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.

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.

Long-term outcome of patients with epiphrenic diverticula: A retrospective single-center analysis over 20 years.

BACKGROUND: Epiphrenic diverticula are extremely rare. Evidence-based treatment recommendations are scarce. The primary study outcome was to examine whether surgical treatment in patients with epiphrenic diverticula leads to improved quality of life by outweighing the perioperative risks compared with conservative treatment. METHODS: All patients with an epiphrenic diverticula at our institution between 2001 and 2021 were retrospectively reviewed and followed-up using a specific questionnaire, including the Eating Assessment Tool, and Gastrointestinal Quality of Life Index quality-of-life scores. RESULTS: Of 51 patients with epiphrenic diverticula, 28 had surgery and 23 had conservative treatment. The most common symptom at presentation was dysphagia. Although 16 patients underwent open surgery, 12 had minimally invasive procedures. A prophylactic stent was applied intraoperatively in 6 patients. The morbidity rate in surgically treated patients was 50% (14/28), with a leakage in 43% (12/28; 33% for prophylactic stenting). Mortality was nil. At a median follow-up of 139 months, patients with surgery had better outcomes than those without (ie, less dysphagia [6/12 vs 11/12; P = .025]), a less likely pathologic Eating Assessment Tool score (4/12 vs 9/12; P = .041), and a nonsignificant better Gastrointestinal Quality of Life Index score (122 vs 112; P = .929). The rate of recurrence/progression of symptoms was significantly higher for conservatively treated patients (11/18 vs 6/27 for any surgery; P = .008), as well as for patients with minimally invasive procedure (5/12 vs 1/15 for open surgery; P = .030). CONCLUSION: Despite the high perioperative morbidity, surgical treatment of epiphrenic diverticula leads to an improved long-term quality of life and lower recurrence rates than conservative treatment.

MRI-Determined Psoas Muscle Fat Infiltration Correlates with Severity of Weight Loss during Cancer Cachexia.

PURPOSE: To evaluate the suitability of psoas and erector spinae muscle proton density fat fraction (PDFF) and fat volume as biomarkers for monitoring cachexia severity in an oncological cohort, and to evaluate regional variances in muscle parameters over time. METHODS: In this prospective study, 58 oncological patients were examined by a 3 T MRI receiving between one and five scans. Muscle volume and PDFF were measured, segmentation masks were divided into proximal, middle and distal muscle section. RESULTS: A regional variation of fat distribution in erector spinae muscle at baseline was found (p < 0.01). During follow-ups significant relative change of muscle parameters was observed. Relative maximum change of erector spinae muscle showed a significant regional variation. Correlation testing with age as a covariate revealed significant correlations for baseline psoas fat volume (r = -0.55, p < 0.01) and baseline psoas PDFF (r = -0.52, p = 0.02) with maximum BMI change during the course of the disease. CONCLUSION: In erector spinae muscles, a regional variation of fat distribution at baseline and relative maximum change of muscle parameters was observed. Our results indicate that psoas muscle PDFF and fat volume could serve as MRI-determined biomarkers for early risk stratification and disease monitoring regarding progression and severity of weight loss in cancer cachexia.

Acute Appendicitis: Trends in Surgical Treatment­A Population-Based Study of Over 800 000 Patients.

BACKGROUND: Appendectomy is the gold standard for treatment of acute appendicitis. However, recent studies favor primary antibiotic therapy. The aim of this observational study was to explore changes in the numbers of operations for acute appendicitis in the period 2010-2017, paying special attention to disease severity. METHODS: Data from diagnosis-related group statistics were used to analyze the trends, mortality, and complication rates in the surgical treatment of appendicitis in Germany between 2010 and 2017. All cases of appendectomy after a diagnosis of appendicitis were included. RESULTS: Altogether, 865 688 inpatient cases were analyzed. The number of appendectomies went down by 9,8%, from 113 614 in 2010 to 102 464 in 2017, while the incidence fell from 139/100 000 in 2010 to 123/100 000 in 2017 (standardized by age group). This decrease is due to the lower number of operations for uncomplicated appendicitis (79 906 in 2017 versus 93 135 in 2010). Hospital mortality decreased both in patients who underwent surgical treatment of complicated appendicitis (0.62% in 2010 versus 0.42% in 2017) and in those with a complicated clinical course (5.4% in 2010 versus 3.4% in 2017). CONCLUSION: Decisions on the treatment of acute appendicitis in German hospitals follow the current trend towards non-surgical management in selected patients. At the same time, the care of acute appendicitis has improved with regard to overall hospital morbidity and hospital mortality.

