Surgical and oncological outcome after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma : A retrospective single center experience.

BACKGROUND: Peritoneal mesothelioma (PM) is a rare disease with various histopathological subtypes. For malignant peritoneal mesothelioma and borderline subgroups locoregional therapy with cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has been implemented. The aim of our study was to retrospectively present the outcome after CRS and HIPEC for patients with different subtypes of peritoneal mesothelioma. METHODS: In total 15 patients received CRS and HIPEC due to peritoneal mesothelioma at our tertiary referral hospital between 2013 and 2022. Surgical and oncologic outcomes of 14 of those patients were retrospectively evaluated as one patient was lost to follow-up. RESULTS: The cohort consisted of 9 patients with diffuse malignant peritoneal mesothelioma (64.3%), 3 patients with multicystic peritoneal mesothelioma (21.4%) and 2 patients with well-differentiated peritoneal mesothelioma (14.3%). Complete cytoreduction was possible in 85.7% (n = 12). The major complication rate was 28.6% (n = 4) and the reoperation rate was 14.3% (n = 2). Median follow-up was 55 months (standard error, SE 15.0%, 95% confidence interval, CI 25.6-84.4 months). Over this time period 64.3% (n = 9) had no evidence of disease, 21.4% (n = 3) were alive with disease and 14.3% (n = 2) died of peritoneal mesothelioma. The median recurrence-free survival of patients was 13 months (SE 13.0%, 95% CI 0.0-32.2 months). None of the patients with multicystic peritoneal mesothelioma had evidence of disease at the time of last follow-up. CONCLUSION: Patients with peritoneal mesothelioma should receive locoregional treatment as good oncological results can be achieved with reasonable postoperative morbidity. Thus, awareness is necessary for this rare but potentially aggressive disease to offer the best medical care.

Effect of systemic FOLFOXIRI plus bevacizumab treatment of colorectal peritoneal metastasis on local and systemic immune cells.

AIM: The immune system plays a crucial role in the outcome of colorectal cancer. Systemic chemotherapies modulate the immune cell composition. Little is known about these changes in peritoneal metastasized colorectal cancer. Thus, we aimed to characterize local and systemic immune cells in the course of systemic chemotherapy. METHODS: We included in total 20 patients with peritoneal metastasized colorectal cancer in our exploratory study. Initially, we investigated the peripheral blood cell distributions before and after systemic chemotherapy in a set of 11 retrospectively collected samples. Then, a prospective clinical cohort was set up to evaluate local and systemic immune cell distribution in detail (n = 9). Tumor tissue, peritoneal fluid, and peripheral blood were collected. The main immune cell subtypes were characterized using flow cytometry and immunohistochemistry, respectively. RESULTS: Neutrophils and the neutrophil-to-lymphocyte ratio significantly declined in response to systemic chemotherapy while circulating T cells increased (CD8+P = .015, CD4+P = .041). In peritoneal fluid, we observed a decrease of CD25+/FOXP3+/CD4+ regulatory T cells (P = .049) without loss of their ability to produce interferon gamma. T-cell infiltration in the tumor microenvironment showed a considerable variability between patients. However, the number of tumor-infiltrating CD8+ lymphocytes was not significantly changed by the application of systemic chemotherapy. Neither tumor cells nor lymphocytes or macrophages showed noteworthy expression of PD1 or PD-L1. CONCLUSION: Our data show that immune cell distribution after systemic chemotherapy changes in peripheral blood. Interestingly, in peritoneal fluid only the inhibitory Treg population decreased and local T cells within peritoneal metastases remain unaffected. These data indicate little to no effect of systemic chemotherapy on the local immune system, supporting the need for new therapeutic options.

Prediction of survival after neoadjuvant therapy in locally advanced rectal cancer - a retrospective analysis.

