sufficient as a single parameter to diagnose POAP.
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http://dx.doi.org/10.1016/j.hpb.2021.01.004DOI Listing
January 2021

Standard of Care and Outcomes of Primary Laparotomy Versus Laparotomy in Patients with Prior Open Abdominal Surgery (ReLap Study; DRKS00013001).

J Gastrointest Surg 2021 Jan 28. Epub 2021 Jan 28.

The Study Center of the German Surgical Society (SDGC), University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Patients undergoing relaparotomy are generally underrepresented in trials, despite how common the procedure is in clinical practice. The aim of this trial was to determine standard of care and gain evidence of intra- and postoperative outcomes for patients undergoing relaparotomy compared to primary laparotomy.

Methods: In this single-center controlled clinical trial, adult patients scheduled for elective abdominal surgery via relaparotomy or primary laparotomy were consecutively screened for eligibility. The perioperative course was monitored prospectively in five study visits during hospital stay and one study visit 1 year after surgery. Intraoperative standards, short and long-term outcomes were statistically explored at a level of significance of 5%.

Results: A total of 131 patients with relaparotomy and 50 patients with primary laparotomy were analyzed. In the relaparotomy group, the access to the abdomen took longer (23.5 min vs. 8.8 min; p = < 0.001) and the peritoneal adhesion index was higher (10.8 vs. 0.4; p = < 0.001). Inadvertent enterotomies were more frequent in the relaparotomy group (relaparotomy 0.3 versus primary laparotomy: 0.0; p = 0.002). The overall comprehensive complication index and rates of surgical site infection and wound dehiscence with evisceration were not different between the two groups. At long-term follow-up, rates of incisional hernia did not differ (relaparotomy: n = 12/104 (11.5%); primary laparotomy: n = 7/35 (20.0%); p = 0.208).

Discussion: In this first prospective comparison of relaparotomy with primary laparotomy, inadvertent enterotomies were more frequent in the relaparotomy group. However, contrary to previous retrospective studies, the risk of complications and incisional hernias was not increased compared to primary laparotomy.

Trial Registration: Deutsches Register Klinischer Studien ( www.germanctr.de ): DRKS00013001.
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http://dx.doi.org/10.1007/s11605-020-04904-zDOI Listing
January 2021

Not all Whipple procedures are equal: Proposal for a classification of pancreatoduodenectomies.

Surgery 2020 Dec 29. Epub 2020 Dec 29.

Department of General, Visceral, and Transplantation Surgery, Heidelberg University Hospital, Germany. Electronic address:

Background: Pancreatoduodenectomy is the standard treatment for pathologies of the pancreatic head and is performed routinely worldwide. The aim of the study was to analyze this procedure in terms of extent of surgery, technical difficulty, and clinical outcomes and thereby provide a standardized surgical categorization of pancreatoduodenectomies for future reference.

Methods: For this cohort study, all patients who underwent pancreatoduodenectomy at a single center within an 18-year period (October 2001 to December 2019) were identified in a prospectively maintained database. Based on technical difficulty and extent of surgery, 4 pancreatoduodenectomy types were proposed: (1) standard pancreatoduodenectomy; (2) pancreatoduodenectomy with portal vein/superior mesenteric vein resection; (3) pancreatoduodenectomy with multivisceral resection; and (4) pancreatoduodenectomy with arterial resection. Patient characteristics, surgical parameters, and perioperative morbidity and mortality were analyzed. The 4 types were compared with regard to their surgical outcomes.

Results: A total of 3,953 pancreatoduodenectomies were performed in the study period. Standard pancreatoduodenectomy (type 1) was the most frequent procedure (n = 2,931, 74.1%), followed by pancreatoduodenectomy with portal vein/superior mesenteric vein resection (type 2: n = 568, 14.4%), pancreatoduodenectomy with multivisceral resection (type 3: n = 415, 10.5%), and pancreatoduodenectomy with arterial resection (type 4: n = 39, 1.0%). Demographic baseline characteristics were clinically comparable among pancreatoduodenectomy types. Mortality within 90-days correlated with the type of pancreatoduodenectomy (type 1: 2.9%; type 2: 4.2%; type 3: 6.3%; type 4: 10.3%; P = .0007). Overall surgical morbidity was 41.7% (type 1), 40.8% (type 2), 52.5% (type 3), and 59.0% (type 4) (P < .0001), including postoperative pancreatic fistula type B/C (type 1: 11.9%; type 2: 7.7%; type 3: 14.7%; type 4: 15.4; P = .0031) and delayed gastric emptying (type 1: 19.4%; type 2: 22.5%; type 3: 22.0%; type 4: 25.6%; P = .187) as the most frequent complications. Relaparotomies were more frequent in type 4 (20.5%) and type 3 (20.6%) than in type 2 (12.0%) or type 1 (10.4%) pancreatoduodenectomy (P < .0001). Intensive care unit stay ≥2 days was more frequent in type 4 (48.7%) compared with type 3 (25.7%) or type 2 (27.1%) and type 1 (18.6%) (P < .0001).

Conclusion: The results show different clinical outcomes for the 4 types of pancreatoduodenectomy. Morbidity and mortality correlate with pancreatoduodenectomy type. The proposed pancreatoduodenectomy classification is useful for reporting pancreatoduodenectomy procedures, enhances the comparability of future studies, may be used for training purposes, and may guide intra and postoperative decision-making.
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http://dx.doi.org/10.1016/j.surg.2020.11.030DOI Listing
December 2020

High Time Resolution Analysis of Voltage-Dependent and Voltage-Independent Calcium Sparks in Frog Skeletal Muscle Fibers.

Front Physiol 2020 15;11:599822. Epub 2020 Dec 15.

Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary.

