Liver Fibrosis Is Associated with Poorer Overall Survival and Higher Recurrence Rate in Patients with Cholangiocarcinoma.

INTRODUCTION: Cholangiocarcinoma is the second most common primary liver tumour worldwide with an increasing incidence in recent decades. While the effects of fibrosis on hepatocellular carcinoma have been widely demonstrated, the impact on cholangiocarcinoma remains unclear. The aim of this study was to evaluate the impact of liver fibrosis on overall survival (OS) and disease-free survival (DFS) in patients who have undergone liver resection for cholangiocarcinoma. METHODS: Eighty patients with cholangiocarcinoma who underwent curatively intended liver surgery between January 2007 and December 2020 were included in this retrospective single-centre study. Clinical and histopathological features were analysed. The primary endpoint was cause-specific survival. Secondary endpoints were DFS and identification of prognostic factors. RESULTS: The present study shows that the median OS is significantly reduced in patients with fibrosis (p < 0.001). The median OS in patients with fibrosis was three times shorter than in the group without fibrosis. In addition, a significantly shorter DFS was observed in patients with fibrosis (p < 0.002). Multivariate analysis showed that fibrosis is the strongest independent factor with a negative impact on OS and DFS. CONCLUSION: Liver fibrosis has a significant impact on OS and DFS in patients with cholangiocarcinoma. Patients with known liver fibrosis require thorough perioperative care and postoperative follow-up.

Liver Resection in Synchronous Bilobar versus Unilobar Colorectal Liver Metastases: A Retrospective Analysis of Oncological Outcomes and Patient Survival.

INTRODUCTION: Resection of colorectal liver metastasis has emerged as the standard treatment. Our study compares oncological outcomes of patients with resected synchronous bilobar versus unilobar colorectal liver metastasis. METHODS: This retrospective study presents long-term follow-up data of 105 consecutive patients with primary colorectal cancer and synchronous liver metastasis. All patients underwent primary tumor and metastasis resections between 2007 and 2019. RESULTS: Fifty-five patients with bilobar and 50 patients with unilobar colorectal liver metastases were included. No significant difference in overall, tumor-specific, or recurrence-free survival was observed between patients with bilobar and unilobar metastases. After case-control matching, the results were confirmed in patients with similar tumor burdens. In the multivariate analysis, chemotherapy following liver metastasis resection was a significant prognostic factor associated with improved overall survival (hazard ratio 0.518, 95% confidence interval: 0.302-0.888, p = 0.017). CONCLUSION: Overall survival, as well as tumor-specific and recurrence-free survival, did not differ between patients with unilobar and bilobar liver metastasis. These findings contribute to the understanding that primary tumor and metastasis resection in eligible patients improve long-term outcomes.

Retrospective study of prognosis of patients with multiple colorectal carcinomas: synchronous versus metachronous makes the difference.

PURPOSE: Little is known about difference between synchronous colorectal cancer (SCRC) and metachronous colorectal cancer (MCRC) despite the relevance for this selected patient group. The aim of this retrospective review was to analyze patients with SCRC and MCRC. METHODS: All patients who underwent surgery for SCRC and MCRC between 1982 and 2019 were included in this retrospective analysis of our tertiary referral center. Clinical, histological, and molecular genetic characteristics were analyzed. The primary endpoint was cause-specific survival, evaluated by the Kaplan-Meier method. Secondary endpoints were recurrence-free survival and the identification of prognostic factors. RESULTS: Overall, 3714 patients were included in this analysis. Of those, 3506 (94.4%) had a primary unifocal colorectal cancer (PCRC), 103 (2.7%) had SCRC, and 105 (2.8%) had MCRC. SCRC occurred more frequently in elderly (p=0.009) and in male patients (p=0.027). There were no differences concerning tumor stages or grading. Patients with SCRC did not show altered recurrence or survival rates, as compared to unifocal tumors. However, MCRC had a lower rate of recurrence, compared to PCRC (24% vs. 41%, p=0.002) and a lower rate of cause-specific death (13% vs. 37%, p<0.001). Five-year cause-specific survival rates were 63±1% for PCRC, 62±6% for SCRC (p=0.588), and 88±4% for MCRC (p<0.001). Multivariable analysis revealed that MCRC were an independent favorable prognostic parameter regarding case-specific survival. CONCLUSION: Patients with SCRC seem to not have a worse prognosis compared to patients with PCRC. Noteworthy, patients with MCRC showed better survival rates in this retrospective analysis.

