Microbiota-dependent activation of the myeloid calcineurin-NFAT pathway inhibits B7H3- and B7H4-dependent anti-tumor immunity in colorectal cancer.

Bacterial sensing by intestinal tumor cells contributes to tumor growth through cell-intrinsic activation of the calcineurin-NFAT axis, but the role of this pathway in other intestinal cells remains unclear. Here, we found that myeloid-specific deletion of calcineurin in mice activated protective CD8+ T cell responses and inhibited colorectal cancer (CRC) growth. Microbial sensing by myeloid cells promoted calcineurin- and NFAT-dependent interleukin 6 (IL-6) release, expression of the co-inhibitory molecules B7H3 and B7H4 by tumor cells, and inhibition of CD8+ T cell-dependent anti-tumor immunity. Accordingly, targeting members of this pathway activated protective CD8+ T cell responses and inhibited primary and metastatic CRC growth. B7H3 and B7H4 were expressed by the majority of human primary CRCs and metastases, which was associated with low numbers of tumor-infiltrating CD8+ T cells and poor survival. Therefore, a microbiota-, calcineurin-, and B7H3/B7H4-dependent pathway controls anti-tumor immunity, revealing additional targets for immune checkpoint inhibition in microsatellite-stable CRC.

Apical bulkheads accumulate as adaptive response to impaired bile flow in liver disease.

Hepatocytes form bile canaliculi that dynamically respond to the signalling activity of bile acids and bile flow. Little is known about their responses to intraluminal pressure. During embryonic development, hepatocytes assemble apical bulkheads that increase the canalicular resistance to intraluminal pressure. Here, we investigate whether they also protect bile canaliculi against elevated pressure upon impaired bile flow in adult liver. Apical bulkheads accumulate upon bile flow obstruction in mouse models and patients with primary sclerosing cholangitis (PSC). Their loss under these conditions leads to abnormally dilated canaliculi, resembling liver cell rosettes described in other hepatic diseases. 3D reconstruction reveals that these structures are sections of cysts and tubes formed by hepatocytes. Mathematical modelling establishes that they positively correlate with canalicular pressure and occur in early PSC stages. Using primary hepatocytes and 3D organoids, we demonstrate that excessive canalicular pressure causes the loss of apical bulkheads and formation of rosettes. Our results suggest that apical bulkheads are a protective mechanism of hepatocytes against impaired bile flow, highlighting the role of canalicular pressure in liver diseases.

A critical spotlight on the paradigms of FFPE-DNA sequencing.

In the late 19th century, formalin fixation with paraffin-embedding (FFPE) of tissues was developed as a fixation and conservation method and is still used to this day in routine clinical and pathological practice. The implementation of state-of-the-art nucleic acid sequencing technologies has sparked much interest for using historical FFPE samples stored in biobanks as they hold promise in extracting new information from these valuable samples. However, formalin fixation chemically modifies DNA, which potentially leads to incorrect sequences or misinterpretations in downstream processing and data analysis. Many publications have concentrated on one type of DNA damage, but few have addressed the complete spectrum of FFPE-DNA damage. Here, we review mitigation strategies in (I) pre-analytical sample quality control, (II) DNA repair treatments, (III) analytical sample preparation and (IV) bioinformatic analysis of FFPE-DNA. We then provide recommendations that are tested and illustrated with DNA from 13-year-old liver specimens, one FFPE preserved and one fresh frozen, applying target-enriched sequencing. Thus, we show how DNA damage can be compensated, even when using low quantities (50 ng) of fragmented FFPE-DNA (DNA integrity number 2.0) that cannot be amplified well (Q129 bp/Q41 bp = 5%). Finally, we provide a checklist called 'ERROR-FFPE-DNA' that summarises recommendations for the minimal information in publications required for assessing fitness-for-purpose and inter-study comparison when using FFPE samples.

Cumulative 10-year performance of endodontically treated teeth with prosthetic restorations of base metal alloy double crowns with friction pins-a retrospective study.