In amphibian skeletal muscle calcium (Ca) sparks occur both as voltage-dependent and voltage-independent ligand-activated release events. However, whether their properties and their origin show similarities are still in debate. Elevated K, constant Cl content solutions were used to initiate small depolarizations of the resting membrane potential to activate dihydropyridine receptors (DHPR) and caffeine to open ryanodine receptors (RyR) on intact fibers. The properties of Ca sparks observed under control conditions were compared to those measured on depolarized cells and those after caffeine treatment. Calcium sparks were recorded on intact frog skeletal muscle fibers using high time resolution confocal microscopy (x-y scan: 30 Hz). Sparks were elicited by 1 mmol/l caffeine or subthreshold depolarization to different membrane potentials. Both treatments increased the frequency of sparks and altered their morphology. Images were analyzed by custom-made computer programs. Both the amplitude (in ΔF/F; 0.259 ± 0.001 vs. 0.164 ± 0.001; = 24942 and 43326, respectively; mean ± SE, < 0.001) and the full width at half maximum (FWHM, in μm; parallel with fiber axis: 2.34 ± 0.01 vs. 1.92 ± 0.01, < 0.001; perpendicular to fiber axis: 2.08 ± 0.01 vs. 1.68 ± 0.01, < 0.001) of sparks was significantly greater after caffeine treatment than on depolarized cells. 9.8% of the sparks detected on depolarized fibers and about one third of the caffeine activated sparks (29.7%) overlapped with another one on the previous frame on x-y scans. Centre of overlapping sparks travelled significantly longer distances between consecutive frames after caffeine treatment then after depolarization (in μm; 1.66 ± 0.01 vs. 0.95 ± 0.01, < 0.001). Our results suggest that the two types of ryanodine receptors, the junctional RyRs controlled by DHPRs and the parajunctional RyRs are activated independently, using alternate ways, with the possibility of cooperation between neighboring release channels.
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http://dx.doi.org/10.3389/fphys.2020.599822DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769825PMC
December 2020

Impact of acute kidney injury after extended liver resections.

HPB (Oxford) 2020 Nov 12. Epub 2020 Nov 12.

Department of Surgery, Division of Hepatobiliary and Pancreatic Surgery, Asklepios Hospital Barmbek, Germany; Semmelweis University of Medicine, Asklepios Campus Hamburg, Hamburg, Germany.

Background: Complex liver resection is a risk factor for the development of AKI, which is associated with increased morbidity and mortality. Aim of this study was to assess risk factors for acute kidney injury (AKI) and its impact on outcome for patients undergoing complex liver surgery.

Methods: AKI was defined according to the KDIGO criteria. Primary endpoint was the occurrence of AKI after liver resection. Secondary endpoints were complications and mortality.

Results: Overall, 146 patients undergoing extended liver resection were included in the study. The incidence of AKI was 21%. The incidence of chronic kidney disease (CKD) and hepatocellular carcinoma were significantly higher in patients with AKI. In the AKI group, the proportion of extended right hepatectomies was the highest (53%), followed by ALPPS (43%). Increased intraoperative blood loss, increased postoperative complications and perioperative mortality was associated with AKI. Besides age and CKD, ALPPS was an independent risk factor for postoperative AKI. A small future liver remnant seemed to increase the risk of AKI in patients undergoing ALPPS.

Conclusion: Following extended liver resection, AKI is associated with an increased morbidity and mortality. ALPPS is a major independent risk factor for the development of AKI and a sufficient future liver remnant could avoid postoperative AKI.
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http://dx.doi.org/10.1016/j.hpb.2020.10.015DOI Listing
November 2020

Genotype-Based Gene Expression in Colon Tissue-Prediction Accuracy and Relationship with the Prognosis of Colorectal Cancer Patients.

Int J Mol Sci 2020 Oct 31;21(21). Epub 2020 Oct 31.

Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Im Neuenheimer Feld 460, 69120 Heidelberg, Germany.

Colorectal cancer (CRC) survival has environmental and inherited components. The expression of specific genes can be inferred based on individual genotypes-so called expression quantitative trait loci. In this study, we used the PrediXcan method to predict gene expression in normal colon tissue using individual genotype data from 91 CRC patients and examined the correlation ρ between predicted and measured gene expression levels. Out of 5434 predicted genes, 58% showed a negative ρ value and only 16% presented a ρ higher than 0.10. We subsequently investigated the association between genotype-based gene expression in colon tissue for genes with ρ > 0.10 and survival of 4436 CRC patients. We identified an inverse association between the predicted expression of and CRC-specific survival for patients with a body mass index greater than or equal to 30 kg/m (HR (hazard ratio) = 0.66 for an expression higher vs. lower than the median, = 0.005). This association was validated using genotype and clinical data from the UK Biobank (HR = 0.74, = 0.04). In addition to the identification of expression in normal colon tissue as a candidate prognostic biomarker for obese CRC patients, our study illustrates the challenges of genotype-based prediction of gene expression, and the advantage of reassessing the prediction accuracy in a subset of the study population using measured gene expression data.
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http://dx.doi.org/10.3390/ijms21218150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7662650PMC
October 2020

Circulating Folate and Folic Acid Concentrations: Associations With Colorectal Cancer Recurrence and Survival.

JNCI Cancer Spectr 2020 Oct 7;4(5):pkaa051. Epub 2020 Jul 7.

Division of Human Nutrition and Health, Wageningen University & Research, Wageningen, the Netherlands.

Background: Folates, including folic acid, may play a dual role in colorectal cancer development. Folate is suggested to be protective in early carcinogenesis but could accelerate growth of premalignant lesions or micrometastases. Whether circulating concentrations of folate and folic acid, measured around time of diagnosis, are associated with recurrence and survival in colorectal cancer patients is largely unknown.