Purpose: The aim of this retrospective analysis was to determine if the response to preoperative radio(chemo)therapy is predictive for survival among patients with locally advanced rectal cancer and may act as a potential surrogate endpoint for disease free survival and overall survival. Results: Eight hundred seventy-eight patients from five centers were analyzed. There were 304 women and 574 men; the median age was 64.7 years. 77.6% and 22.4% of patients received neoadjuvant radiochemotherapy or short-course radiotherapy, resulting in a pathological complete response in 7.3%. T-downstaging and N-downstaging occurred in 50.5% and 37% of patients after neoadjuvant therapy. In patients with T-downstaging, the 10-year DFS and 10-year OS were 64.8% and 66.8% compared to 37.1% and 45.9% in patients without T-downstaging. N-downstaging resulted in 10-year DFS and 10-year OS in 56.2% and 62.5% compared to 47.3% and 52.3% without N-downstaging. Based on routinely evaluated clinical parameters, an absolute risk prediction calculator was generated for 5-year disease-free survival, and 5-year overall survival. Conclusion: T-downstaging and N-downstaging after neoadjuvant radiochemotherapy or short-course radiotherapy resulted in better DFS and OS compared to patients without response. Based on clinical parameters, 5-year DFS, and 5-year OS can be predicted using a prediction calculator.

Early postoperative CRP predicts major complications following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC).

Objectives: Cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC) is associated with significant postoperative complications. Early detection of at-risk patients may lead to improved outcomes. The role of C-reactive protein (CRP) in predicting postoperative complications has only been recently investigated. Methods: Postoperative complications were categorized according to Clavien-Dindo classification and further divided into minor (Grade <3) and major complications (Grade ≥3A). Absolute CRP counts (mg/L) on postoperative days (POD) 1-7, and proportional change in CRP was compared and the area under (AUC) receiver operating characteristics (ROC) curve was calculated. Univariate and multivariate analysis was performed. Significant findings were externally validated. Results: Twenty-five percent of patients experienced one or more major complications. A CRP level of ≥106 mg/L on POD 2 and 65.5 mg/L on POD 4 were significantly associated with an increased risk of major complications with an AUC of 0.658 and 0.672, respectively. The proportional increase in CRP between POD 1 and 4 (ΔCRP POD 1/4) at a cut-off of 30 % had the best AUC of 0.744 and was the only independent risk factor for major complications (p<0.0001) on multivariate analysis. ∆CRP had an AUC of 0.716 (p=0.002) when validated in an independent database. Conclusions: CRP can be used in a variety of ways to predict major complications after CRS and HIPEC. However, the ∆CRP POD 1/4>30 % is the best indicator of major complications. Serial CRP measurements in the early postoperative period may lead to early detection of patients at risk of major complications allowing for alternative management strategies to improve outcomes.

Meeting actual benchmarks for short- and long-term outcomes after cytoreductive surgery for peritoneal surface malignancy at a newly established academic treatment center.

BACKGROUND: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy is a curative treatment for selected patients with peritoneal surface malignancy. Reaching actual outcomes benchmarks is challenging given the complex nature of peritoneal surface malignancy surgery. The aim of this study was to assess how the benchmarks for morbidity and oncologic outcome can be reached at a newly established program for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. METHODS: Building on existing institutional experience in complex abdominal surgery and interdisciplinary ovarian cancer treatment, a peritoneal surface malignancy center for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy was established at the Medical University of Vienna using a structured mentoring process. This is a retrospective analysis of the first 100 consecutive patients. Morbidity and mortality were assessed using the Clavien-Dindo classification, and oncologic outcomes using overall survival. RESULTS: Major morbidity and mortality were 26% and 3%, and median overall survival was 49.0 months. In patients with colorectal peritoneal metastases, the median overall survival was 35.1 months (all colorectal peritoneal metastases patients) and 48.8 months in the subgroup with Peritoneal Surface Disease Severity Score ≤3. No median overall survival could be calculated in patients with low-grade appendiceal mucinous neoplasms, appendiceal adenocarcinoma, or peritoneal mesothelioma due to >50% of patients being alive at the end of follow-up. CONCLUSION: We show that the current morbidity and oncological outcomes benchmarks can be reached within the first 100 cases of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at a newly established peritoneal surface malignancy center. Previous institutional experience in complex abdominal surgery and a structured mentoring process are key factors in achieving this goal.