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.

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.

A novel tissue inhibitor of metalloproteinases-1/liver/cachexia score predicts prognosis of gastrointestinal cancer patients.

BACKGROUND: Cachexia, a devastating syndrome in cancer patients, critically determines survival and life quality. It is characterized by impaired homeostasis of multiple organs including the liver, involves tissue wasting, and is conventionally diagnosed and classified by weight loss (WL). However, recent studies pointed at the problem that WL is not sufficient for precise classification of cancer patients according to disease severity (i.e. prognosis). Tissue inhibitor of metalloproteinases-1 (TIMP-1) is an easily accessible cachexia-associated biomarker in the blood, known to alter liver homeostasis. Here, we investigated the value of combining blood levels of TIMP-1 with parameters of liver functionality towards establishment of a cachexia-associated clinical score, which predicts survival of cancer patients, reflects the clinical manifestation of cachexia, and is easily accessible in the clinic. METHODS: The TIMP-1/liver cachexia (TLC) score, expressed as numerical value ranging from 0 to 1, was calculated by categorizing the blood levels of TIMP-1 and parameters of liver functionality (C-reactive protein, ferritin, gamma-glutamyl transferase, albumin, and total protein) for each patient as below/above a certain risk threshold. The TLC score was tested in a cohort of colorectal cancer (CRC) patients (n = 82, 35.4% women, 64.6% men, median age: 70 years) and validated in a cohort of pancreatic cancer (PC) patients (n = 84, 54.8% women, 45.2% men, median age: 69 years). RESULTS: In CRC patients, the TLC score positively correlated with presence of cachexia-related symptoms (WL, impaired liver function), predicted survival [P < 0.001, hazard ratio (HR): 96.91 (9.85-953.90)], and allowed classification of three prognostically distinct patient subpopulations [low (LO)-risk, intermediate (IM)-risk, and high (HI)-risk groups; LO vs. IM: P = 0.003, LO vs. HI: P < 0.001, IM vs. HI: P = 0.029]. The prognostic power of the cachexia-associated TLC score [P < 0.001, HR: 7.37 (2.80-19.49)] and its application to define risk groups (LO vs. IM: P = 0.032, LO vs. HI: P < 0.001, IM vs. HI: P = 0.014) was confirmed in a cohort of PC patients. The prognostic power of the TLC score was independent of presence of liver metastases in CRC or PC patients and was superior to clinically established staging classifications. CONCLUSIONS: The TLC score, a result of straightforward determination of blood parameters, is an objective cachexia-associated clinical tool for precise survival prediction of gastrointestinal cancer patients.

[Effects of the SARS-CoV-2 pandemic on surgery - a national cross-sectional study]. / Auswirkungen der SARS-CoV-2-Pandemie auf die Chirurgie ­ Eine nationale Querschnittsstudie.

BACKGROUND AND AIMS: From the beginning of the SARS-CoV­2 pandemic the German healthcare system focused on the treatment of COVID-19 patients. This was accompanied by the suspension of all elective operations. The aim of this study was to investigate the impact of the SARS-CoV­2 pandemic on general and visceral surgery in university hospitals in Germany. METHODS: This cross-sectional study was based on an anonymous survey, which was accessible online from 3 April 2020 to 17 April 2020 for the surgical departments of university hospitals in Germany. In total 73% (n = 29/40) of the hospitals participated in the survey. RESULTS: Cooperation with the authorities and the hospital administration was generally considered adequate; however, only 3% (1/29) and 7% (2/29) fully agreed with the statement that the health authorities at the federal and state level, respectively, were supportive of general and visceral surgery. The hospital directors expect an average loss of revenues of 28 ± 16%. There was an average reduction in beds or operating room capacity of 38% and 45%, respectively. In addition, 11% of the medical personnel in general and visceral surgery were reallocated to other departments. CONCLUSION: The SARS-CoV­2 pandemic has a significant impact on academic general and visceral surgery in Germany. The reduction in beds and operating room capacity can lead to considerable delays in urgent surgical interventions and financial burdens in 2020 and subsequent years.