Crohn's disease: a population-based study of surgery in the age of biological therapy.

PURPOSE: Despite primary conservative therapy for Crohn's disease, a considerable proportion of patients ultimately needs to undergo surgery. Presumably, due to the increased use of biologics, the number of surgeries might have decreased. This study aimed to delineate current case numbers and trends in surgery in the era of biological therapy for Crohn's disease. METHODS: Nationwide standardized hospital discharge data (diagnosis-related groups statistics) from 2010 to 2017 were used. All patients who were admitted as inpatient Crohn's disease cases in Germany were included. Time-related development of admission numbers, rate of surgery, morbidity, and mortality of inpatient Crohn's disease cases were analyzed. RESULTS: A total number of 201,165 Crohn's disease cases were included. Within the analyzed time period, the total number of hospital admissions increased by 10.6% (n = 23,301 vs. 26,069). While gender and age distribution remained comparable, patients with comorbidities such as stenosis formation (2010: 10.1%, 2017: 13.4%) or malnutrition (2010: 0.8%, 2017: 3.2%) were increasingly admitted. The total number of all analyzed operations for Crohn's disease increased by 7.5% (2010: n = 1567; 2017: n = 1694). On average, 6.8 ± 0.2% of all inpatient patients received ileocolonic resections. Procedures have increasingly been performed minimally invasive (2010: n = 353; 2017: n = 687). The number of postoperative complications remained low. CONCLUSION: Despite the development of novel immunotherapeutics, the number of patients requiring surgery for Crohn's disease remains stable. Interestingly, patients have been increasingly hospitalized with stenosis and malnutrition. The trend towards more minimally invasive operations has not relevantly changed the rate of overall complications.

Novel role for CRK adaptor proteins as essential components of SRC/FAK signaling for epithelial-mesenchymal transition and colorectal cancer aggressiveness.

Epithelial-mesenchymal transition (EMT) is a cell plasticity process required for metastasis and chemoresistance of carcinoma cells. We report a crucial role of the signal adaptor proteins CRK and CRKL in promoting EMT and tumor aggressiveness, as well as resistance against chemotherapy in colorectal and pancreatic carcinoma. Genetic loss of either CRKL or CRK partially counteracted EMT in three independent cancer cell lines. Strikingly, complete loss of the CRK family shifted cells strongly toward the epithelial phenotype. Cells exhibited greatly increased E-cadherin and grew as large, densely packed clusters, completely lacked invasiveness and the ability to undergo EMT induced by cytokines or genetic activation of SRC. Furthermore, CRK family-deficiency significantly reduced cell survival, proliferation and chemoresistance, as well as ERK1/2 phosphorylation and c-MYC protein levels. In accordance, MYC-target gene expression was identified as novel hallmark process positively regulated by CRK family proteins. Mechanistically, CRK proteins were identified as pivotal amplifiers of SRC/FAK signaling at focal adhesions, mediated through a novel positive feedback loop depending on RAP1. Expression of the CRK family and the EMT regulator ZEB1 was significantly correlated in samples from colorectal cancer patients, especially in invasive regions. Further, high expression of CRK family genes was significantly associated with reduced survival in locally advanced colorectal cancer, as well as in pan-cancer datasets from the TCGA project. Thus, CRK family adaptor proteins are promising therapeutic targets to counteract EMT, chemoresistance, metastasis formation and minimal residual disease. As proof of concept, CRK family-mediated oncogenic signaling was successfully inhibited by a peptide-based inhibitor.

MALDI-2 Mass Spectrometry and Immunohistochemistry Imaging of Gb3Cer, Gb4Cer, and Further Glycosphingolipids in Human Colorectal Cancer Tissue.