Circulating caspase-cleaved cytokeratin 18 correlates with tumour burden and response to therapy in patients with colorectal cancer liver metastasis.

BACKGROUND AND AIMS: Systemic chemotherapy followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CRCLM) but reliable biomarkers predicting response to therapy are needed. Spontaneous apoptosis of single tumour cells is common in CRCLM. We explored the potential of circulating apoptosis markers to predict treatment response. MATERIALS AND METHODS: Fifty-eight patients with CRCLM or hepatocellular carcinoma (HCC) were included in this study. Tumour tissue and blood samples were obtained before and after initiation of chemotherapy. Immunohistochemistry and ELISA assays were utilized to quantify the apoptosis marker caspase-cleaved cytokeratin 18 (M30) in tissue and circulation. RESULTS: CRCLM tissues showed more apoptotic tumour cells than HCC, or healthy liver. This was associated with elevated levels of circulating M30 (median = 244 U/l vs. 37 U/l in healthy controls, p = 0.009) which correlated with tumour volume (r2 = 0.92). Patients with progressive disease during chemotherapy showed higher M30 levels before therapy than responders (745 U/l vs. 136 U/l, p = 0.016). The predictive potential of M30 was higher than that of the tumour markers CA19-9 or CEA (AUC: 0.93, 0.63, and 0.78, respectively). CONCLUSIONS: Apoptotic tumour cells release cellular debris into the circulation, which provides information about tumour size and vitality.

Metastatic colorectal carcinoma-associated fibroblasts have immunosuppressive properties related to increased IGFBP2 expression.

Fibroblasts are the most abundant stromal constituents of the tumour microenvironment in primary as well as metastatic colorectal cancer (CRC). Their supportive effect on tumour cells is well established. There is growing evidence that stromal fibroblasts also modulate the immune microenvironment in tumours. Here, we demonstrate a difference in fibroblast-mediated immune modulation between primary CRC and peritoneal metastasis. Cancer-associated fibroblasts (CAFs) were isolated from primary cancer and from peritoneal metastases (MAFs) from a total of 17 patients. The ectoenzyme CD38 was consistently expressed on the surface of all MAFs, while it was absent from CAFs. Furthermore, MAFs secreted higher levels of IGFBP2, CXCL2, CXCL6, CXCL12, PDGF-AA, FGFb, and IL-6. This was associated with a decreased activation of macrophages and a suppression of CD25 expression and proliferation of co-cultivated T-cells. Downregulation of IGFBP2 abolished these immunosuppressive effects of MAFs. Taken together, these results show that MAFs contribute to an immunosuppressive tumour microenvironment in CRC metastases by modulating the phenotype of immune cells through an IGFBP2-dependent mechanism.

Tumour cell apoptosis modulates the colorectal cancer immune microenvironment via interleukin-8-dependent neutrophil recruitment.

Sporadic apoptosis of tumour cells is a commonly observed feature of colorectal cancer (CRC) and strongly correlates with adverse patient prognosis. The uptake of apoptotic cell debris by neutrophils induces a non-inflammatory, pro-regenerative, and hence potentially pro-tumorigenic phenotype. In this study, we therefore sought to investigate the impact of apoptotic CRC cells on neutrophils and its consequence on other immune cells of the tumour microenvironment. Apoptosis induced by combined TNFα-treatment and UV-C irradiation, as well as various chemotherapeutic agents, led to a substantial release of neutrophil-attracting chemokines, most importantly interleukin-8 (IL-8), in both primary patient-derived and established CRC cells. Accordingly, conditioned media of apoptotic tumour cells selectively stimulated chemotaxis of neutrophils, but not T cells or monocytes. Notably, caspase-inhibition partially reduced IL-8 secretion, suggesting that caspase activity might be required for apoptosis-induced IL-8 release. Moreover, apoptotic tumour cell-conditioned media considerably prolonged neutrophil lifespan and induced an activated CD66bhighCD11bhighCD62Llow phenotype, comparable to that of tumour-associated neutrophils in CRC patients, as assessed by flow cytometry of dissociated CRC tissues. Immunohistochemical analyses of 35 CRC patients further revealed a preferential accumulation of neutrophils at sites of apoptotic tumour cells defined by the expression of epithelial cell-specific caspase-cleaved cytokeratin-18. The same areas were also highly infiltrated by macrophages, while T cells were virtually absent. Notably, neutrophils induced an M2-like CD86lowCD163+CD206+ phenotype in co-cultured monocyte-derived macrophages and suppressed LPS-induced pro-inflammatory cytokine release. In an in vitro transwell model, IL-8 blockade efficiently prevented neutrophil-induced anti-inflammatory macrophage polarisation by inhibiting neutrophil migration towards IL-8 gradients generated by apoptotic CRC cells. To conclude, our data suggest that apoptotic cancer cells release chemotactic factors that attract neutrophils into the tumour, where their interaction with neighbouring macrophages might promote an immunologically unfavourable tumour microenvironment. This effect may contribute to tumour recurrence after chemotherapy-induced apoptosis.