Survival data on timing of resection of liver metastases in colorectal cancer patients.

Between 2007 and 2016, 140 consecutive patients who underwent resection of colorectal cancer with simultaneous liver metastases at a single university hospital were retrospectively analysed. In order to gather information regarding potential survival differences for n = 68 simultaneous versus n = 72 staged resections of the colorectal primary tumor and the liver metastases, Clinical, histopathological, serological, and survival data were compared for those two patient groups. The rate of simultaneous tumor resections increased from approximately 25% in 2007 to >75% in 2016. There was no difference in tumor specific survival for patients with simultaneous vs. staged resection (p = 0.631). This effect continued after excluding patients with extrahepatic metastases (p = 0.440). Further, neoadjuvant treatment did not lead to differences in the tumor-specific survival (p = 0.123). Factors associated with an increased tumor-specific survival were low ASA score (p < 0.001), low number of tumor-affected lymph nodes (p < 0.001), histological grading G1/2 (p = 0.001), and a low number of liver metastases (p = 0.044). There was no significant survival difference for the primary tumor stage (pT), the Clavien-Dindo complication rate, the resection status (R0), and minor versus major hepatectomies.

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.

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.

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.

Young GI Societies in Europe: 2019 update.

BACKGROUND: One of the aims of the Young Talent Group (YTG) is to make United European Gastroenterology (UEG) more attractive to young fellows interested in gastroenterology (GI), and to actively involve them in UEG activities and the activities of their respective national societies. In 2017, we conducted a survey among the Friends of the UEG YTG with the aim of identifying the state of organization and needs of Young GI Sections (YGISs) throughout Europe, highlighting areas for further development and improvement. AIMS: The aim of the current web-based survey was to assess the progress of YGISs over 1 year, and persisting hurdles in forming and running a YGIS. RESULTS: Overall, 38 of 42 Friends answered the survey (91%). The number of YGISs has increased significantly from 12 in 2017 to 25 in 2019. Young gastroenterologists remained supported, but not influenced, by national societies. Results of the survey suggest that a lack of dedicated and motivated fellows has replaced a lack of funding as the most prevalent hurdle in forming these types of sections. CONCLUSION: Our survey shows that the development of YGISs has improved markedly within the last 2 years. However, several limitations, like underrepresentation in subcommittees of national societies, remain and need to be addressed in order to involve young gastroenterologists in their respective national societies and within UEG, to pave the way for future research, education and excellent quality of care, and reduce health inequalities across Europe.

Two Isoforms of the Guanine Nucleotide Exchange Factor, Daple/CCDC88C Cooperate as Tumor Suppressors.

Previously, Aznar et al., showed that Daple/CCDC88C enables Wnt receptors to transactivate trimeric G-proteins during non-canonical Wnt signaling via a novel G-protein binding and activating (GBA) motif. By doing so, Daple serves two opposing roles; earlier during oncogenesis it suppresses neoplastic transformation and tumor growth, but later it triggers epithelial-to-mesenchymal-transition (EMT). We have identified and characterized two isoforms of the human Daple gene. While both isoforms cooperatively suppress tumor growth via their GBA motif, only the full-length transcript triggers EMT and invasion. Both isoforms are suppressed during colon cancer progression, and their reduced expression carries additive prognostic significance. These findings provide insights into the opposing roles of Daple during cancer progression and define the G-protein regulatory GBA motif as one of the minimal modules essential for Daple's role as a tumor suppressor.

Non-operative management of blunt hepatic and splenic injury: a time-trend and outcome analysis over a period of 17 years.