Methods: Circulating concentrations of folate, folic acid, and folate catabolites p-aminobenzoylglutamate and p-acetamidobenzoylglutamate were measured by liquid chromatography-tandem mass spectrometry at diagnosis in 2024 stage I-III colorectal cancer patients from European and US patient cohort studies. Multivariable-adjusted Cox proportional hazard models were used to assess associations between folate, folic acid, and folate catabolites concentrations with recurrence, overall survival, and disease-free survival.

Results: No statistically significant associations were observed between folate, p-aminobenzoylglutamate, and p-acetamidobenzoylglutamate concentrations and recurrence, overall survival, and disease-free survival, with hazard ratios ranging from 0.92 to 1.16. The detection of folic acid in the circulation (yes or no) was not associated with any outcome. However, among patients with detectable folic acid concentrations (n = 296), a higher risk of recurrence was observed for each twofold increase in folic acid (hazard ratio = 1.31, 95% confidence interval = 1.02 to 1.58). No statistically significant associations were found between folic acid concentrations and overall and disease-free survival.

Conclusions: Circulating folate and folate catabolite concentrations at colorectal cancer diagnosis were not associated with recurrence and survival. However, caution is warranted for high blood concentrations of folic acid because they may increase the risk of colorectal cancer recurrence.
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http://dx.doi.org/10.1093/jncics/pkaa051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583160PMC
October 2020

Identification of BCL-XL as highly active survival factor and promising therapeutic target in colorectal cancer.

Cell Death Dis 2020 10 17;11(10):875. Epub 2020 Oct 17.

Department of Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, 69120, Heidelberg, Germany.

Since metastatic colorectal cancer (CRC) is a leading cause of cancer-related death, therapeutic approaches overcoming primary and acquired therapy resistance are an urgent medical need. In this study, the efficacy and toxicity of high-affinity inhibitors targeting antiapoptotic BCL-2 proteins (BCL-2, BCL-XL, and MCL-1) were evaluated. By RNA sequencing analysis of a pan-cancer cohort comprising >1500 patients and subsequent prediction of protein activity, BCL-XL was identified as the only antiapoptotic BCL-2 protein that is overactivated in CRC. Consistently, pharmacologic and genetic inhibition of BCL-XL induced apoptosis in human CRC cell lines. In a combined treatment approach, targeting BCL-XL augmented the efficacy of chemotherapy in vitro, in a murine CRC model, and in human ex vivo derived CRC tissue cultures. Collectively, these data show that targeting of BCL-XL is efficient and safe in preclinical CRC models, observations that pave the way for clinical translation.
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http://dx.doi.org/10.1038/s41419-020-03092-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7568722PMC
October 2020

Ghost ileostomy versus conventional loop ileostomy in patients undergoing low anterior resection for rectal cancer (DRKS00013997): protocol for a randomised controlled trial.

BMJ Open 2020 10 15;10(10):e038930. Epub 2020 Oct 15.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Introduction: Anastomotic leakage is the most important complication in colorectal surgery occurring in up to 20% after low anterior rectal resection. Therefore, a diverting ileostomy is usually created during low anterior resection to protect the anastomosis or rather to diminish the consequences in case of anastomotic leakage. The so-called virtual or ghost ileostomy is a pre-stage ostomy that can be easily exteriorised, if anastomotic leakage is suspected, in order to avoid the severe consequences of anastomotic leakage. On the other hand, an actual ileostomy can be avoided in patients, who do not develop anastomotic leakage.

Methods And Analysis: The GHOST trial is a randomised controlled pilot trial comparing ghost ileostomy with conventional loop ileostomy in patients undergoing low anterior resection with total mesorectal excision for rectal cancer. After screening for eligibility and obtaining informed consent, a total of 60 adult patients are included in the trial. Patients are intraoperatively randomised to the trial groups in a 1:1 ratio after assuring that none of the intraoperative exclusion criteria are present. The main outcome parameter is the comprehensive complication index as a measure of safety. Further outcomes include specific complications, stoma-related complications, complications of ileostomy closure, frequency of transformation of ghost ileostomy into conventional ileostomy, frequency of terminal ostomy creation, proportion of patients with an ostomy at 6 months after index surgery, anorectal function (Wexner score) and quality of life assessed by the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and CR29 questionnaires. Follow-up for each individual patient will be 6 months.

Ethics And Dissemination: The GHOST trial has been approved by the Medical Ethics Committee of Heidelberg University (reference number S-694/2017). If the intervention proves to be safe, loop ileostomy could be spared in a large proportion of patients, thus also avoiding stoma-related complications and a second operation (ileostomy closure) with its inherent complications in these patients.

Trial Registration Number: German Clinical Trials Registry (DRKS00013997); Universal Trial Number: U1111-1208-9742.
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http://dx.doi.org/10.1136/bmjopen-2020-038930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7566726PMC
October 2020

Arterial Resection in Pancreatic Cancer Surgery: Effective After a Learning Curve.

Ann Surg 2020 Jun 12. Epub 2020 Jun 12.

*Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany †Institute for Medical Biometry and Informatics, Heidelberg University, Heidelberg, Germany.

Objective: To investigate the perioperative and oncologic long-term outcomes of patients with LAPC after surgical resection at a high-volume center for pancreatic surgery.

Background: The role of surgery in LAPC with arterial involvement is controversial.

Methods: We analyzed 385 consecutive patients undergoing PAR (n = 195) or PAD (n = 190) of the encased artery for LAPC between January 1, 2003 and April 30, 2019.