Intensive care unit occupancy predictions in the COVID-19 pandemic based on age-structured modelling and differential flatness.

The COVID-19 pandemic confronts governments and their health systems with great challenges for disease management. In many countries, hospitalization and in particular ICU occupancy is the primary measure for policy makers to decide on possible non-pharmaceutical interventions. In this paper a combined methodology for the prediction of COVID-19 case numbers, case-specific hospitalization and ICU admission rates as well as hospital and ICU occupancies is proposed. To this end, we employ differential flatness to provide estimates of the states of an epidemiological compartmental model and estimates of the unknown exogenous inputs driving its nonlinear dynamics. A main advantage of this method is that it requires the reported infection cases as the only data source. As vaccination rates and case-specific ICU rates are both strongly age-dependent, specifically an age-structured compartmental model is proposed to estimate and predict the spread of the epidemic across different age groups. By utilizing these predictions, case-specific hospitalization and case-specific ICU rates are subsequently estimated using deconvolution techniques. In an analysis of various countries we demonstrate how the methodology is able to produce real-time state estimates and hospital/ICU occupancy predictions for several weeks thus providing a sound basis for policy makers.

Multiplexed DNA Methylation Analysis in Colorectal Cancer Using Liquid Biopsy and Its Diagnostic and Predictive Value.

Early diagnosis of colorectal cancer (CRC) is of high importance as prognosis depends on tumour stage at the time of diagnosis. Detection of tumour-specific DNA methylation marks in cfDNA has several advantages over other approaches and has great potential for solving diagnostic needs. We report here the identification of DNA methylation biomarkers for CRC and give insights in our methylation-sensitive restriction enzyme coupled qPCR (MSRE-qPCR) system. Targeted microarrays were used to investigate the DNA methylation status of 360 cancer-associated genes. Validation was done by qPCR-based approaches. A focus was on investigating marker performance in cfDNA from 88 patients (44 CRC, 44 controls). Finally, the workflow was scaled-up to perform 180plex analysis on 110 cfDNA samples, to identify a DNA methylation signature for advanced colonic adenomas (AA). A DNA methylation signature (n = 44) was deduced from microarray experiments and confirmed by quantitative methylation-specific PCR (qMSP) and by MSRE-qPCR, providing for six genes' single areas under the curve (AUC) values of >0.85 (WT1, PENK, SPARC, GDNF, TMEFF2, DCC). A subset of the signatures can be used for patient stratification and therapy monitoring for progressed CRC with liver metastasis using cfDNA. Furthermore, we identified a 35-plex classifier for the identification of AAs with an AUC of 0.80.

Estimation of exogenous drivers to predict COVID-19 pandemic using a method from nonlinear control theory.