The main cellular receptors of Shiga toxins (Stxs), the neutral glycosphingolipids (GSLs), globotriaosylceramide (Gb3Cer/CD77) and globotetraosylceramide (Gb4Cer), are significantly upregulated in about half of the human colorectal carcinomas (CRC) and in other cancers. Therefore, conjugates exploiting the Gb3Cer/Gb4Cer-binding B subunit of Stx (StxB) have attracted great interest for both diagnostic and adjuvant therapeutic interventions. Moreover, fucosylated GSLs were recognized as potential tumor-associated targets. One obstacle to a broader use of these receptor/ligand systems is that the contribution of specific GSLs to tumorigenesis, in particular, in the context of an altered lipid metabolism, is only poorly understood. A second is that also nondiseased organs (e.g., kidney) and blood vessels can express high levels of certain GSLs, not least Gb3Cer/Gb4Cer. Here, we used, in a proof-of-concept study, matrix-assisted laser desorption/ionization mass spectrometry imaging combined with laser-induced postionization (MALDI-2-MSI) to simultaneously visualize the distribution of several Gb3Cer/Gb4Cer lipoforms and those of related GSLs (e.g., Gb3Cer/Gb4Cer precursors and fucosylated GSLs) in tissue biopsies from three CRC patients. Using MALDI-2 and StxB-based immunofluorescence microscopy, Gb3Cer and Gb4Cer were mainly found in dedifferentiated tumor cell areas, tumor stroma, and tumor-infiltrating blood vessels. Notably, fucosylated GSL such as Fuc-(n)Lc4Cer generally showed a highly localized expression in dysplastic glands and indian file-like cells infiltrating adipose tissue. Our "molecular histology" approach could support stratifying patients for intratumoral GSL expression to identify an optimal therapeutic strategy. The improved chemical coverage by MALDI-2 can also help to improve our understanding of the molecular basis of tumor development and GSL metabolism.

Validation of the revised 2018 AAST-OIS classification and the CT severity index for prediction of operative management and survival in patients with blunt spleen and liver injuries.

OBJECTIVES: Non-operative management (NOM) is increasingly utilised in blunt abdominal trauma. The 1994 American Association of Surgery of Trauma grading (1994-AAST) is applied for clinical decision-making in many institutions. Recently, classifications incorporating contrast extravasation such as the CT severity index (CTSI) and 2018 update of the liver and spleen AAST were proposed to predict outcome and guide treatment, but validation is pending. METHODS: CT images of patients admitted 2000-2016 with blunt splenic and hepatic injury were systematically re-evaluated for 1994/2018-AAST and CTSI grading. Diagnostic accuracy, diagnostic odds ratio (DOR), and positive and negative predictive values were calculated for prediction of in-hospital mortality. Correlation with treatment strategy was assessed by Cramer V statistics. RESULTS: Seven hundred and three patients were analysed, 271 with splenic, 352 with hepatic and 80 with hepatosplenic injury. Primary NOM was applied in 83% of patients; mortality was 4.8%. Comparing prediction of mortality in mild and severe splenic injuries, the CTSI (3.1% vs. 10.3%; diagnostic accuracy = 75.4%; DOR = 3.66; p = 0.006) and 1994-AAST (3.3% vs. 10.5%; diagnostic accuracy = 77.9%; DOR = 3.45; p = 0.010) were more accurate compared with the 2018-AAST (3.4% vs. 8%; diagnostic accuracy = 68.2%; DOR = 2.50; p = 0.059). In hepatic injuries, the CTSI was superior to both AAST classifications in terms of diagnostic accuracy (88.7% vs. 77.1% and 77.3%, respectively). CTSI and 2018-AAST correlated better with the need for surgery in severe vs. mild hepatic (Cramer V = 0.464 and 0.498) and splenic injuries (Cramer V = 0.273 and 0.293) compared with 1994-AAST (Cramer V = 0.389 and 0.255; all p < 0.001). CONCLUSIONS: The 2018-AAST and CTSI are superior to the 1994-AAST in correlation with operative treatment in splenic and hepatic trauma. The CTSI outperforms the 2018-AAST in mortality prediction. KEY POINTS: • Non-operative management of blunt abdominal trauma is increasingly applied and correct patient stratification is crucial. • CT-based scoring systems are used to assess injury severity and guide clinical decision-making, whereby the 1994 version of the American Association of Surgery of Trauma Organ Injury Scale (AAST-OIS) is currently most commonly utilised. • Including contrast media extravasation in CT-based grading improves management and outcome prediction. While the 2018-AAST classification and the CT-severity-index (CTSI) better correlate with need for surgery compared to the 1994-AAST, the CTSI is superior in outcome-prediction to the 2018-AAST.

Simultaneous Versus Staged Resection of Colorectal Cancer Liver Metastasis: A Retrospective Single-Center Study.