Results: There were 183 total pancreatectomies, 113 partial pancreatoduodenectomies, 79 distal pancreatectomies, and 10 resections for tumor recurrences, including 121 multivisceral resections and 171 venous resections. Forty-three patients (11.4%) had resectable oligometastatic disease. All of the 190 patients undergoing PAD (100%) and 95 of the 195 patients undergoing PAR (48.7%) received neoadjuvant chemotherapy. The R0 (circumferential resection margin negative) resection rate was 28%. The median hospital stay was 15 days (range: 3-236). The median survival after surgery for LAPC was 20.1 months and the overall 5-year survival rate 12.5%. In-hospital mortality was 8.8% for the entire patient cohort (n = 385). With increasing case load and growing expertise, there was a significant reduction of in-hospital mortality to 4.8% (n = 186) after 2013 (P = 0.005). The learning curve of experienced pancreatic surgeons for PAR was 15 such procedures.

Conclusion: Our data demonstrate that an arterial surgical approach is effective in LAPC with promising long-term survival. PAD after neoadjuvant treatment is safe. PAR is a technically demanding procedure and requires a high level of expertise.
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http://dx.doi.org/10.1097/SLA.0000000000004054DOI Listing
June 2020

Periarterial divestment in pancreatic cancer surgery.

Surgery 2020 Oct 5. Epub 2020 Oct 5.

Department of General, Visceral, and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address:

Background: Modern pancreatic cancer surgery changed with the introduction of effective neoadjuvant therapies. Complete tumor resection is the mainstay for long-term, disease-free, and overall survival and has been a prerequisite for decreasing local recurrence. The medial resection margin in the area of the superior mesenteric vessels limits the radicalness of the resection, especially in borderline and locally advanced cases. Therefore, the periarterial soft tissue around the peripancreatic visceral arteries must be completely cleared. This procedure, namely periarterial divestment, is technically demanding but often represents an alternative to arterial resection.

Objective: Here we describe the technique and our initial experience with periarterial divestment along the peripancreatic visceral arteries during pancreatic surgery. This technique, in combination with previously published resection strategies, such as artery first maneuver and mesenterico-portal venous bypass first, enables tumor resection in locally advanced pancreatic cancer.

Conclusion: Periarterial divestment can prevent the need for arterial resection in borderline and locally advanced pancreatic cancer, especially after neoadjuvant therapy. The feasibility, improved safety, and oncologic equivalence of arterial divestment versus arterial resection for pancreatic cancer surgery must be evaluated by clinical trials.
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http://dx.doi.org/10.1016/j.surg.2020.08.030DOI Listing
October 2020

Mechanoactivation of NOX2-generated ROS elicits persistent TRPM8 Ca signals that are inhibited by oncogenic KRas.

Proc Natl Acad Sci U S A 2020 10 5;117(42):26008-26019. Epub 2020 Oct 5.

Department of Pharmacology, School of Medicine, University of Maryland, Baltimore, MD 21201;

Changes in the mechanical microenvironment and mechanical signals are observed during tumor progression, malignant transformation, and metastasis. In this context, understanding the molecular details of mechanotransduction signaling may provide unique therapeutic targets. Here, we report that normal breast epithelial cells are mechanically sensitive, responding to transient mechanical stimuli through a two-part calcium signaling mechanism. We observed an immediate, robust rise in intracellular calcium (within seconds) followed by a persistent extracellular calcium influx (up to 30 min). This persistent calcium was sustained via microtubule-dependent mechanoactivation of NADPH oxidase 2 (NOX2)-generated reactive oxygen species (ROS), which acted on transient receptor potential cation channel subfamily M member 8 (TRPM8) channels to prolong calcium signaling. In contrast, the introduction of a constitutively active oncogenic KRas mutation inhibited the magnitude of initial calcium signaling and severely blunted persistent calcium influx. The identification that oncogenic KRas suppresses mechanically-induced calcium at the level of ROS provides a mechanism for how KRas could alter cell responses to tumor microenvironment mechanics and may reveal chemotherapeutic targets for cancer. Moreover, we find that expression changes in both NOX2 and TRPM8 mRNA predict poor clinical outcome in estrogen receptor (ER)-negative breast cancer patients, a population with limited available treatment options. The clinical and mechanistic data demonstrating disruption of this mechanically-activated calcium pathway in breast cancer patients and by KRas activation reveal signaling alterations that could influence cancer cell responses to the tumor mechanical microenvironment and impact patient survival.
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http://dx.doi.org/10.1073/pnas.2009495117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584994PMC
October 2020

Hyperamylasemia and acute pancreatitis after pancreatoduodenectomy: Two different entities.

Surgery 2021 Feb 25;169(2):369-376. Epub 2020 Sep 25.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Background: Serum amylase activity greater than the institutional upper limit of normal (hyperamylasemia) on postoperative day 0-2 has been suggested as a criterion to define postoperative acute pancreatitis after pancreatoduodenectomy, but robust evidence supporting this definition is lacking.

Background: To assess the clinical impact of hyperamylasemia after pancreatoduodenectomy and to define postoperative acute pancreatitis.

Methods: Data of 1,235 consecutive patients who had undergone pancreatoduodenectomy between January 2010 and December 2014 were extracted from a prospective database and analyzed. Postoperative acute pancreatitis was defined based on the computed tomography severity index. Logistic regression modeling was used to calculate the postoperative acute pancreatitis rate of the entire study population.

Results: Hyperamylasemia on postoperative day 1 was found in 52% of patients after pancreatoduodenectomy. Patients with hyperamylasemia on postoperative day 1 had statistically significantly greater morbidity and mortality than patients with a normal serum amylase activity on postoperative day 1 with the rates of postoperative pancreatic fistula of 14.5% vs 2.1%, and 90-day mortality of 6.6% vs 2.2%, respectively. Of the 364 patients who underwent postoperative computed tomography, 103 (28%) had radiologic signs of acute pancreatitis, thus defining them as having postoperative acute pancreatitis by our definition. Logistic regression modeling showed a 14.7% rate of postoperative acute pancreatitis for the entire patient cohort and 29.2% for patients with hyperamylasemia on postoperative day 1. Outcomes of patients with postoperative acute pancreatitis defined based on the computed tomography severity index showed a rate of postoperative pancreatic fistula of 32.4% and a 90-day mortality rate of 11.8%, which were worse than those of patients with hyperamylasemia on postoperative day 1 alone.