The currently ongoing COVID-19 pandemic confronts governments and their health systems with great challenges for disease management. Epidemiological models play a crucial role, thereby assisting policymakers to predict the future course of infections and hospitalizations. One difficulty with current models is the existence of exogenous and unmeasurable variables and their significant effect on the infection dynamics. In this paper, we show how a method from nonlinear control theory can complement common compartmental epidemiological models. As a result, one can estimate and predict these exogenous variables requiring the reported infection cases as the only data source. The method allows to investigate how the estimates of exogenous variables are influenced by non-pharmaceutical interventions and how imminent epidemic waves could already be predicted at an early stage. In this way, the concept can serve as an "epidemometer" and guide the optimal timing of interventions. Analyses of the COVID-19 epidemic in various countries demonstrate the feasibility and potential of the proposed approach. The generic character of the method allows for straightforward extension to different epidemiological models.

Gender differences in molecular-guided therapy recommendations for metastatic malignant mesothelioma.

BACKGROUND: Malignant mesothelioma is an aggressive cancer and has a poor prognosis. Here, we analyzed the feasibility, molecular and gender aspects of targeted therapy recommendations for malignant mesothelioma based on the individual molecular tumor profile. METHODS: In this single-center, real-world retrospective analysis of our platform for precision medicine, we evaluated the molecular profiling of malignant mesothelioma in 14 patients, including nine men and five women. Tumor samples of the patients were examined with a 50 gene next-generation sequencing (NGS) panel, immunohistochemistry, and fluorescence in situ hybridization, to detect possible molecular aberrations which may be targeted by off-label therapy custom-tailored to the individual patient. RESULTS: In total, we identified 11 mutations in six of the 14 patients, including BAP1, FANCA, NF1, NF2, PD-L1, RAD52D, SETD2, SRC, and TP53. No mutation was detected in eight of the 14 patients. Targeted therapy was recommended for 11 out of the 14 patients. All recommendations were mainly based on the molecular characteristics determined by immunohistochemistry. Targeted therapy recommendations were significantly more often for men than women due to gender-specific differences in PDGFRα expression. Eventually, four patients received the targeted therapy, of whom one patient subsequently achieved stable disease. CONCLUSIONS: Our observations suggest that a molecular-guided treatment approach is feasible for the management of advanced malignant mesothelioma. Our analysis revealed gender specific differences in PDGFRα expression that should be further evaluated in clinical trials.

Plasma metabolites associated with colorectal cancer stage: Findings from an international consortium.

Colorectal cancer is the second most common cause of cancer-related death globally, with marked differences in prognosis by disease stage at diagnosis. We studied circulating metabolites in relation to disease stage to improve the understanding of metabolic pathways related to colorectal cancer progression. We investigated plasma concentrations of 130 metabolites among 744 Stages I-IV colorectal cancer patients from ongoing cohort studies. Plasma samples, collected at diagnosis, were analyzed with liquid chromatography-mass spectrometry using the Biocrates AbsoluteIDQ™ p180 kit. We assessed associations between metabolite concentrations and stage using multinomial and multivariable logistic regression models. Analyses were adjusted for potential confounders as well as multiple testing using false discovery rate (FDR) correction. Patients presented with 23, 28, 39 and 10% of Stages I-IV disease, respectively. Concentrations of sphingomyelin C26:0 were lower in Stage III patients compared to Stage I patients (pFDR < 0.05). Concentrations of sphingomyelin C18:0 and phosphatidylcholine (diacyl) C32:0 were statistically significantly higher, while citrulline, histidine, phosphatidylcholine (diacyl) C34:4, phosphatidylcholine (acyl-alkyl) C40:1 and lysophosphatidylcholines (acyl) C16:0 and C17:0 concentrations were lower in Stage IV compared to Stage I patients (pFDR < 0.05). Our results suggest that metabolic pathways involving among others citrulline and histidine, implicated previously in colorectal cancer development, may also be linked to colorectal cancer progression.

Surgical Complexity and Outcome During the Implementation Phase of a Robotic Colorectal Surgery Program-A Retrospective Cohort Study.

