Multivisceral Oncological Resections Involving the Pancreas: Protocol for a Systematic Review and Meta-Analysis.

BACKGROUND: With the continuous advancement of cancer treatments, a comprehensive analysis of the impact of multivisceral oncological pancreatic resections on morbidity, mortality, and long-term survival is currently lacking. OBJECTIVE: This manuscript presents the protocol for a systematic review and meta-analysis designed to summarize the existing evidence concerning the outcomes of multivisceral oncological pancreatic resections across diverse tumor entities. METHODS: We will conduct a systematic search of the PubMed or MEDLINE, Embase, Cochrane Library, CINAHL, and ClinicalTrials.gov databases in strict accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The predefined outcomes encompass postoperative mortality, postoperative morbidity, overall and disease-free survival (1- to 5-year survival rates), the proportion of macroscopically complete (R0) resections (according to the Royal College of Pathologists definition), duration of hospital stay (in days), reoperation rate (%), postoperative complications (covering all complications according to the Clavien-Dindo classification), as well as pancreatic fistula, postpancreatectomy hemorrhage, and delayed gastric emptying (all according to the definitions of the International Study Group of Pancreas Surgery). RESULTS: Systematic database searches will begin in July 2024. The completion of the meta-analysis is anticipated by December 2024. Before completion, the literature search will be checked for new publications that must be considered in the context of the work. CONCLUSIONS: The forthcoming findings will provide an up-to-date overview of the feasibility, safety, and oncological efficacy of multivisceral pancreatic resections across diverse tumor entities. This data will serve as a valuable resource for health care professionals and patients to make well-informed clinical decisions. TRIAL REGISTRATION: PROSPERO CRD42023437858; https://tinyurl.com/bde5xmfw. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/54089.

Approaches for the treatment of perforated peptic ulcers: a network meta-analysis of randomised controlled trials - study protocol.

INTRODUCTION: Perforated peptic ulcers are a life-threatening complication associated with high morbidity and mortality. Several treatment approaches are available. The aim of this network meta-analysis (NMA) is to compare surgical and alternative approaches for the treatment of perforated peptic ulcers regarding mortality and other patient-relevant outcomes. METHODS AND ANALYSIS: A systematic literature search of PubMed/MEDLINE, Cochrane Library, Embase, CINAHL, ClinicalTrials.gov trial registry and ICTRP will be conducted with predefined search terms.To address the question of the most effective treatment approach, an NMA will be performed for each of the outcomes mentioned above. A closed network of interventions is expected. The standardised mean difference with its 95% CI will be used as the effect measure for the continuous outcomes, and the ORs with 95% CI will be calculated for the binary outcomes. ETHICS AND DISSEMINATION: In accordance with the nature of the data used in this meta-analysis, which involves aggregate information from previously published studies ethical approval is deemed unnecessary. Results will be disseminated directly to decision-makers (eg, surgeons, gastroenterologists) through publication in peer-reviewed journals and presentation at conferences. PROSPERO REGISTRATION NUMBER: CRD42023482932.

Treatment of esophageal leakages with the Microtech®-VAC-Stent: a monocentric early experience of three cases.

Background: Endoscopic approaches in the treatment of transmural esophageal defects, either after esophageal resection or due to perforation, have demonstrated convincing feasibility. Surgical options are limited and associated with high morbidity and mortality rates. Currently, internal endoscopic drainage with pigtail stents, self-expanding metal stent (SEMS), or endoscopic vacuum therapy (EVT) are options for first-line treatment. Here, we report the outcome of the recently developed combination of SEMS and EVT using the endoscopic Microtech®-VAC-Stent (EVS). Methods: Between June and July 2022, three consecutive patients (one female and two males) with esophageal transmural defects were treated with the Microtech®-VAC-Stent. Two patients suffered from an anastomotic leak after oncologic gastroesophageal surgery, and one patient presented with esophageal perforation due to Boerhaave syndrome. Results: Three consecutive patients were successfully treated with EVS. In one patient, one EVS treatment was sufficient, whereas the other two patients needed two and six EVS exchanges. Exchanges were scheduled every 7 days and no procedural adverse events were observed. Conclusion: In line with the former case series, EVS therapy is a promising new approach for the treatment of esophageal leaks. Exchange of the EVS seems feasible every 7 days reducing interventions for the individual patient. Prospective studies comparing EVS with other endoscopic therapies are needed to define the best therapeutic approach.