OBJECTIVES: This 120-month follow-up study aimed to investigate the complication rate of abutment teeth after endodontic pretreatment with base metal alloy double crowns with friction pins. MATERIALS AND METHODS: A total of 158 participants (n = 71, 44.9% women) aged 62.5 ± 12.7 years with 182 prostheses on 520 abutment teeth (n = 459, 88.3% vital) were retrospectively analyzed between 2006 and 2022. Of the endodontically treated abutment teeth, 6.9% (n = 36) were additionally treated with post and core reconstructions. Cumulative complication rates were calculated using the Kaplan-Meier estimator and log-rank test. In addition, Cox regression analysis was performed. RESULTS: The cumulative complication rate at 120 months for the entire set of abutment teeth was 39.6% (confidence interval [CI]: 33.0-46.2). Endodontically treated abutment teeth (33.8%; CI: 19.6-48.0) were found to have a significantly higher cumulative fracture rate than vital teeth (19.9%; CI: 13.9-25.9, p < 0.001). Endodontically treated teeth restored with post and core reconstructions (30.4%; CI: 13.2-47.6) showed a nonsignificant lower cumulative fracture rate than that of teeth with root fillings only (41.6%; CI: 16.4-66.8, p = 0.463). CONCLUSIONS: Higher 120-month cumulative fracture rates were observed in endodontically treated teeth. Comparable performance was observed in teeth with post and core reconstructions compared to teeth with root fillings only. CLINICAL RELEVANCE: If endodontically treated teeth are used as abutments for double crowns, the risk of complications from these teeth should be considered when planning treatment and communicating with the patient.

Ten-year clinical performance of non-precious metal double crowns with friction pins in severely reduced dentitions-a retrospective study.

OBJECTIVES: This follow-up study aimed at collecting long-term data for removable partial dentures (RPDs) retained by double crowns with spark-eroded friction pins (DCP) and comparing them in the presence of severely reduced dentition (SRD) and non-SRD (NSRD, i.e. residual dentition with more than three abutment teeth) after a 10-year wearing period. MATERIALS AND METHODS: A total of 158 participants (n = 71, 44.9% women) aged 62.5 ± 12.7 years with 182 prostheses on 520 abutment teeth were followed up between 2006 and 2022. The SRD group included 144 RPDs supported by 314 abutment teeth. The data collection was performed retrospectively. 10-year survival rates of RPDs and abutment teeth were determined using the Kaplan-Meier method and compared using the log-rank test for SRD and NSRD, among others. Cox regression analyses were conducted to isolate risk factors for the survival of both RPDs and abutment teeth. RESULTS: The 10-year cumulative survival rate of all abutment teeth was 65.6% with significantly lower values in the SRD group (53.5%) (p < 0.001). The survival rate for all RPDs was 65.5%. The SRD group showed lower survival rates (57.9%) (p = 0.004). The number and location of the abutment teeth had a significant influence on the survival rates of the RPDs and the abutment teeth. Age, sex, jaw, relining, and vitality had a significant influence on the abutment teeth survival rates. CONCLUSIONS: RPDs showed an acceptable clinical survival rate after 10 years. The number, location, and vitality of abutment teeth were factors that influenced the survival of both RPDs and abutment teeth. CLINICAL RELEVANCE: Consideration of the influencing factors found can help improve the prognostic assessment of double crown-retained dentures in the context of prosthetic therapy planning.

Temperature profile and residual heat of monopolar laparoscopic and endoscopic dissection instruments.

BACKGROUND: Endoscopic and laparoscopic electrosurgical devices (ED) are of great importance in modern medicine but can cause adverse events such as tissue injuries and burns from residual heat. While laparoscopic tools are well investigated, detailed insights about the temperature profile of endoscopic knives are lacking. Our aim is to investigate the temperature and the residual heat of laparoscopic and endoscopic monopolar instruments to increase the safety in handling ED. METHODS: An infrared camera was used to measure the temperature of laparoscopic and endoscopic instruments during energy application and to determine the cooling time to below 50 °C at a porcine stomach. Different power levels and cutting intervals were studied to investigate their impact on the temperature profile. RESULTS: During activation, the laparoscopic hook exceeded 120 °C regularly for an up to 10 mm shaft length. With regards to endoknives, only the Dual Tip Knife showed a shaft temperature of above 50 °C. The residual heat of the laparoscopic hook remained above 50 °C for at least 15 s after activation. Endoknives cooled to below 50 °C in 4 s. A higher power level and longer cutting duration significantly increased the shaft temperature and prolonged the cooling time (p < 0.001). CONCLUSION: Residual heat and maximum temperature during energy application depend strongly on the chosen effect and cutting duration. To avoid potential injuries, the user should not touch any tissue with the laparoscopic hook for at least 15 s and with the endoknives for at least 4 s after energy application. As the shaft also heats up to over 120 °C, the user should be careful to avoid tissue contact during activation with the shaft. These results should be strongly considered for safety reasons when handling monopolar ED.