BACKGROUND: Robotic surgery holds particular promise for complex oncologic colorectal resections, as it can overcome many limitations of the laparoscopic approach. However, similar to the situation in laparoscopic surgery, appropriate case selection (simple vs. complex) with respect to the actual robotic expertise of the team may be a critical determinant of outcome. The present study aimed to analyze the clinical outcome after robotic colorectal surgery over time based on the complexity of the surgical procedure. METHODS: All robotic colorectal resections (n = 85) performed at the Department of Surgery, Medical University of Vienna, between the beginning of the program in April 2015 until December 2019 were retrospectively analyzed. To compare surgical outcome over time, the cohort was divided into 2 time periods based on case sequence (period 1: patients 1-43, period 2: patients 44-85). Cases were assigned a complexity level (I-IV) according to the type of resection, severity of disease, sex and body mass index (BMI). Postoperative complications were classified using the Clavien-Dindo classification. RESULTS: In total, 47 rectal resections (55.3%), 22 partial colectomies (25.8%), 14 abdomino-perineal resections (16.5%) and 2 proctocolectomies (2.4%) were performed. Of these, 69.4% (n = 59) were oncologic cases. The overall rate of major complications (Clavien Dindo III-V) was 16.5%. Complex cases (complexity levels III and IV) were more often followed by major complications than cases with a low to medium complexity level (I and II; 25.0 vs. 5.4%, p = 0.016). Furthermore, the rate of major complications decreased over time from 25.6% (period 1) to 7.1% (period 2, p = 0.038). Of note, the drop in major complications was associated with a learning effect, which was particularly pronounced in complex cases as well as a reduction of case complexity from 67.5% to 45.2% in the second period (p = 0.039). CONCLUSIONS: The risk of major complications after robotic colorectal surgery increases significantly with escalating case complexity (levels III and IV), particularly during the initial phase of a new colorectal robotic surgery program. Before robotic proficiency has been achieved, it is therefore advisable to limit robotic colorectal resection to cases with complexity levels I and II in order to keep major complication rates at a minimum.

Outcome of no oral antibiotic prophylaxis and bowel preparation in Crohn's diseases surgery.

BACKGROUND: Recent studies support the use of mechanical bowel preparation and/or oral antibiotic prophylaxis in patients operated on for Crohn's disease (CD); however, data are scarce, especially for laparoscopic surgery. Therefore, this study was carried out to investigate the effect of laparoscopic surgery on complication rates in patients not undergoing standardized bowel preparation but single shot antibiotics. METHODS: In this study 255 consecutive patients who underwent a laparoscopic intestinal resection for CD at a tertiary referral center between 1997 and 2014 were retrospectively analyzed. Superficial surgical site infections (SSI), organ/space infections and ileus were recorded and grouped according to the type of resection (colorectal vs. small intestine ± ileocecal). RESULTS: The baseline characteristics of the groups were comparable. Colorectal resections showed a significantly increased risk of organ/space infection (4.6% in small intestine ± ileocecal vs. 14.3% in colorectal resections p = 0.039). The superficial SSI rate was low in both groups (1.8% in small intestine ± ileocecal resection vs. 0% in colorectal resections, p = 1.000). Univariate binary logistic regression analysis revealed a statistically significant influence of duration of surgery (p = 0.001) and type of resection (p = 0.031) on organ/space infection. In multivariate analysis, only duration of surgery (OR 1.111, 95% CI 1.026-1.203 for every 10 min, p = 0.009) remained significant for postoperative organ/space infections. CONCLUSIONS: Single-shot antibiotic therapy without bowel preparation is safe in patients undergoing minimally invasive surgery and was associated with a low number of complications; however, organ/space infections were more common if colorectal resections were performed. Therefore, combined bowel preparation might be beneficial when the (sigmoid) colon or rectum are involved.

Immunological differences between colorectal cancer and normal mucosa uncover a prognostically relevant immune cell profile.