BACKGROUND: For patients with colorectal cancer and synchronous liver metastasis, either a simultaneous, or a two-staged resection of the primary tumor and the liver metastases is possible. There are currently no guidelines preferring one approach to the other. MATERIAL AND METHODS: Consecutive patients who underwent hepatic resection at our university hospital from 2007-2016 were included. Clinical, histopathologic, serologic, and survival data were analyzed. The primary end point was tumor-specific survival for patients with simultaneous versus staged resections. RESULTS: Of all 140 patients, 68 underwent simultaneous resection and 72 underwent staged resection. The characteristics of both groups were comparable. Patients with simultaneous resections had a shorter duration of cumulative operation time (299 versus 460 min; P = 0.003) and a shorter cumulative length of hospital stay (23 versus 43 d; P = 0.002). Perioperative mortality (P = 0.257) did not differ significantly; however, patients with simultaneous resections had higher rates of grade 2 complications according to Clavien-Dindo (P < 0.001). Tumor-specific 1-y survival was 85 ± 5% for simultaneous and 83 ± 5% for staged resection (P = 0.631). On multivariable analysis, pT4 (P = 0.038), pN3 (P = 0.003), and G3/4 (P = 0.041) of the primary tumor and postoperative complications (Clavien-Dindo 3/4/5, P = 0.003) were poor prognostic factors regarding tumor-specific survival. CONCLUSIONS: This is one of the largest and most thoroughly documented retrospective single-center studies of consecutive patients with synchronous hepatic metastases. Simultaneous resection of colorectal cancer together with hepatic metastases is a safe procedure in selected patients and does not have a significant influence on long-term survival.

Gut microbiota modulate T cell trafficking into human colorectal cancer.

OBJECTIVE: Tumour-infiltrating lymphocytes (TILs) favour survival in human colorectal cancer (CRC). Chemotactic factors underlying their recruitment remain undefined. We investigated chemokines attracting T cells into human CRCs, their cellular sources and microenvironmental triggers. DESIGN: Expression of genes encoding immune cell markers, chemokines and bacterial 16S ribosomal RNA (16SrRNA) was assessed by quantitative reverse transcription-PCR in fresh CRC samples and corresponding tumour-free tissues. Chemokine receptor expression on TILs was evaluated by flow cytometry on cell suspensions from digested tissues. Chemokine production by CRC cells was evaluated in vitro and in vivo, on generation of intraperitoneal or intracecal tumour xenografts in immune-deficient mice. T cell trafficking was assessed on adoptive transfer of human TILs into tumour-bearing mice. Gut flora composition was analysed by 16SrRNA sequencing. RESULTS: CRC infiltration by distinct T cell subsets was associated with defined chemokine gene signatures, including CCL5, CXCL9 and CXCL10 for cytotoxic T lymphocytes and T-helper (Th)1 cells; CCL17, CCL22 and CXCL12 for Th1 and regulatory T cells; CXCL13 for follicular Th cells; and CCL20 and CCL17 for interleukin (IL)-17-producing Th cells. These chemokines were expressed by tumour cells on exposure to gut bacteria in vitro and in vivo. Their expression was significantly higher in intracecal than in intraperitoneal xenografts and was dramatically reduced by antibiotic treatment of tumour-bearing mice. In clinical samples, abundance of defined bacteria correlated with high chemokine expression, enhanced T cell infiltration and improved survival. CONCLUSIONS: Gut microbiota stimulate chemokine production by CRC cells, thus favouring recruitment of beneficial T cells into tumour tissues.

Genetic and immunological biomarkers predict metastatic disease recurrence in stage III colon cancer.

BACKGROUND: Even though the post-operative outcome varies greatly among patients with nodal positive colon cancer (UICC stage III), personalized prediction of systemic disease recurrence is currently insufficient. We investigated in a retrospective setting whether genetic and immunological biomarkers can be applied for stratification of distant metastasis occurrence risk. METHODS: Eighty four patients with complete resection (R0) of stage III colon cancer from two clinical centres were analysed for genetic biomarkers: microsatellite instability, oncogenic mutations in KRAS exon2 and BRAF exon15, expression of osteopontin and the metastasis-associated genes SASH1 and MACC1. Tumor-infiltrating CD3 and CD8 positive T-cells were quantified by immunocytochemistry. Results were correlated with outcome and response to 5-FU based adjuvant chemotherapy, using Cox's proportional hazard models and integrative two-step cluster analysis. RESULTS: Distant metastasis risk was significantly correlated with oncogenic KRAS mutations (p = 0.015), expression of SASH1 (p = 0.016), and the density of CD8-positive T-cells (p = 0.007) in Kaplan-Meier analysis. Upon multivariate Cox-regression analysis, KRAS mutation (p = 0.008) and density of CD8-positive TILs (p = 0.009) were retained as prognostic parameters for metachronous distant metastasis. Integrative two-step cluster analysis was used to combine all genetic markers, allowing stratification of patient subgroups. Post-operative distant metastasis risk ranged from 31% (low-risk) to 41% (intermediate), and 57% (high-risk) (p = 0.032). Increased expression of osteopontin (p = 0.019) and low density of CD8-positive T-cells (p = 0.043) were significantly associated with unfavourable response to 5-FU. CONCLUSIONS: Integrative biomarker analysis allows stratification of stage III colon cancer patients for the risk of metastatic disease recurrence and may indicate response to 5-FU. Thus, biomarker analysis might facilitate the use of adjuvant therapy for high risk patients.