Is it feasible and ethical to randomize patients between surgery and non-surgical treatments for gastrointestinal cancers?

Background: In several settings in the treatment of gastrointestinal cancers, it is unclear if the addition of surgery to a multimodal treatment strategy, or in some circumstances its omission, lead to a better outcome for patients. In such situations of clinical equipoise, high-quality evidence from randomised-controlled trials is needed to decide which treatment approach is preferable. Objective: In this article, we outline the importance of randomised trials comparing surgery with non-surgical therapies for specific scenarios in the treatment of gastrointestinal cancers. We explain the difficulties and solutions of designing these trials and recruiting patients in this context. Methods: We performed a selective review based on a not systematic literature search in core databases, supplemented by browsing health information journals and citation searching. Only articles in English were selected. Based on this search, we discuss the results and methodological characteristics of several trials which randomised patients with gastrointestinal cancers between surgery and non-surgical treatments, highlighting their differences, advantages, and limitations. Results and conclusions: Innovative and effective cancer treatment requires randomised trials, also comparing surgery and non-surgical treatments for defined scenarios in the treatment of gastrointestinal malignancies. Nevertheless, potential obstacles to designing and carrying out these trials must be recognised ahead of time to avoid problems before or during the trial.

Systematic review and meta-analysis of surgery for hilar cholangiocarcinoma with arterial resection.

BACKGROUND: With the advances in multimodality treatment, an analysis of the outcome of arterial resections (AR) in surgery of cholangiocarcinoma is lacking. The aim of this meta-analysis was to summarize the currently available evidence onof AR for the treatment of cholangiocarcinoma. METHODS: A systematic literature search was carried out according to PRISMA guidelines. RESULTS: 10 retrospective cohort studies published from 2007 to 2020 with 2530 patients (408 AR group and 2122 control group) were identified. Higher in-hospital mortality rates (6.8% vs 3.3%, OR 2.65, 95% CI [1.27; 5.32], p = 0.009), higher morbidity rates (Clavien-Dindo classification ≥3 ) (52% vs 47%, OR 1.44, 95% CI [1.02; 1.75], p = 0.04) and lower 1-year, 3-year and 5-year survival rates (54% vs 69%, OR 0.55, 95% CI [0.34; 0.91 p = 0.02), (34% vs 38%, OR 0.74, 95% CI [0.55; 0.98, p = 0.03), (18% vs 29%, OR 0.54, 95% CI [0.39; 0.75, p = 0.0002) were observed in the AR group when compared to the control group. CONCLUSION: Evidence from non-randomized studies shows a higher morbidity and mortality and shorter long-term survival in patients undergoing AR. However, the results are prone to selection bias, and only randomized trials comparing AR and palliative treatments AR might reveal a possible benefit of AR. SYSTEMATIC REVIEW REGISTRATION: PROSPERO ID 223396.

HIPEC-Induced Acute Kidney Injury: A Retrospective Clinical Study and Preclinical Model.

BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) combined with cytoreductive surgery (CRS) is the treatment of choice for selected patients with peritoneal malignancies. HIPEC is accompanied by moderate-to-high patient morbidity, including acute kidney injury. The significance of nephrotoxic agents such as cisplatin versus hyperthermia in HIPEC-induced nephrotoxicity has not been defined yet. PATIENTS AND METHODS: A total of 153 patients treated with HIPEC were divided into groups with (AKI+) and without (AKI-) kidney injury. Laboratory parameters and data concerning patient demographics, underlying disease, surgery, complications, and HIPEC were gathered to evaluate risk factors for HIPEC-induced AKI. A preclinical mouse model was applied to assess the significance of cisplatin and hyperthermia in HIPEC-induced AKI, as well as protective effects of the cytoprotective agent amifostine. RESULTS: AKI occurred in 31.8% of patients undergoing HIPEC. Treatment with cisplatin-containing HIPEC regimens represented a major risk factor for HIPEC-related AKI (p < 0.001). Besides, angiotensin receptor blockers and increased preoperative creatinine and urea levels were independent risk factors for AKI after HIPEC. In a preclinical mouse model, intraperitoneal perfusion with cisplatin induced AKI, whereas hyperthermia alone, or in combination with cisplatin, did not induce or enhance renal injury. Amifostine failed to confer nephroprotective effects in a miniaturized HIPEC model. CONCLUSIONS: AKI is a frequent complication after HIPEC. The risk of renal injury is particularly high in patients treated with cisplatin-containing HIPEC regimens. Hyperthermic perfusion of the abdomen by itself does not seem to induce or aggravate HIPEC-induced renal injury.