Oral health status of nursing staff in Ilembula, Wanging'ombe District, Njombe region, Tanzania: a cross-sectional study.

BACKGROUND: Owing to the reduced dental treatment infrastructure in the Tanzanian highlands, maintaining good oral health is a challenge for not only the general population but also individual professional groups. In this study, the caries prevalence and, subsequently, the prosthetic treatment needs of the nurses of the Ilembula Lutheran Hospital (ILH) and Ilembula Institute of Health and Allied Sciences (IIHAS), Tanzania, were investigated. MATERIALS AND METHODS: One hundred and sixty-eight ILH and IIHAS nurses and nursing students (87 women, 81 men; age 23.1 ± 6.1 years, range 18-58 years) participated in this cross-sectional study conducted in February 2020. The participants were examined at the dental office of ILH. The Decayed, Missing, and Filled Teeth (DMF/T) Index, Simplified Oral Hygiene Index, and details regarding edentulism, nutrition habits, and socioeconomic factors were collected. Linear regression and binary logistic regression were used for statistical analysis. RESULTS: The mean DMF/T-Index was 6.30 ± 4.52. In 7.14% of the investigated nurses, no dental plaque was detected. An enhanced prosthodontic treatment (Kennedy Class III) demand was identified in 31.50% of the participants, and 4.80% of the participants required treatment for acute malocclusion. Oral hygiene products were used by 99.4% of the patients. CONCLUSIONS: The current oral health situation of the study participants showed a moderate restorative and prosthetic treatment demand in the rural area of Tanzania. The development of an interdisciplinary oral health prophylaxis system could be a means to remedy this situation.

Loss of hepatic Mboat7 leads to liver fibrosis.

OBJECTIVE: The rs641738C>T variant located near the membrane-bound O-acyltransferase domain containing 7 (MBOAT7) locus is associated with fibrosis in liver diseases, including non-alcoholic fatty liver disease (NAFLD), alcohol-related liver disease, hepatitis B and C. We aim to understand the mechanism by which the rs641738C>T variant contributes to pathogenesis of NAFLD. DESIGN: Mice with hepatocyte-specific deletion of MBOAT7 (Mboat7Δhep) were generated and livers were characterised by histology, flow cytometry, qPCR, RNA sequencing and lipidomics. We analysed the association of rs641738C>T genotype with liver inflammation and fibrosis in 846 NAFLD patients and obtained genotype-specific liver lipidomes from 280 human biopsies. RESULTS: Allelic imbalance analysis of heterozygous human liver samples pointed to lower expression of the MBOAT7 transcript on the rs641738C>T haplotype. Mboat7Δhep mice showed spontaneous steatosis characterised by increased hepatic cholesterol ester content after 10 weeks. After 6 weeks on a high fat, methionine-low, choline-deficient diet, mice developed increased hepatic fibrosis as measured by picrosirius staining (p<0.05), hydroxyproline content (p<0.05) and transcriptomics, while the inflammatory cell populations and inflammatory mediators were minimally affected. In a human biopsied NAFLD cohort, MBOAT7 rs641738C>T was associated with fibrosis (p=0.004) independent of the presence of histological inflammation. Liver lipidomes of Mboat7Δhep mice and human rs641738TT carriers with fibrosis showed increased total lysophosphatidylinositol levels. The altered lysophosphatidylinositol and phosphatidylinositol subspecies in MBOAT7Δhep livers and human rs641738TT carriers were similar. CONCLUSION: Mboat7 deficiency in mice and human points to an inflammation-independent pathway of liver fibrosis that may be mediated by lipid signalling and a potentially targetable treatment option in NAFLD.