Elevated systemic levels of the matrix metalloproteinase inhibitor TIMP-1 correlate with clinical markers of cachexia in patients with chronic pancreatitis and pancreatic cancer.

BACKGROUND: Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a candidate diagnostic and prognostic biomarker for pancreatic ductal adenocarcinoma (PDAC). Here, we determined the possible association of systemic TIMP-1 levels with cachexia and jaundice, two common PDAC-associated conditions. METHODS: Plasma TIMP-1 was measured by ELISA in patients diagnosed with PDAC (n = 36) and chronic pancreatitis (CP) (n = 25). Patients without pancreatic pathologies and known malignancies of other origin served as controls (n = 13). TIMP-1 levels in these patients were tested for asscociation with jaundice and chachexia, and furthermore correlated with cachexia-related clinical parameters such as weight loss and ferritin, parameters of lung function, hemoglobin and liver synthesis parameters. RESULTS: TIMP-1 plasma levels were mostly higher in CP and PDAC patients with concomitant jaundice or cachexia. Elevated plasma TIMP-1 levels were also associated with clinical cachexia markers, including absolute and relative values of weight loss and lung function, as well as ferritin, hemoglobin, and cholinesterase levels. TIMP-1 levels significantly correlated with cachexia only in patients without jaundice. Jaundice also impaired the use of TIMP-1 as a prognostic marker in cancer patients. Relating to cachexia status alone, a slightly improved association of TIMP-1 levels with survival of PDAC patients was observed. CONCLUSION: This retrospective study reports for the first time that plasma levels of TIMP-1 are associated with pancreatic lesion-induced cachexia in patients without jaundice. TIMP-1 is counterindicated as a survival marker in patients with jaundice.

The impact of surgically placed, intraperitoneal drainage on morbidity and mortality after pancreas resection- A systematic review & meta-analysis.

BACKGROUND: Although routinely used, the benefit of surgically placed intraperitoneal drains after pancreas resection is still under debate. To assess the true impact of intraperitoneal drains in pancreas resection, a systematic review with meta-analysis was performed. METHODS: For this, the Preferred-Reporting-Items-for-Systematic-review-and-Meta-Analysis/PRISMA-guidelines were conducted and Pubmed/Medline, Embase, Scopus and The Cochrane Library were screened for relevant studies. RESULTS: 8 retrospective and 3 prospective studies were included in the systematic review. No difference was found between patients with or without intraperitoneal drains in mortality (Risk-ratio/RR 0.74, 95%-Confidence-interval/CI: 0.47-1.18, p = 0.20), in Grade B/C-postoperative pancreatic fistulas/POPF (RR 1.31, 95%-CI: 0.74-2.32, p = 0.35), in intraabdominal abscesses (RR 0.92, 95%-CI: 0.65-1.30, p = 0.64), in surgical site infection (RR 1.20, 95%-CI: 0.85-1.70, p = 0.30), in delayed gastric emptying (RR 1.11, 95%-CI: 0.65-1.90, p = 0.71), in postoperative haemorrhages (RR 0.92 95%-CI: 0.63-1.33, p = 0.65), in reoperations (RR 1.15, 95%-CI: 0.87-1.52, p = 0.33), or in radiological reinterventions (RR 0.95, 95%-CI: 0.69-1.31, p = 0.76). The risk for overall morbidity (RR 1.16, 95%-CI: 1.04-1.29, p = 0.008), of any POPF (RR 2.15, 95%-CI: 1.52-3.04, p < 0.0001) and of readmissions (RR 1.23, 95%-CI: 1.04-1.45, p = 0.01) was increased for patients with intraperitoneal drain compared to patients without following pancreatic resection. CONCLUSION: Regarding the controversial results of the recent prospective, randomized trials this meta-analysis revealed no difference in mortality but an increased risk for postoperative morbidity, POPF and readmissions of patients with intraperitoneal drains after pancreatic resection. Therefore, the indication for intraperitoneal drains should be critically weighed in patients undergoing pancreatic resections.