Interventions to reduce the incidence of surgical site infection in colorectal resections: systematic review with multicomponent network meta-analysis (INTRISSI): study protocol.

OBJECTIVE: To assess the relative contribution of intravenous antibiotic prophylaxis, mechanical bowel preparation, oral antibiotic prophylaxis, and combinations thereof towards the reduction of surgical site infection (SSI) incidence in elective colorectal resections. METHODS AND ANALYSIS: A systematic search of randomised controlled trials comparing interventions to reduce SSI incidence will be conducted with predefined search terms in the following databases: MEDLINE, LILACS, Cochrane Central Register of Controlled Trials (CENTRAL) and the Cochrane Database of Systematic Reviews (CDSR). Additionally, several online databases will be searched for ongoing trials, and conference proceedings and reference lists of retrieved articles will be hand searched. The title-abstract screening will be partly performed by means of a semiautomated supervised machine learning approach, which will be trained on a subset of the identified titles and abstracts identified through traditional screening methods.The primary analysis will be a multicomponent network meta-analysis, as we expect to identify studies that investigate combinations of interventions (eg, mechanical bowel preparation combined with oral antibiotics) as well as studies that focus on individual components (mechanical bowel preparation or oral antibiotics). By means of a multicomponent network meta-analysis, we aim at estimating the effects of the separate components along the effects of the observed combinations. To account for between-trial heterogeneity, a random-effect approach will be combined with inverse variance weighting for estimation of the treatment effects. Associated 95% CIs will be calculated as well as the ranking for each component in the network using P scores. Results will be visualised by network graphics and forest plots of the overall pairwise effect estimates. Comparison-adjusted funnel plots will be used to assess publication bias. ETHICS AND DISSEMINATION: Ethical approval by the Ethical Committee of the Medical Faculty of the Martin-Luther-University Halle-Wittenberg (ID of approval: 2021-148). Results shall be disseminated directly to decision-makers (eg, surgeons, gastroenterologists, wound care specialists) by means of publication in peer-reviewed journals, presentation at conferences and through the media (eg, radio, TV, etc). PROSPERO REGISTRATION NUMBER: CRD42021267322.

Surgery With Arterial Resection for Hilar Cholangiocarcinoma: Protocol for a Systematic Review and Meta-analysis.

BACKGROUND: In light of recent advances in multimodality treatment, an analysis of vascular resection outcomes in surgery for hilar cholangiocarcinoma is lacking. OBJECTIVE: The aim of this meta-analysis is to summarize the currently available evidence on outcomes of patients undergoing arterial resection for the treatment of hilar cholangiocarcinoma. METHODS: A systematic literature search in the databases PubMed/MEDLINE, Cochrane Library, and CINAHL, and the trial registries ClinicalTrials.gov and the World Health Organization International Clinical Trials Registry Platform will be carried out. Predefined outcomes are mortality (100-day and in-hospital), morbidity (Clavien-Dindo classification, any type of complication), vascular complications (thrombosis or stenosis of the portal vein or hepatic artery, pseudoaneurysms), liver failure, postoperative bleeding, duration of surgery, reoperation rate, length of hospital stay, survival time, actuarial survival (2-, 3-, and 5-year survival), complete/incomplete resection rates, histologic arterial invasion, and lymph node positivity (number of positive lymph nodes and lymph node ratio). RESULTS: Database searches will commence in December 2020. The meta-analysis will be completed by December 2021. CONCLUSIONS: Our findings will enable us to present the current evidence on the feasibility, safety, and oncological effectiveness of surgery for hilar cholangiocarcinoma with arterial resection. Our data will support health care professionals and patients in their clinical decision-making. TRIAL REGISTRATION: PROSPERO 223396; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=223396. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/31212.