Conclusion: Hyperamylasemia on postoperative day 1 is a frequent finding after pancreatoduodenectomy, but hyperamylasemia on postoperative day 1 alone is not synonymous with postoperative acute pancreatitis because only 29.2% of such patients have acute pancreatitis based on computed tomography findings. Postoperative acute pancreatitis is a dangerous complication after pancreatoduodenectomy, but its prevalence, according to the gold standard of CT, is not as high as reported previously. Our data suggest that hyperamylasemia on postoperative day 1 and postoperative acute pancreatitis are 2 different entities.
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http://dx.doi.org/10.1016/j.surg.2020.07.050DOI Listing
February 2021

Does Side Really Matter? Survival Analysis among Patients with Right- Versus Left-Sided Colon Cancer: A Propensity Score-Adjusted Analysis.

Ann Surg Oncol 2020 Sep 21. Epub 2020 Sep 21.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany.

Background: Right- and left-sided colon cancer are increasingly regarded as two independent disease entities based on different gene expression profiles as well as underlying genetic mutations. Data regarding prognosis and survival are heterogeneous and more favorable in cases of left-sided colon cancer.

Objective: The purpose of this study was to evaluate the long-term oncological outcome for patients with left-sided versus right-sided stage I-III colon cancer.

Methods: Overall, 318 consecutive patients who underwent surgery for right- or left-sided sided colon cancer between 2001 and 2014 were analyzed. Analysis was performed applying a prospectively maintained database with respect to overall, disease-specific, and relative survival, using Cox regression and propensity score analyses.

Results: A total of 155 patients (48.7%) presented with right-sided colon cancer and 163 patients (51.3%) presented with left-sided colon cancer. In risk-adjusted Cox regression analysis, tumor location had no significant impact on overall survival (hazard ratio [HR] 1.53, 95% confidence interval [CI] 0.80-2.92; p = 0.197), disease-specific survival (HR 1.36, 95% CI 0.76-2.44; p = 0.301), and relative survival (HR 1.70, 95% CI 0.89-3.27; p = 0.107). After propensity score matching, the results from risk-adjusted Cox regression analysis were confirmed. Stratified by American Joint Committee on Cancer stage, patients with right-sided stage II colon cancer had a statistically significant superior relative survival compared with patents with left-sided colon cancer.

Conclusions: No significant negative impact on overall, disease-specific, or relative survival could be observed in patients with right- versus left-sided colon cancer after risk adjustment, using multivariable Cox regression and propensity score analyses.
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http://dx.doi.org/10.1245/s10434-020-09116-yDOI Listing
September 2020

Cavernous transformation of the portal vein in pancreatic cancer surgery-venous bypass graft first.

Langenbecks Arch Surg 2020 Nov 11;405(7):1045-1050. Epub 2020 Sep 11.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: In recent years, several techniques have been introduced to allow safe oncologic resections of cancers of the pancreatic head. While resections of the mesenterico-portal axis became now a part of the routine treatment, patients with a cavernous transformation of the portal vein still pose a surgical challenge and are regularly deemed unresectable.

Objective: Here, we describe a technique of initial venous bypass graft placement between the superior mesenteric vein or its tributaries and the portal vein before the resection of the pancreatic head. This approach avoids uncontrollable bleeding as well as venous congestion of the intestine with a continuous hepatic perfusion and facilitates oncologic resection of pancreatic head cancers. This technique, in combination with previously published resection strategies, enables tumor resection in locally advanced pancreatic head cancers.

Conclusions: Venous bypass graft first operations facilitate and enable the resection of the pancreatic head cancers in patients with a cavernous transformation of the portal vein thus rendering these patients resectable.
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http://dx.doi.org/10.1007/s00423-020-01974-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541372PMC
November 2020

Commentary: Neoadjuvant treatment of resectable pancreatic cancer: Lack of level III evidence.

Surgery 2020 12 29;168(6):1015-1016. Epub 2020 Aug 29.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.surg.2020.07.033DOI Listing
December 2020

Alternative signaling pathways from IGF1 or insulin to AKT activation and FOXO1 nuclear efflux in adult skeletal muscle fibers.

J Biol Chem 2020 11 31;295(45):15292-15306. Epub 2020 Aug 31.

Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, USA

Muscle atrophy is regulated by the balance between protein degradation and synthesis. FOXO1, a transcription factor, helps to determine this balance by activating pro-atrophic gene transcription when present in muscle fiber nuclei. Foxo1 nuclear efflux is promoted by AKT-mediated Foxo1 phosphorylation, eliminating FOXO1's atrophy-promoting effect. AKT activation can be promoted by insulin-like growth factor 1 (IGF1) or insulin via a pathway including IGF1 or insulin, phosphatidylinositol 3-kinase, and AKT. We used confocal fluorescence time-lapse imaging of FOXO1-GFP in adult isolated living muscle fibers maintained in culture to explore the effects of IGF1 and insulin on FOXO1-GFP nuclear efflux with and without pharmacological inhibitors. We observed that although AKT inhibitor blocks the IGF1- or insulin-induced effect on FOXO1 nuclear efflux, phosphatidylinositol 3-kinase inhibitors, which we show to be effective in these fibers, do not. We also found that inhibition of the protein kinase ACK1 or ATM contributes to the suppression of FOXO1 nuclear efflux after IGF1. These results indicate a novel pathway that has been unexplored in the IGF1- or insulin-induced regulation of FOXO1 and present information useful both for therapeutic interventions for muscle atrophy and for further investigative areas into insulin insensitivity and type 2 diabetes.
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http://dx.doi.org/10.1074/jbc.RA120.013634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7650253PMC
November 2020

Postoperative liver regeneration does not elicit recurrence of colorectal cancer liver metastases after major hepatectomy.