IL-4 mRNA Is Downregulated in the Liver of Pancreatic Cancer Patients Suffering from Cachexia.

BACKGROUND: Interleukin-4 (IL-4) together with interleukin-13 (IL-13) play an important role in inflammation and wound repair, and are known to be upregulated in human skeletal muscle after strenuous physical exercise. Additionally, these cytokines may act as autocrine growth factors in pancreatic cancer cells. We hypothesize that IL-4, IL-13, and their corresponding receptors are involved in mechanism of cancer cachexia. METHODS: Tissue samples from human skeletal muscle, white fat, liver, healthy pancreas, and pancreatic ductal adenocarcinoma were analyzed by quantitative real-time polymerase chain reaction for mRNA expression levels of IL-4, IL-13, IL-4 receptor α, and IL-13 receptor α1. RESULTS: We demonstrate for the first time that liver IL-4 mRNA is downregulated in vivo in patients with pancreatic cancer and cachexia. Additionally, IL-4 mRNA in the liver inversely correlated with musculus psoas thickness. CONCLUSION: We speculate that suppression of IL-4 is involved in cancer cachexia, although the exact mechanisms have to be further elucidated.

What to do after R1-resection of adenocarcinomas of the esophagogastric junction?

BACKGROUND AND OBJECTIVES: The management of R1-resected adenocarcinoma of the esophagogastric junction (AEG) is unclear. We aimed to identify risk factors and prevalence of R1 resections, their recurrence and prognosis, and efficacy of postoperative therapy. METHODS: A single center cohort of 766 consecutive patients undergoing curative intent resection for AEG was analyzed retrospectively. RESULTS: R1-resection rate was 13%. Poorer tumor differentiation, higher T-, N-, and UICC/AJCC-stages were associated with R1-resections. Compared to R0-resected patients, R1-resected patients had a higher incidence of tumor recurrence (77% vs. 32%; P < 0.001) and worse overall survival (5-year overall survival 43% vs. 10%; P < 0.001). The pattern of recurrence did not differ between R0- and R1-resections with distant metastases in 90% and 87% of patients with tumor recurrence. We found a trend towards better overall survival for R1-resected patients receiving postoperative therapy compared to R1-resected patients without postoperative therapy (median 17.4 vs. 14.6 months, P = 0.056). CONCLUSIONS: The association of R1-resections with poor tumor characteristics allows for identification of patients at risk for R1-resection. As in R0-resections, tumor recurrence in R1-resections is mainly systemic, not local. The potential benefit of additive local postoperative therapies in R1-resected patients must be balanced against overall prognosis and therapy-specific morbidity and mortality. J. Surg. Oncol. 2016;114:428-433. © 2016 Wiley Periodicals, Inc.

Right Sided Colon Cancer as a Distinct Histopathological Subtype with Reduced Prognosis.

BACKGROUND/AIMS: Recent data suggest that tumors of the right and left colon should be distinguished as they differ in clinical and molecular characteristics. METHODS: A total of 1,319 patients who underwent surgical resection for colon cancer (CC) were investigated. Tumors between the ileocecal valve and the hepatic flexure were classified as right CC (RCC), tumors between the splenic flexure and the rectum as left CC (LCC). RESULTS: RCC revealed a higher cause-specific mortality risk (hazard ratio 1.36, 95% CI 1.10-1.68, p = 0.005) and lower 5-year cause-specific (RCC 64.9%, 95% CI 60.4-69.4, LCC 70.7%, 95% CI 67.2-74.2, p = 0.032) and disease-free (RCC 56.0%, 95% CI 51.5-60.5, LCC 59.9%, 95% CI 56.2-63.6, p = 0.025) survival rates. RCCs were more often microsatellite instable (RCC 37.2%, LCC 13.0%, p < 0.001) and more often showed KRAS (RCC 42.5%, LCC 18.9%, p = 0.001) and BRAF mutations (RCC 26.6%, LCC 3.2%, p < 0.001). CONCLUSION: RCC and LCC differ significantly regarding clinical, histopathological and molecular genetic features and can be considered as distinct entities. The reduced prognosis of RCC may be caused by higher rates of microsatellite instability, KRAS and BRAF mutations.