Management problems in patients with pancreatic cancer from a surgeon's perspective.

Pancreatic cancer is one of the most lethal gastrointestinal tumor entities. Surgery is the only chance for cure; however, only a minority of patients can be offered this option. Due to the anatomic location of the gland, tumor-related problems and complications affecting the surrounding structures are common, leading to biliary and gastric outlet obstruction as well as portal vein thrombosis. This review article summarizes the management of pancreatic cancer-related problems from a surgical point of view. We further describe surgical treatment options in unresectable, metastasized and recurring pancreatic cancer, highlighting potential resection of oligometastatic disease in selected settings.

Still proliferating CD44+/Ki67+ tumor cells after neoadjuvant radiochemotherapy identify rectal cancer patients with poor survival.

INTRODUCTION: Distant recurrence, especially liver metastases, occurs in one-third of rectal cancer patients initially treated with curative therapy and is still an unsolved problem. The identification of patients at risk is crucial for enabling individualized treatment. MATERIAL AND METHODS: All patients undergoing curative resection for histologically confirmed rectal cancer after neoadjuvant radiochemotherapy between January 2001 and December 2015 were included. Sections were stained for Ki67, CD44, apoptosis and CD133. Patients were categorized based on whether they were found to have (CD44+/Ki67+) or not have (CD44+/Ki67+) still proliferating tumor cells. RESULTS: 218 patients who underwent R0 resection for stage I-III rectal cancer were selected. In 37 (17%) of these patients, CD44+/Ki67+ tumor cells were found. In multivariable Cox regression analysis, patients with CD44+/Ki67+ cells had significantly impaired overall (hazard ratio (HR): 3.84, 95% CI: 1.77-8.31, p = 0.001) and relative survival (HR 3.44, 95% CI: 1.46-8.09). The previous results were confirmed after propensity-score matching. In mediation-analysis, the presence of CD44+/Ki67+ cells was associated with a substantial direct effect on overall (HR 1.92, 95% CI: 1.09-9.28) and relative survival (HR 1.63, 95% CI: 1.31-6.38). CONCLUSIONS: The presence of still proliferating CD44+/Ki67+ tumor cells after neoadjuvant radiochemotherapy was associated with impaired oncological long-term outcomes. Characterization of these cells should be performed.

Inhibition of HIF-prolyl hydroxylases improves healing of intestinal anastomoses.

Anastomotic leakage (AL) accounts for a major part of in-house mortality in patients undergoing colorectal surgery. Local ischemia and abdominal sepsis are common risk factors contributing to AL and are characterized by upregulation of the hypoxia-inducible factor (HIF) pathway. The HIF pathway is critically regulated by HIF-prolyl hydroxylases (PHDs). Here, we investigated the significance of PHDs and the effects of pharmacologic PHD inhibition (PHI) during anastomotic healing. Ischemic or septic colonic anastomoses were created in mice by ligation of mesenteric vessels or lipopolysaccharide-induced abdominal sepsis, respectively. Genetic PHD deficiency (Phd1-/-, Phd2+/-, and Phd3-/-) or PHI were applied to manipulate PHD activity. Pharmacologic PHI and genetic PHD2 haplodeficiency (Phd2+/-) significantly improved healing of ischemic or septic colonic anastomoses, as indicated by increased bursting pressure and reduced AL rates. Only Phd2+/- (but not PHI or Phd1-/-) protected from sepsis-related mortality. Mechanistically, PHI and Phd2+/- induced immunomodulatory (M2) polarization of macrophages, resulting in increased collagen content and attenuated inflammation-driven immune cell recruitment. We conclude that PHI improves healing of colonic anastomoses in ischemic or septic conditions by Phd2+/--mediated M2 polarization of macrophages, conferring a favorable microenvironment for anastomotic healing. Patients with critically perfused colorectal anastomosis or abdominal sepsis could benefit from pharmacologic PHI.