Genome-wide analysis of 944 133 individuals provides insights into the etiology of haemorrhoidal disease.

OBJECTIVE: Haemorrhoidal disease (HEM) affects a large and silently suffering fraction of the population but its aetiology, including suspected genetic predisposition, is poorly understood. We report the first genome-wide association study (GWAS) meta-analysis to identify genetic risk factors for HEM to date. DESIGN: We conducted a GWAS meta-analysis of 218 920 patients with HEM and 725 213 controls of European ancestry. Using GWAS summary statistics, we performed multiple genetic correlation analyses between HEM and other traits as well as calculated HEM polygenic risk scores (PRS) and evaluated their translational potential in independent datasets. Using functional annotation of GWAS results, we identified HEM candidate genes, which differential expression and coexpression in HEM tissues were evaluated employing RNA-seq analyses. The localisation of expressed proteins at selected loci was investigated by immunohistochemistry. RESULTS: We demonstrate modest heritability and genetic correlation of HEM with several other diseases from the GI, neuroaffective and cardiovascular domains. HEM PRS validated in 180 435 individuals from independent datasets allowed the identification of those at risk and correlated with younger age of onset and recurrent surgery. We identified 102 independent HEM risk loci harbouring genes whose expression is enriched in blood vessels and GI tissues, and in pathways associated with smooth muscles, epithelial and endothelial development and morphogenesis. Network transcriptomic analyses highlighted HEM gene coexpression modules that are relevant to the development and integrity of the musculoskeletal and epidermal systems, and the organisation of the extracellular matrix. CONCLUSION: HEM has a genetic component that predisposes to smooth muscle, epithelial and connective tissue dysfunction.

[The Importance of Anatomy in the Training of the Vascular Surgeon]. / Der Stellenwert der Anatomie in der Weiterbildung des Gefäßchirurgen.

Vascular surgery has developed very dynamically in recent years, especially with the introduction of endovascular techniques. However, this has also changed surgeons' requirements. Classical surgical procedures have been almost completely displaced by endovascular techniques; new hybrid interventions have emerged while complex operations are concentrated in few centres. Therefore, developing expertise in open aortic surgery is increasingly challenging in vascular surgical training programs.Cadaver models provide an opportunity for exposure and repetitive training of individual surgical steps without endangering patients.As part of the training of highly complex vascular surgery operations, we carried out and evaluated the thoracoabdominal aortic replacement with 13 participants in 6 ethanol-preserved corpses.A simulation of surgical procedures on human cadaveric models cannot fully replace real experiences, but allows surgeons in training to practice and achieve dexterity in performing procedures in a safe and reproducible way.

Rapid response of stage IV colorectal cancer with APC/TP53/KRAS mutations to FOLFIRI and Bevacizumab combination chemotherapy: a case report of use of liquid biopsy.

BACKGROUND: Liquid biopsies of blood plasma cell free DNA can be used to monitor treatment response and potentially detect mutations that are present in resistant clones in metastatic cancer patients. CASE PRESENTATION: In our non-interventional liquid biopsy study, a male patient in his fifties diagnosed with stage IV colorectal cancer and polytope liver metastases rapidly progressed after completing chemotherapy and deceased 8 months after diagnosis. Retrospective cell free DNA testing showed that the APC/TP53/KRAS major clone responded quickly after 3 cycles of FOLFIRI + Bevacizumab. Retrospective exome sequencing of pre-chemotherapy and post-chemotherapy tissue samples including metastases confirmed that the APC/TP53/KRAS and other major clonal mutations (GPR50, SLC5A, ZIC3, SF3A1 and others) were present in all samples. After the last chemotherapy cycle, CT imaging, CEA and CA19-9 markers validated the cfDNA findings of treatment response. However, 5 weeks later, the tumour had rapidly progressed. CONCLUSION: As FOLFIRI+Bevacizumab has recently also been associated with sustained complete remission in a APC/TP53/KRAS triple-mutated patient, these driver genes should be tested and monitored in a more in-depth manner in future patients. Patients with metastatic disease should be monitored more closely during and after chemotherapy, ideally using cfDNA.