Surg Oncol 2020 Dec 31;35:24-33. Epub 2020 Jul 31.

Department of General, Visceral and Transplant Surgery, University Hospital Heidelberg, Heidelberg, Germany. Electronic address:

Background And Objectives: Recurrence is a frequent concern in curatively resected CRC liver metastases. Translational research suggests that regeneration upon hepatectomy may also alleviate metastatic recurrence; however, the significance in patients is unclear. We therefore sought to study the effect of liver regeneration on tumor recurrence in patients.

Methods: In this retrospective cohort study, we included 58 out of 186 potentially eligible patients from our prospectively maintained database of CRC liver metastasis patients between 2001 and 2012 with a median follow-up of 42 months who underwent a formal right or left hemihepatectomy. Liver regeneration in CT volumetry was correlated with recurrence of CRC liver metastases and overall survival.

Results: Liver regeneration increased up to 14 months to 21.0% for left and 122.6% for right hemihepatectomy, respectively, with comparable final volumes. Regeneration was independent of initial tumor stage, number of metastases, and preoperative chemotherapy. Patients with lower liver regeneration showed earlier recurrence of CRC liver metastases (p = 0.006). Overall survival did not differ in patients with weak versus strong liver regeneration.

Conclusions: The extent of liver regeneration after major hepatectomy does not impede overall survival. Therefore, our data encourage aggressive therapeutical regimes for CRC liver metastases involving major hepatectomies as part of a curative approach.
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http://dx.doi.org/10.1016/j.suronc.2020.07.001DOI Listing
December 2020

Multi-omics Analysis Reveals Adipose-tumor Crosstalk in Patients with Colorectal Cancer.

Cancer Prev Res (Phila) 2020 10 12;13(10):817-828. Epub 2020 Jul 12.

Huntsman Cancer Institute, Salt Lake City, Utah.

Obesity and obesity-driven cancer rates are continuing to rise worldwide. We hypothesize that adipocyte-colonocyte interactions are a key driver of obesity-associated cancers. To understand the clinical relevance of visceral adipose tissue in advancing tumor growth, we analyzed paired tumor-adjacent visceral adipose, normal mucosa, and colorectal tumor tissues as well as presurgery blood samples from patients with sporadic colorectal cancer. We report that high peroxisome proliferator-activated receptor gamma () visceral adipose tissue expression is associated with glycoprotein VI (GPVI) signaling-the major signaling receptor for collagen-as well as fibrosis and adipogenesis pathway signaling in colorectal tumors. These associations were supported by correlations between visceral adipose tissue expression and circulating levels of plasma 4-hydroxyproline and serum intercellular adhesion molecule 1 (ICAM1), as well as gene set enrichment analysis and joint gene-metabolite pathway results integration that yielded significant enrichment of genes defining epithelial-to-mesenchymal transition-as in fibrosis and metastasis-and genes involved in glycolytic metabolism, confirmed this association. We also reveal that elevated prostaglandin-endoperoxide synthase 2 () colorectal tumor expression is associated with a fibrotic signature in adipose-tumor crosstalk via GPVI signaling and dendritic cell maturation in visceral adipose tissue. Systemic metabolite and biomarker profiling confirmed that high expression in colorectal tumors is significantly associated with higher concentrations of serum amyloid A and glycine, and lower concentrations of sphingomyelin, in patients with colorectal cancer. This multi-omics study suggests that adipose-tumor crosstalk in patients with colorectal cancer is a critical microenvironment interaction that could be therapeutically targeted..
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http://dx.doi.org/10.1158/1940-6207.CAPR-19-0538DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7877796PMC
October 2020

Actual Five-year Survival After Upfront Resection for Pancreatic Ductal Adenocarcinoma: Who Beats the Odds?

Ann Surg 2020 Jul 7. Epub 2020 Jul 7.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany.

Objective: To determine actual five-year survival (5YS) rates associated with a strategy of upfront surgery and adjuvant therapy in pancreatic ductal adenocarcinoma (PDAC).

Background: The rate of actual 5YS in PDAC remains controversial. Available data is restricted to cohorts acquired over several decades and series of resection after patient selection by neoadjuvant therapy.

Methods: All patients undergoing upfront resection for resectable and borderline-resectable PDAC from 10/2001 to 12/2011 were identified from a prospective database. Actual overall survival was assessed after a follow-up of at least 5 years. Uni- and multivariable logistic regression analyses were performed.

Results: Median survival of 937 patients was 22.1 months. The actual 5YS rate was 17.0% (n = 159) including 89 (9.5%) patients without evidence of disease >5 years after resection. 5YS rates in patients with or without adjuvant therapy were 18.8% vs. 12.2%, respectively. Tumor grading, number of positive lymph nodes, a context of intraductal papillary mucinous neoplasia, and vascular resections were independently associated with 5YS. Patient-related parameters and CA 19-9 levels were associated with observed survival up to 3 years, but lost relevance thereafter. The extent of lymph node involvement was the strongest predictor of 5YS. Patients with pN0R0 had a 5YS rate of 38.2%. In patients with exclusively favorable factors the observed 5YS rate was above 50%.

Conclusions: This is the largest series of long-term survivors with histologically confirmed PDAC. With upfront resection and adjuvant therapy an actual overall 5YS rate of 18.8% can be expected. In favorable subgroups actual 5YS is above 50%.
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http://dx.doi.org/10.1097/SLA.0000000000004147DOI Listing
July 2020

Associations between physical activity, sedentary behavior, and urinary oxidized guanine in colorectal cancer patients: results from the ColoCare Study.