Background: A widespread shift to non-operative management (NOM) for blunt hepatic and splenic injuries has been observed in most centers worldwide. Furthermore, many countries introduced safety measures to systematically reduce severe traffic and leisure sports injuries. This study aims to evaluate the effect of these nationwide implementations on individual patient characteristics and outcomes through a time-trend analysis over 17 years in an Austrian high-volume trauma center. Methods: A retrospective review of all emergency trauma patients admitted to the Medical University of Innsbruck from 2000 to 2016. Injury severity, clinical data on admission, operative and non-operative treatment parameters, complications, and in-hospital mortality were evaluated. Results: In total, 731 patients were treated with blunt hepatic and/or splenic injuries. Among these, 368 had a liver injury, 280 splenic injury, and 83 combined hepatic/splenic injury. Initial NOM was performed in 82.6% of all patients (93.5% in hepatic and 71.8% in splenic injuries) with a success rate of 96.7%. The secondary failure rate of NOM was 3.3% and remained consistent over 17 years (p = 0.515). In terms of injury severity, we observed a reduction over time, resulting in an overall mortality rate of 4.8% and 3.5% in the NOM group (decreasing from 7.5 to 1.9% and from 5.6 to 1.3%, respectively). These outcomes confirmed an improved utilization of the NOM approach. Conclusion: Our cohort represents one of the largest Central European single-center experiences available in the literature. NOM is the standard of care for blunt hepatic and splenic injuries and successful in > 96% of all patients. This rate was quite constant over 17 years (p = 0.515). Overall, national and regional safety measures resulted in a significantly decreased severity of observed injury patterns and deaths due to blunt hepatic or splenic trauma. Although surgery is nowadays only applied in about one third of splenic injury patients in our center, these numbers might further decrease by intensified application of interventional radiology and modern coagulation management.

The Tumor Suppressor SASH1 Interacts With the Signal Adaptor CRKL to Inhibit Epithelial-Mesenchymal Transition and Metastasis in Colorectal Cancer.

Background & Aims: The tumor-suppressor sterile α motif- and Src-homology 3-domain containing 1 (SASH1) has clinical relevance in colorectal carcinoma and is associated specifically with metachronous metastasis. We sought to identify the molecular mechanisms linking decreased SASH1 expression with distant metastasis formation. Methods: SASH1-deficient, SASH1-depleted, or SASH1-overexpressing HCT116 colon cancer cells were generated by the Clustered Regularly Interspaced Short Palindromic Repeats/CRISPR-associated 9-method, RNA interference, and transient plasmid transfection, respectively. Epithelial-mesenchymal transition (EMT) was analyzed by quantitative reverse-transcription polymerase chain reaction, immunoblotting, immunofluorescence microscopy, migration/invasion assays, and 3-dimensional cell culture. Yeast 2-hybrid assays and co-immunoprecipitation/mass-spectrometry showed V-Crk avian sarcoma virus CT10 oncogene homolog-like (CRKL) as a novel interaction partner of SASH1, further confirmed by domain mapping, site-directed mutagenesis, co-immunoprecipitation, and dynamic mass redistribution assays. CRKL-deficient cells were generated in parental or SASH1-deficient cells. Metastatic capacity was analyzed with an orthotopic mouse model. Expression and significance of SASH1 and CRKL for survival and response to chemotherapy was assessed in patient samples from our department and The Cancer Genome Atlas data set. Results: SASH1 expression is down-regulated during cytokine-induced EMT in cell lines from colorectal, pancreatic, or hepatocellular cancer, mediated by the putative SASH1 promoter. Deficiency or knock-down of SASH1 induces EMT, leading to an aggressive, invasive phenotype with increased chemoresistance. SASH1 counteracts EMT through interaction with the oncoprotein CRKL, inhibiting CRKL-mediated activation of SRC kinase, which is crucially required for EMT. SASH1-deficient cells form significantly more metastases in vivo, depending entirely on CRKL. Patient tumor samples show significantly decreased SASH1 and increased CRKL expression, associated with significantly decreased overall survival. Patients with increased CRKL expression show significantly worse response to adjuvant chemotherapy. Conclusions: We propose SASH1 as an inhibitor of CRKL-mediated SRC signaling, introducing a potentially druggable mechanism counteracting chemoresistance and metastasis formation.