Clinical performance of non-precious metal double crowns with friction pins in severely reduced dentitions.

OBJECTIVES: Several in vitro studies have investigated the retention of double crowns with friction pins (DCP); however, clinical data on their long-term success have not been reported. We sought to evaluate the 5-year survival rate of DCPs in patients with severely reduced dentition (SRD) and not severely reduced dentition (NSRD). MATERIALS AND METHODS: A total of 158 patients were treated with 182 dentures on 520 abutment teeth between 2006 and 2016. The SRD group included 144 dentures that had been inserted on 314 abutment teeth. We evaluated the influence of age, sex, jaw, number, tooth vitality, and abutment teeth localization (according to Steffel's classification) on the 60-month survival rates of dentures and abutment teeth using the Kaplan-Meier estimator, logrank test, and Cox regression. RESULTS: The cumulative 60-month survival rate was 84.3% (CI 77.1-91.5%) for all dentures; however, the survival rate in the SRD group (80.3%; CI 71.5-89.1%) was significantly lower than in the NSRD group (100%; p = 0.04). Dentures classified in Steffel's class A had the lowest survival rate (51.5%; CI 30.9-72.1%). Number, location, and vitality of the abutment teeth had a significant impact on survival rate. CONCLUSIONS: DCP dentures showed comparable clinical long-term success to double crown systems that have been previously reported in the literature. The number, localization, and vitality of abutment teeth had the greatest influence on the survival rates of denture and abutment teeth. CLINICAL RELEVANCE: DCP dentures have an acceptable 5-year survival rate. Clinical treatment planning must take into account key factors associated with the prognosis of the abutment teeth.

Complications of endodontically treated abutment teeth after restoration with non-precious metal double crowns.

OBJECTIVES: This study aimed to evaluate the effects of endodontic treatment on the complication rate in abutment teeth following double crown treatment. MATERIALS AND METHODS: Data of 233 patients supplied with 278 prostheses on 773 teeth were retrospectively analyzed. The 60-month cumulative complication rate for vital, root filled, and post and core reconstructed abutment teeth is calculated using the Kaplan-Meier method. Cox regression is performed to evaluate factors including age, sex, jaw, and tooth number. RESULTS: After 60 months, the cumulative complication rate for all abutment teeth was 24.1% (CI: 19.7-28.5%). A significantly higher cumulative fracture rate (log-rank test, p < 0.001) was found for devital (51.7%; CI: 35.3-68.1%) compared to vital abutment teeth (20.6%; CI: 16.2-25%). Devital teeth restored with post and core reconstructions (46.3%; CI: 26.1-66.5%) showed a lower cumulative fracture rate than abutment teeth with only root fillings (60.9%; CI: 33.5-88.3%). Abutment teeth in severely reduced dentitions (≤ 3 teeth) were found to have significantly lower survival rates than abutment teeth in not severely reduced dentitions (≥ 4 teeth, p = 0.031, HR = 0.609). CONCLUSION: Lower abutment teeth survival rates were associated with non-vitality and a reduced number of abutment teeth. Devital teeth with post and core reconstructions showed higher survival rates than root filled devital teeth. CLINICAL RELEVANCE: After 5 years, devital teeth with double crowns have a fracture rate twice as high as vital teeth. This prognosis should be taken into account during treatment planning, especially in the severely reduced dentition.

Heterozygous carriage of the alpha1-antitrypsin Pi*Z variant increases the risk to develop liver cirrhosis.