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

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.

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

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.

Prognostic relevance of programmed death-ligand 1 expression and microsatellite status in small bowel adenocarcinoma.

Background: Small bowel adenocarcinoma (SBA) is a dreadful disease. Patient prognosis is limited due to late presentation and ineffective chemotherapy. PD-1/PD-L1 checkpoint immunotherapy is regarded as a promising approach in several cancer entities. The association of PD-1/PD-L1 expression and its impact on patient prognosis with SBA is unclear. Material and methods: Seventy-five consecutive patients who underwent surgery for SBA were retrospectively analyzed and stained for PD-L1 expression in the tumour or the stroma. Analysis of mismatch repair genes was performed to determine microsatellite status. Kaplan-Meier estimate was used to analyze patient survival. Univariate and multivariable Cox regression-analyses were used to assess the impact of PD-L1 expression and microsatellite status on patient survival.Results: PD-L1 was weakly upregulated within the tumour or the stroma and associated with prolonged survival (p = .0071 and p = .0472, respectively). Fifty-one tumours (68%) revealed microsatellite stability (MSS) and 24 tumours (32%) were microsatellite instable (MSI) without correlating with patient survival (p = .611). Neither PD-L1 expression in the tumour nor in the stroma was identified as an independent risk factor influencing survival (p = .572 and p = .3055).Conclusion: Although PD-L1 expression is associated with prolonged survival, it was not identified as an independent prognostic marker. Microsatellite status did not influence long-term survival.

VEGFR1+ Metastasis-Associated Macrophages Contribute to Metastatic Angiogenesis and Influence Colorectal Cancer Patient Outcome.

PURPOSE: To investigate the clinical relevance of macrophages in liver metastasis of colorectal cancer and their influence on angiogenesis and patient survival. Moreover to evaluate specific blood monocytes as markers of disease recurrence.Experimental design: In a mouse model with spontaneous liver metastasis, the angiogenic characteristics of tumor- and metastasis (MAM)-associated macrophages were evaluated. Macrophages and the vasculature from 130 primary tumor (pTU) and 123 patients with liver metastasis were assessed. In vivo and in human samples, the clinical relevance of macrophage VEGFR1 expression was analyzed. Blood samples from patients (n = 157, 80 pTU and 77 liver metastasis) were analyzed for assessing VEGFR1-positive (VEGFR1+) cells as suitable biomarkers of disease recurrence. RESULTS: The number of macrophages positively correlated with vascularization in metastasis. Both in the murine model as well as in primary isolated human cells, a subpopulation of MAMs expressing VEGFR1 were found highly angiogenic. While VEGFR1 expression in pTU patients did not predict prognosis; high percentage of VEGFR1+ cells in liver metastasis was associated with worse patient outcome. Interestingly, VEGFR1+-circulating monocytes in blood samples from patients with liver metastasis not only predicted progression but also site of recurrence. CONCLUSIONS: Our findings identify a new subset of proangiogenic VEGFR1+ MAMs in colorectal cancer that support metastatic growth and may become a liquid biomarker to predict disease recurrence in the liver.

Splenectomy reduces lung metastases and tumoral and metastatic niche inflammation.