Appl Physiol Nutr Metab 2020 Nov 22;45(11):1306-1309. Epub 2020 Jun 22.

Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.

To determine associations between physical activity (PA), sedentary behavior (SB), and oxidative stress in colorectal cancer patients, ColoCare Study participants in Germany wore an accelerometer 6 and/or 12 months after surgery. Spearman partial correlations were used to assess associations between PA and urinary concentrations of oxidized guanine, a validated marker of oxidative stress. There were no significant associations between PA or SB and oxidized guanine in = 76 measurements (ng/mg creatinine; = 0.03, = 0.76 for PA, = -0.05, = 0.69 for SB). Objectively measured PA was not associated with a marker of oxidative stress in colorectal cancer patients.
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http://dx.doi.org/10.1139/apnm-2019-0836DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7609563PMC
November 2020

Expression of Angiogenic Proteins in Tumor and Stroma Affects Survival in Patients With Gastric Cancer.

J Surg Res 2020 11 18;255:172-180. Epub 2020 Jun 18.

Department of General, Visceral and Transplant Surgery, University of Heidelberg, Heidelberg, Germany. Electronic address:

Background: Gastric cancer is one of the most frequent malignancies worldwide. Angiogenic growth factors play a crucial role in mediating the crosstalk between cancer cells and the surrounding microenvironment. In this exploratory study, we investigate the impact of angiogenic proteins within the tumor cell or stroma compartment on survival of patients with gastric cancer.

Materials And Methods: In 29 patients, tumor and stromal compartments were separated using laser capture microdissection. Angiogenic protein expression was measured using a bead-based immunoassay and correlated with tumor stage and overall survival.

Results: Overall survival was significantly shorter in patients with a high stroma concentration of vascular endothelial growth factor (VEGF)-A (23.5 (±17.6) versus 33.6 (±21.0) mo; P = 0.009) and stem cell factor (22.2 (±18.5) versus 33.6 (±21.8) mo; P = 0.01) compared with patients with a low stroma concentration. High stromal VEGF-D showed a trend toward worse survival (26.8 (±22.0) versus 37.2 (±19.0) mo; P = 0.09). We did not observe any significant correlation between tumor-specific expression of angiogenic cytokines and survival.

Conclusions: This translational study highlights the difference in clinical impact between tumor and stromal expression of angiogenic proteins. Compartment-specific concentrations of VEGF-A and stem cell factor affect the clinical prognosis and help to identify the best therapy for patients with gastric cancer.
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http://dx.doi.org/10.1016/j.jss.2020.05.045DOI Listing
November 2020

Reduction of Liver Metastasis Stiffness Improves Response to Bevacizumab in Metastatic Colorectal Cancer.

Cancer Cell 2020 06;37(6):800-817.e7

Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, University Heidelberg, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany. Electronic address:

Tumors are influenced by the mechanical properties of their microenvironment. Using patient samples and atomic force microscopy, we found that tissue stiffness is higher in liver metastases than in primary colorectal tumors. Highly activated metastasis-associated fibroblasts increase tissue stiffness, which enhances angiogenesis and anti-angiogenic therapy resistance. Drugs targeting the renin-angiotensin system, normally prescribed to treat hypertension, inhibit fibroblast contraction and extracellular matrix deposition, thereby reducing liver metastases stiffening and increasing the anti-angiogenic effects of bevacizumab. Patients treated with bevacizumab showed prolonged survival when concomitantly treated with renin-angiotensin inhibitors, highlighting the importance of modulating the mechanical microenvironment for therapeutic regimens.
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http://dx.doi.org/10.1016/j.ccell.2020.05.005DOI Listing
June 2020

Randomised-controlled feasibility trial on abdominal wall closure techniques in patients undergoing relaparotomy (ReLap study; DRKS00013001).

Langenbecks Arch Surg 2020 Jun 6;405(4):427-434. Epub 2020 Jun 6.

Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany.

Background: Patients undergoing relaparotomy are generally underrepresented in clinical trials, despite how common the procedure is in clinical practice. Specifically, techniques for re-do abdominal wall closure have never been evaluated in a randomised-controlled trial. The aim of this trial was to identify the optimal abdominal wall closure technique in patients undergoing relaparotomy.

Methods: In this monocentric, randomised feasibility trial, patients scheduled for elective relaparotomy were randomised to abdominal wall closure with either the small stitches technique, using Monomax® 2-0, or the large stitches technique, using PDS II® 1 loop. Patients' postoperative courses were followed for 1 year after the index operation. Effectiveness and safety outcomes were compared at a level of significance of 5% between the two techniques.

Results: A total of 100 out of 131 patients (76.3%) were evenly randomised to the small stitches and large stitches groups. The time for abdominal wall closure did not differ between the two techniques (small stitches 27.5 ± 9.5 min versus large stitches 25.3 ± 12.4 min; p = 0.334). The overall comprehensive complication index was 14.4 ± 15.5 in the small stitches group and 19.9 ± 23.4 in the large stitches group (p = 0.168). Specifically, rates of surgical site infection (small stitches 30.0% versus large stitches 36.0%; p = 0.524) and burst abdomen (small stitches 4.0% versus large stitches 0.0%; p = 0.495) did not differ. After 1 year, incisional hernia rate was 7.5% in the small stitches group and 10.0% in the large stitches group (p > 0.999).

Discussion: Both abdominal wall closure techniques investigated in this trial were feasible in relaparotomy patients. This exploratory trial revealed no noticeable difference in the effectiveness or safety of the small stitches technique with Monomax® 2-0 versus the large stitches technique with PDS II® 1 loop. Therefore, surgeons should stay with their preferred suture technique in relaparotomy patients.