OBJECTIVE: Homozygous alpha1-antitrypsin (AAT) deficiency increases the risk for developing cirrhosis, whereas the relevance of heterozygous carriage remains unclear. Hence, we evaluated the impact of the two most relevant AAT variants ('Pi*Z' and 'Pi*S'), present in up to 10% of Caucasians, on subjects with non-alcoholic fatty liver disease (NAFLD) or alcohol misuse. DESIGN: We analysed multicentric case-control cohorts consisting of 1184 people with biopsy-proven NAFLD and of 2462 people with chronic alcohol misuse, both cohorts comprising cases with cirrhosis and controls without cirrhosis. Genotyping for the Pi*Z and Pi*S variants was performed. RESULTS: The Pi*Z variant presented in 13.8% of patients with cirrhotic NAFLD but only in 2.4% of counterparts without liver fibrosis (p<0.0001). Accordingly, the Pi*Z variant increased the risk of NAFLD subjects to develop cirrhosis (adjusted OR=7.3 (95% CI 2.2 to 24.8)). Likewise, the Pi*Z variant presented in 6.2% of alcohol misusers with cirrhosis but only in 2.2% of alcohol misusers without significant liver injury (p<0.0001). Correspondingly, alcohol misusers carrying the Pi*Z variant were prone to develop cirrhosis (adjusted OR=5.8 (95% CI 2.9 to 11.7)). In contrast, the Pi*S variant was not associated with NAFLD-related cirrhosis and only borderline with alcohol-related cirrhosis (adjusted OR=1.47 (95% CI 0.99 to 2.19)). CONCLUSION: The Pi*Z variant is the hitherto strongest single nucleotide polymorphism-based risk factor for cirrhosis in NAFLD and alcohol misuse, whereas the Pi*S variant confers only a weak risk in alcohol misusers. As 2%-4% of Caucasians are Pi*Z carriers, this finding should be considered in genetic counselling of affected individuals.

Genome-wide association analysis of diverticular disease points towards neuromuscular, connective tissue and epithelial pathomechanisms.

OBJECTIVE: Diverticular disease is a common complex disorder characterised by mucosal outpouchings of the colonic wall that manifests through complications such as diverticulitis, perforation and bleeding. We report the to date largest genome-wide association study (GWAS) to identify genetic risk factors for diverticular disease. DESIGN: Discovery GWAS analysis was performed on UK Biobank imputed genotypes using 31 964 cases and 419 135 controls of European descent. Associations were replicated in a European sample of 3893 cases and 2829 diverticula-free controls and evaluated for risk contribution to diverticulitis and uncomplicated diverticulosis. Transcripts at top 20 replicating loci were analysed by real-time quatitative PCR in preparations of the mucosal, submucosal and muscular layer of colon. The localisation of expressed protein at selected loci was investigated by immunohistochemistry. RESULTS: We discovered 48 risk loci, of which 12 are novel, with genome-wide significance and consistent OR in the replication sample. Nominal replication (p<0.05) was observed for 27 loci, and additional 8 in meta-analysis with a population-based cohort. The most significant novel risk variant rs9960286 is located near CTAGE1 with a p value of 2.3×10-10 and 0.002 (ORallelic=1.14 (95% CI 1.05 to 1.24)) in the replication analysis. Four loci showed stronger effects for diverticulitis, PHGR1 (OR 1.32, 95% CI 1.12 to 1.56), FAM155A-2 (OR 1.21, 95% CI 1.04 to 1.42), CALCB (OR 1.17, 95% CI 1.03 to 1.33) and S100A10 (OR 1.17, 95% CI 1.03 to 1.33). CONCLUSION: In silico analyses point to diverticulosis primarily as a disorder of intestinal neuromuscular function and of impaired connective fibre support, while an additional diverticulitis risk might be conferred by epithelial dysfunction.

EUS-guided drainage in the management of postoperative pancreatic leaks and fistulas (with video).

BACKGROUND AND AIMS: Postoperative pancreatic leakage and fistulae (POPF) are a leading adverse event after partial pancreatic resection. Treatment algorithms are currently not standardized. Evidence regarding the role of endoscopy is scarce. METHODS: One hundred ninety-six POPF patients with (n = 132) and without (n = 64) concomitant pancreatic fluid collections (PFCs) from centers in Berlin, Kiel, and Dresden were analyzed retrospectively. Clinical resolution was used as the primary endpoint of analysis. RESULTS: Analysis was stratified by the presence or absence of a PFC because these patients differed in treatment pathway and the presence of systemic inflammation with a median C-reactive protein of 30.7 mg/dL in patients without a PFC versus 131.0 mg/dL in patients with a PFC (P = 3.4 × 10-4). In patients with PFCs, EUS-guided intervention led to resolution in a median of 8 days as compared with 25 days for percutaneous drainage and 248 days for surgery (P = 3.75 × 10-14). There was a trend toward a higher success rate of EUS-guided intervention as a primary treatment modality with 85% (P = .034), followed by percutaneous drainage (64%) and surgery (41%). When applied as a rescue intervention (n = 24), EUS led to clinical resolution in 96% of cases. In patients without PFCs, EUS-guided internalization in a novel endoscopic technique led to resolution after a median of 4 days as compared with 51 days for a remaining surgical drainage (P = 9.3 × 10-9). CONCLUSIONS: In this retrospective analysis, EUS-guided drainage of POPF led to a more rapid resolution. EUS may be considered as a viable option in the management of PFCs and POPF and should be evaluated in prospective studies.