T cells in colorectal cancer (CRC) are associated with improved survival. However, checkpoint immunotherapies antagonizing the suppression of these cells are ineffective in the great majority of patients. To better understand the immune cell regulation in CRC, we compared tumor-associated T lymphocytes and macrophages to the immune cell infiltrate of normal mucosa. Human colorectal tumor specimen and tumor-distant normal mucosa tissues of the same patients were collected. Phenotypes and functionality of tissue-derived T cells and macrophages were characterized using immunohistochemistry, RNA in situ hybridization, and multiparameter flow cytometry. CRC contained significantly higher numbers of potentially immunosuppressive CD39 and Helios-expressing regulatory T cells in comparison to normal mucosa. Surprisingly, we found a concomitant increase of pro-inflammatory IFNγ -producing T cells. PD-L1+ stromal cells were decreased in the tumor tissue. Macrophages in the tumor compared to tumor-distant normal tissue appear to have an altered phenotype, identified by HLA-DR, CD14, CX3CR1, and CD64, and tolerogenic CD206+ macrophages are quantitatively reduced. The prognostic effect of these observed differences between distant mucosa and tumor tissue on the overall survival was examined using gene expression data of 298 CRC patients. The combined gene expression of increased FOXP3, IFNγ, CD14, and decreased CD206 correlated with a poor prognosis in CRC patients. These data reveal that the CRC microenvironment promotes the coexistence of seemingly antagonistic suppressive and pro-inflammatory immune responses and might provide an explanation why a blockade of the PD1/PD-L1 axis is ineffective in CRC. This should be taken into account when designing novel treatment strategies.

Plasma metabolites associated with colorectal cancer: A discovery-replication strategy.

Colorectal cancer is known to arise from multiple tumorigenic pathways; however, the underlying mechanisms remain not completely understood. Metabolomics is becoming an increasingly popular tool in assessing biological processes. Previous metabolomics research focusing on colorectal cancer is limited by sample size and did not replicate findings in independent study populations to verify robustness of reported findings. Here, we performed a ultrahigh performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UHPLC-QTOF-MS) screening on EDTA plasma from 268 colorectal cancer patients and 353 controls using independent discovery and replication sets from two European cohorts (ColoCare Study: n = 180 patients/n = 153 controls; the Colorectal Cancer Study of Austria (CORSA) n = 88 patients/n = 200 controls), aiming to identify circulating plasma metabolites associated with colorectal cancer and to improve knowledge regarding colorectal cancer etiology. Multiple logistic regression models were used to test the association between disease state and metabolic features. Statistically significant associated features in the discovery set were taken forward and tested in the replication set to assure robustness of our findings. All models were adjusted for sex, age, BMI and smoking status and corrected for multiple testing using False Discovery Rate. Demographic and clinical data were abstracted from questionnaires and medical records.

The ASAMET trial: a randomized, phase II, double-blind, placebo-controlled, multicenter, 2 × 2 factorial biomarker study of tertiary prevention with low-dose aspirin and metformin in stage I-III colorectal cancer patients.

BACKGROUND: Epidemiological studies and cardiovascular prevention trials have shown that low-dose aspirin can reduce colorectal cancer (CRC) incidence and mortality, including inhibition of distant metastases. Metformin has also been associated with decreased colon adenoma recurrence in clinical trials and lower CRC incidence and mortality in epidemiological studies in diabetics. While both drugs have been tested as single agents, their combination has not been tested in cancer prevention trials. METHODS/DESIGN: This is a randomized, placebo-controlled, double-blind, 2 × 2 biomarker trial of aspirin and metformin to test the activity of either agent alone and the potential synergism of their combination on a set of surrogate biomarkers of colorectal carcinogenesis. After surgery, 160 patients with stage I-III CRC are randomly assigned in a four-arm trial to either aspirin (100 mg day), metformin (850 mg bis in die), their combination, or placebo for one year. The primary endpoint biomarker is the change of IHC expression of nuclear factor kappa-B (NFκB) in the unaffected mucosa of proximal and distal colon obtained by multiple biopsies in two paired colonoscopies one year apart. Additional biomarkers will include: 1) the measurement of circulating IL-6, CRP and VEGF; 2) the IHC expression of tissue pS6K, p53, beta-catenin, PI3K; 3) the associations of genetic markers with treatment response as assessed by next generation sequencing of primary tumors; 4) the genomic profile of candidate genes, pathways, and overall genomic patterns in tissue biopsies by genome wide gene expression arrays; and 5) the evaluation of adenoma occurrence at 1 year. DISCUSSION: A favorable biomarker modulation by aspirin and metformin may provide important clues for a subsequent phase III adjuvant trial aimed at preventing second primary cancer, delaying recurrence and improving prognosis in patients with CRC. TRIAL REGISTRATION: EudraCT Number: 2015-004824-77; ClinicalTrial.gov Identifier: NCT03047837 . Registered on February 1, 2017.