Trial Registration: Deutsches Register Klinischer Studien ( www.germanctr.de ): DRKS00013001.
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http://dx.doi.org/10.1007/s00423-020-01903-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359135PMC
June 2020

Metabolomics profiling of visceral and abdominal subcutaneous adipose tissue in colorectal cancer patients: results from the ColoCare study.

Cancer Causes Control 2020 Aug 19;31(8):723-735. Epub 2020 May 19.

Huntsman Cancer Institute, Salt Lake City, UT, USA.

Purpose: Underlying mechanisms of the relationship between body fatness and colorectal cancer remain unclear. This study investigated associations of circulating metabolites with visceral (VFA), abdominal subcutaneous (SFA), and total fat area (TFA) in colorectal cancer patients.

Methods: Pre-surgery plasma samples from 212 patients (stage I-IV) from the ColoCare Study were used to perform targeted metabolomics. VFA, SFA, and TFA were quantified by computed tomography scans. Partial correlation and linear regression analyses of VFA, SFA, and TFA with metabolites were computed and corrected for multiple testing. Cox proportional hazards were used to assess 2-year survival.

Results: In patients with metastatic tumors, SFA and TFA were statistically significantly inversely associated with 16 glycerophospholipids (SFA: p range 0.017-0.049; TFA: p range 0.029-0.048), while VFA was not. Doubling of ten of the aforementioned glycerophospholipids was associated with increased risk of death in patients with metastatic tumors, but not in patients with non-metastatic tumors (p range: 0.00044-0.049). Doubling of PC ae C34:0 was associated with ninefold increased risk of death in metastatic tumors (Hazard Ratio [HR], 9.05; 95% confidence interval [CI] 2.17-37.80); an inverse association was observed in non-metastatic tumors (HR 0.17; 95% CI 0.04-0.87; p = 0.00044).

Conclusion: These data provide initial evidence that glycerophospholipids in metastatic colorectal cancer are uniquely associated with subcutaneous adiposity, and may impact overall survival.
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http://dx.doi.org/10.1007/s10552-020-01312-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7425810PMC
August 2020

Impact of Perfusate Concentration on Hyperthermic Intraperitoneal Chemotherapy Efficacy and Toxicity in a Rodent Model.

J Surg Res 2020 09 7;253:262-271. Epub 2020 May 7.

Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Heidelberg, Germany. Electronic address:

Background: Cytoreductive surgery followed by hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to be beneficial in treating limited peritoneal carcinomatosis (PC) from colorectal cancer (CRC). Perfusate volume directly affects treatment concentration and therefore is a key parameter defining HIPEC; yet little is known about the impact of perfusate concentration on systemic toxicity and treatment morbidity.

Materials And Methods: PC was induced through intraperitoneal injection of human CRC cell lines. A novel perfusion model was developed to treat athymic nude mice with continuous circulation of adequately miniaturized volumes of heated perfusate. Oxaliplatin HIPEC was performed applying different volumes of perfusate with fixed doses or fixed concentrations. Early postoperative mortality and morbidity were assessed as well as long-term survival. In addition, antiproliferative and proapoptotic effects of HIPEC were determined in vitro and in vivo.

Results: Perfusate concentration crucially affected the toxicity of fixed-dose oxaliplatin HIPEC as indicated by postoperative weight loss and early postoperative mortality. Applying different perfusate volumes at a fixed concentration did not influence toxicity. Adequately miniaturized HIPEC with oxaliplatin did not exert relevant cytotoxic effects toward PC arising from human CRC cells in vivo.

Conclusions: We describe a novel murine model that adequately miniaturizes all physical parameters of HIPEC as applied in humans. HIPEC drug concentration is a crucial parameter determining excess toxicity and should be better standardized. HIPEC with oxaliplatin fails to induce relevant antitumor activity or to improve survival in this murine model of PC from CRC.
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http://dx.doi.org/10.1016/j.jss.2020.03.067DOI Listing
September 2020

The Role of CT-Quantified Body Composition on Longitudinal Health-Related Quality of Life in Colorectal Cancer Patients: The Colocare Study.

Nutrients 2020 Apr 28;12(5). Epub 2020 Apr 28.

Population Sciences, Huntsman Cancer Institute, Salt Lake City, UT 84112, USA.

Background: Obesity, defined by body mass index (BMI), measured at colorectal cancer (CRC) diagnosis has been associated with postoperative complications and survival outcomes. However, BMI does not allow for a differentiation between fat and muscle mass. Computed tomography (CT)-defined body composition more accurately reflects different types of tissue and their associations with health-related quality of life (HRQoL) during the first year of disease, but this has not been investigated yet. We studied the role of visceral and subcutaneous fat area (VFA and SFA) and skeletal muscle mass (SMM) on longitudinally assessed HRQoL in CRC patients.

Methods: A total of 138 newly diagnosed CRC patients underwent CT scans at diagnosis and completed questionnaires prior to and six and twelve months post-surgery. We investigated the associations of VFA, SFA, and SMM with HRQoL at multiple time points.

Results: A higher VFA was associated with increased pain six and twelve months post-surgery (β = 0.06, = 0.04 and β = 0.07, = 0.01) and with worse social functioning six months post-surgery (β = -0.08, = 0.01). Higher SMM was associated with increased pain twelve months post-surgery (β = 1.03, < 0.01).

Conclusions: CT-quantified body composition is associated with HRQoL scales post-surgery. Intervention strategies targeting a reduction in VFA and maintaining SMM might improve HRQoL in CRC patients during the first year post-surgery.
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http://dx.doi.org/10.3390/nu12051247DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7282010PMC
April 2020