Resectability After First-Line FOLFIRINOX in Initially Unresectable Locally Advanced Pancreatic Cancer: A Single-Center Experience.

BACKGROUND: FOLFIRINOX is an active but relatively toxic chemotherapeutic regimen for patients with metastatic pancreatic ductal adenocarcinoma (PDAC). The increased frequency of responding tumors shift interest to neoadjuvant approaches. We report our institutional experience with FOLFIRINOX for therapy-naïve patients with locally advanced and initially unresectable PDAC. METHODS: All patients with unresectable locally advanced PDAC who underwent treatment with FOLFIRINOX at a single center between 2011 and 2014 were identified and evaluated retrospectively regarding chemotherapy response, toxicity, conversion to resectability, and survival. Resectability, response to chemotherapy, and postoperative complications were reported according to NCCN-guidelines, RECIST-criteria, and Clavien-Dindo-classification, respectively. RESULTS: Overall, 14 patients received FOLFIRINOX as first-line therapy for locally advanced and unresectable PDAC. Fifty-seven percent of the patients had severe tumor-related comorbidities at the time of diagnosis, and in 86 %, dose reduction due to toxicity was necessary during a median of seven cycles. Nevertheless, only one patient had progressive disease during FOLFIRINOX, whereas the others experienced stable disease (n = 6) or partial remission (n = 6; no restaging in one patient). Oncological tumor resection was possible in 4 patients (29 % of all patients) with no postoperative mortality and only one grade 2 surgical complication. After a median follow-up of 10 months, 4 of the 14 patients were still in remission, 5 were alive with stable disease under ongoing systemic chemotherapy, and 5 died tumor-related. CONCLUSIONS: FOLFIRINOX is a powerful first-line regimen that leads to resectability in a substantial portion of patients with initially unresectable pancreatic cancer.

Intra-operative wound irrigation to reduce surgical site infections after abdominal surgery: a systematic review and meta-analysis.

PURPOSE: Surgical site infection (SSI) remains to be one of the most frequent infectious complications following abdominal surgery. Prophylactic intra-operative wound irrigation (IOWI) before skin closure has been proposed to reduce bacterial wound contamination and the risk of SSI. However, current recommendations on its use are conflicting especially concerning antibiotic and antiseptic solutions because of their potential tissue toxicity and enhancement of bacterial drug resistances. METHODS: To analyze the existing evidence for the effect of IOWI with topical antibiotics, povidone-iodine (PVP-I) solutions or saline on the incidence of SSI following open abdominal surgery, a systematic review and meta-analysis of randomized controlled trials (RCTs) was carried out according to the recommendations of the Cochrane Collaboration. RESULTS: Forty-one RCTs reporting primary data of over 9000 patients were analyzed. Meta-analysis on the effect of IOWI with any solution compared to no irrigation revealed a significant benefit in the reduction of SSI rates (OR = 0.54, 95 % confidence Interval (CI) [0.42; 0.69], p < 0.0001). Subgroup analyses showed that this effect was strongest in colorectal surgery and that IOWI with antibiotic solutions had a stronger effect than irrigation with PVP-I or saline. However, all of the included trials were at considerable risk of bias according to the quality assessment. CONCLUSION: These results suggest that IOWI before skin closure represents a pragmatic and economical approach to reduce postoperative SSI after abdominal surgery and that antibiotic solutions seem to be more effective than PVP-I solutions or simple saline, and it might be worth to re-evaluate their use for specific indications.

Outcome after surgery for acute right-sided colonic ischemia without feasible vascular intervention: a single center experience of 58 patients over 6 years.