Predictive and Prognostic Implication of Bowel Resections During Primary Cytoreductive Surgery in Advanced Epithelial Ovarian Cancer.

OBJECTIVES: The aims of this study were to assess anastomotic leakage (AL) rate and risk factors for AL in patients with advanced epithelial ovarian cancer (EOC) undergoing cytoreductive surgery including bowel resections and to evaluate the prognostic implication of AL. METHODS: Data of 350 consecutive patients with International Federation of Gynecology and Obstetrics EOC stage IIB-IV who underwent cytoreductive surgery at the Department of General Gynecology and Gynecologic Oncology of the General Hospital of Vienna between 2003 and 2017 were collected. Within this cohort, 192 patients (54.9%) underwent at least 1 bowel resection and were further analyzed. Preoperative risk factors for AL were computed using logistic regression models. Prognostic factors for overall survival were evaluated by using log-rank tests and multivariable Cox regression model. RESULTS: Overall, the AL rate was 4.7% for patients with advanced EOC undergoing cytoreductive surgery with at least 1 bowel resection, including patients with multiple large bowel resections. The AL rate for patients with isolated rectosigmoid resection was 1.9%. In univariate analysis, the number of anastomoses per surgery (P = 0.04) was associated with the occurrence of AL. In multivariable analysis, rectosigmoid resection with additional large bowel resection was associated with a higher risk of AL compared with isolated rectosigmoid resection (P = 0.046; odds ratio, 7.23 [95% confidence interval, 1.04-50.39]). Anastomotic leakage was associated with decreased overall survival (P = 0.04) in univariate but not in multivariable survival analysis. CONCLUSIONS: Anastomotic leakage rate after rectosigmoid resection in advanced EOC is acceptably low and outweighs increased perioperative risks when performed in a high-volume institution. Nonetheless, the occurrence of AL is a severe adverse event, which even seems to negatively affect patients' overall prognosis. As no factor could be identified to clearly predict AL, extensive procedures comprising multiple bowel resections, should be avoided particularly when complete resection cannot be achieved.

Circulating Free Methylated Tumor DNA Markers for Sensitive Assessment of Tumor Burden and Early Response Monitoring in Patients Receiving Systemic Chemotherapy for Colorectal Cancer Liver Metastasis.

BACKGROUND: Neoadjuvant chemotherapy (neoCTx) followed by hepatic resection is the treatment of choice for patients with colorectal cancer liver metastasis (CLM). Treatment response is generally assessed using radiologic imaging after several cycles of chemotherapy. However, earlier assessment of response would be desirable since nonresponders could be switched early to an alternative chemotherapy regimen. Recent evidence suggests that circulating free methylated tumor DNA is a highly sensitive biomarker and may more accurately reflect tumor burden and treatment response than conventional markers for CRC. PATIENTS AND METHODS: Thirty-four patients with CLM who received neoCTx prior to intended hepatic resection were included in this prospective nonrandomized study. Peripheral blood plasma was collected at baseline and before each cycle of neoCTx and was then analyzed for aberrant methylation of 48 CRC-associated genes. Methylation marker levels were correlated with baseline tumor volume and treatment response and compared with the standard tumor markers CEA and CA 19-9. RESULTS: The methylation markers SEPT9, DCC, BOLL, and SFRP2 were present in all patients at baseline and displayed a stronger correlation with tumor volume than CEA and CA 19-9. Serial measurement of these methylation markers allowed for discrimination between operated and nonoperated patients already after 1 cycle of neoCTx with high sensitivity and specificity. The early dynamic changes of SEPT9 and DCC also seemed to correlate with pathohistological response. CONCLUSION: Our data suggest that serial measurements of CRC-associated methylation markers could be a particularly valuable tool for early response assessment in patients receiving neoCTx for CLM.