The immune microenvironment plays a crucial role in supporting tumor growth and metastasis. Tumor-associated macrophages (TAMs) and neutrophils (TANs) are essential components of this microenvironment and affect tumor growth and progression in almost all solid neoplasms. Furthermore, TAMs, TANs and tumor-infiltrating dendritic cells (TIDCs) are found to infiltrate specific distant organs to prepare them as a site for metastatic cell seeding, forming the pre-metastatic niche. The spleen was identified as a major reservoir and source of circulating and tumor infiltrating immune cells. However, discrepancies about its role in supporting tumor growth exist. Thus, here we investigated the role of splenectomy in primary tumor and metastatic growth, and in the formation of an inflammatory niche. In a murine 4T1 and E0771 breast and Panc02 pancreatic cancer model, our results show that while splenectomy reduces the number of infiltrating TAMs, TANs and TIDCs within primary tumors, it does not affect its growth. In line, fewer TAMs, TANs and TIDCs accumulate in the metastatic microenvironment after splenectomy. Interestingly though, this affected metastatic growth depending on the metastatic route/site. The number of hematogenous breast cancer lung metastases was reduced after splenectomy but no effect was observed in breast or pancreatic lymph node metastases. Moreover, we observed that the immune composition of the pre-metastatic niche in lungs of breast cancer bearing mice was altered, and that this could cause the reduction of metastases. Altogether, our results highlight that splenectomy affects the immune microenvironment not only of primary tumors but also of pre-metastatic and metastatic sites.

High hepatic expression of PDK4 improves survival upon multimodal treatment of colorectal liver metastases.

BACKGROUND: Patients with borderline resectable colorectal liver metastases (CRLM) frequently receive neoadjuvant chemotherapy (NC) to reduce tumour burden, thus making surgical resection feasible. Even though NC can induce severe liver injury, most studies investigating tissue-based prognostic markers focus on tumour tissue. Here, we assessed the prognostic significance of pyruvate-dehydrogenase-kinase isoenzyme 4 (PDK4) within liver tissue of patients undergoing surgical resection due to CRLM. METHODS: Transcript levels of hypoxia-adaptive genes (such as PDK isoenzymes) were assessed in the tissue of healthy liver, corresponding CRLM, healthy colon mucosa and corresponding tumour. Uni- and multivariate analyses were performed. Responses to chemotherapy upon up- or down-regulation of PDK4 were studied in vitro. RESULTS: PDK4 expression within healthy liver tissue was associated with increased overall survival and liver function following surgical resection of CRLM. This association was enhanced in patients with NC. PDK4 expression in CRLM tissue did not correlate with overall survival. Up-regulation of PDK4 increased the resistance of hepatocytes and colon cancer cells against chemotherapy-induced toxicity, whereas knockdown of PDK4 enhanced chemotherapy-associated cell damage. CONCLUSION: Our findings suggest that up-regulated PDK4 expression reduces hepatic chemotherapy-induced oxidative stress and is associated with improved postoperative liver function in patients undergoing multimodal treatment and resection of CRLM.

Salinomycin: Anti-tumor activity in a pre-clinical colorectal cancer model.

OBJECTIVES: Salinomycin is a polyether antibiotic with selective activity against human cancer stem cells. The impact of salinomycin on patient-derived primary human colorectal cancer cells has not been investigated so far. Thus, here we aimed to investigate the activity of salinomycin against tumor initiating cells isolated from patients with colorectal cancer. METHODS: Primary tumor-initiating cells (TIC) isolated from human patients with colorectal liver metastases or from human primary colon carcinoma were exposed to salinomycin and compared to treatment with 5-FU and oxaliplatin. TICs were injected subcutaneously into NOD/SCID mice to induce a patient-derived mouse xenograft model of colorectal cancer. Animals were treated either with salinomycin, FOLFOX regimen, or salinomycin and FOLFOX. Human colorectal cancer cells were used to delineate an underlying molecular mechanism of salinomycin in this tumor entity. RESULTS: Applying TICs isolated from human patients with colorectal liver metastases or from human primary colon carcinoma, we demonstrated that salinomycin exerts increased antiproliferative activity compared to 5-fluorouracil and oxaliplatin treatment. Consistently, salinomycin alone or in combination with FOLFOX exerts superior antitumor activity compared to FOLFOX therapy in a patient-derived mouse xenograft model of colorectal cancer. Salinomycin induces apoptosis of human colorectal cancer cells, accompanied by accumulation of dysfunctional mitochondria and reactive oxygen species. These effects are associated with expressional down-regulation of superoxide dismutase-1 (SOD1) in response to salinomycin treatment. CONCLUSION: Collectively, the results of this pre-clinical study indicate that salinomycin alone or in combination with 5-fluorouracil and oxaliplatin exerts increased antitumoral activity compared to common chemotherapy.