BACKGROUND: The predilection site of non-occlusive mesenteric ischemia is the right-sided colon. Surgical exploration followed by segmental bowel resection and primary anastomosis or ileostomy is recommended, if vascular interventions are not feasible and conservative treatment fails. We assessed the outcome of patients in this life-threatening condition. METHODS: From a prospective database 58 patients with urgent surgery for acute right-sided colonic ischemia without feasible vascular intervention (as a surrogate for non-occlusive mesenteric ischemia) were identified. Retrospectively the patients' characteristics, reason for ischemia, extent of resection, rate of ileostomy creation, 30 day and one year mortality, and rate of ileostomy-reversal at one year postoperative were assessed. RESULTS: Radiologically mesenteric arteriosclerotic disease was present in 54% of the patients. Vaso-occlusive mesenteric disease was suspected in 15% of the patients, but not confirmed intra-operatively. Ten patients underwent (extended) right-sided hemicolectomy with primary anastomosis (30-days mortality 20%, 1-year mortality 30%). Sixteen patients had (extended) right-sided hemicolectomy with creation of an ileostomy (30-days mortality 44%, 1-year mortality 86%, ostomy reversal in one patient). Twenty-five patients had (sub-) total colectomy with ileostomy creation (30-days mortality 60%, 1-year mortality 72%, ostomy reversal in two patients). Seven patients had exploration only (30-days mortality 86%, 1-year mortality 86%). Overall, the 30-days mortality-rate was 52% and the 1-year mortality-rate was 70%. Only 7% of the patients requiring an ostomy experienced ostomy-reversal. CONCLUSIONS: Patients with urgent surgery for acute right-sided colonic ischemia without feasible vascular intervention have a very high short and long-term mortality. The rate of ostomy-reversal is very low.

Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition.

In most colorectal cancer (CRC) patients, outcome cannot be predicted because tumors with similar clinicopathological features can have differences in disease progression and treatment response. Therefore, a better understanding of the CRC biology is required to identify those patients who will benefit from chemotherapy and to find a more tailored therapy plan for other patients. Based on unsupervised classification of whole genome data from 188 stages I-IV CRC patients, a molecular classification was developed that consist of at least three major intrinsic subtypes (A-, B- and C-type). The subtypes were validated in 543 stages II and III patients and were associated with prognosis and benefit from chemotherapy. The heterogeneity of the intrinsic subtypes is largely based on three biological hallmarks of the tumor: epithelial-to-mesenchymal transition, deficiency in mismatch repair genes that result in high mutation frequency associated with microsatellite instability and cellular proliferation. A-type tumors, observed in 22% of the patients, have the best prognosis, have frequent BRAF mutations and a deficient DNA mismatch repair system. C-type patients (16%) have the worst outcome, a mesenchymal gene expression phenotype and show no benefit from adjuvant chemotherapy treatment. Both A-type and B-type tumors have a more proliferative and epithelial phenotype and B-types benefit from adjuvant chemotherapy. B-type tumors (62%) show a low overall mutation frequency consistent with the absence of DNA mismatch repair deficiency. Classification based on molecular subtypes made it possible to expand and improve CRC classification beyond standard molecular and immunohistochemical assessment and might help in the future to guide treatment in CRC patients.

Expression analysis of heat shock protein 90 (HSP90) and Her2 in colon carcinoma.

PURPOSE: The molecular chaperone heat shock protein 90 (HSP90) plays an important role in several types of tumors also participating in the modulation of the activity of receptor tyrosine kinases activity such as members of the Her family. We evaluated the significance of HSP90 and Her2 expression in colon cancer. METHODS: HSP90 and Her2 expression was determined by immunohistochemistry and by fluorescence in situ hybridization (FISH) on 355 primary resected colon carcinomas. Results were correlated with pathologic features (Union for International Cancer Control (UICC) pTNM category, tumor localisation, tumor differentiation), additional molecular genetic characteristics (BRAF, KRAS mutational status, mismatch repair genes (MMR)), and survival. RESULTS: HSP90 immunoreactivity was observed in various degrees. Fifty-one cases (14 %) were positive for Her2 (score 2+ and 3+) with 16/43 cases with Her2 2+ staining pattern showing amplification of Her2 determined by FISH. There was a significant correlation between high HSP90 expression and Her2 overexpression (p = 0.011). High HSP90 expression was associated with earlier tumor stages (p = 0.019), absence of lymph node (p = 0.006), and absence of distant metastases (p = 0.001). Patients with high tumoral HSP90 levels had a better survival (p = 0.032), but this was not independent from other prognostic relevant pathologic parameters. Her2 expression was not associated with any of the investigated histopathological, molecular, or clinical parameters. CONCLUSIONS: High HSP90 levels are reflecting lower malignant potential in colon cancer. Her2 positivity can be observed in a small number of cases. Targeting HSP90 and/or Her2 may be an alternative therapeutic approach in colon cancer in a subset of patients.