[Acute Cholecystitis]. / Die akute Cholezystitis.

Acute cholecystitis is inflammation of the gallbladder and is triggered by cholelithiasis in about 90% of cases. Gallstone-associated diseases are among the most expensive in the field of gastroenterology and are therefore of great economic importance. Development of gallstones is multifactorial. The risk of gallstone disease increases with age. In particular, the carbohydrate- and fat-rich diet and the lack of physical activity in the Western world are involved in the formation of gallstones. Another important risk factor is genetic variants in cholesterol transporters. Diagnosis is based on the combination of the medical history, the physical examination, abdominal ultrasound and infection parameters in clinical chemistry. Typical symptoms include colic-like upper abdominal pain lasting more than six hours, fever or leukocytosis, and ultrasound gallbladder wall oedema in combination with a positive Murphy sign. The treatment of choice is early laparoscopic cholecystectomy.

Detection of circulating tumor cells with CK20 RT-PCR is an independent negative prognostic marker in colon cancer patients - a prospective study.

BACKGROUND: Detection of circulating (CTC) or disseminated tumor cells (DTC) has been associated with negative prognosis and outcome in patients with colorectal cancer, though testing for these cells is not yet part of clinical routine. There are several different methodological approaches to detect tumor cells but standardized detection assays are not implemented so far. METHODS: In this prospective monocentric study 299 patients with colon cancer were included. CTC and DTC were detected using CK20 RT-PCR as well as immunocytochemistry staining with anti-pan-keratin and anti-EpCAM antibodies. The primary endpoints were: Evaluation of CTC and DTC at the time of surgery and correlation with main tumor characteristics and overall (OS) and disease free survival (DFS). RESULTS: Patients with detectable CTC had a 5-year OS rate of 68% compared to a 5-year OS rate of 85% in patients without detectable CTC in the blood (p = 0.002). Detection of DTC in the bone marrow with CK20 RT-PCR was not associated with a worse OS or DFS. Detection of pan-cytokeratin positive DTC in the bone marrow correlated with a significantly reduced 5-year OS rate (p = 0.048), but detection of DTC in the bone marrow with the anti-EpCAM antibody did not significantly influence the 5-year OS rate (p = 0.958). By multivariate analyses only detection of CTC with CK20 RT-PCR in the blood was revealed to be an independent predictor of worse OS (HR1.94; 95% CI 1.0-3.7; p = 0.04) and DFS (HR 1.94; 95% CI 1.1-3.7; p = 0.044). CONCLUSIONS: Detection of CTC with CK20 RT-PCR is a highly specific and independent prognostic marker in colon cancer patients. Detection of DTC in the bone marrow with CK20 RT-PCR or immunohistochemistry with anti-EpCAM antibody is not associated with a negative prognostic influence.

Cytokeratin 20 positive circulating tumor cells are a marker for response after neoadjuvant chemoradiation but not for prognosis in patients with rectal cancer.

BACKGROUND: Several studies have shown, that circulating tumor cells (CTC) have a negative prognostic value in colorectal cancer patients. Aim of this study was to evaluate the role of CTC in specifically rectal cancer patients regarding the influence on overall survival and to elucidate the impact of CTC in predicting response after chemoradiation (RCTX). METHODS: In this prospective monocentric study 267 patients with rectal cancer were included. Patients with locally advanced tumors were treated with RCTX followed by surgery. The primary endpoints were: Evaluation of CTC at the time of surgery and correlation with main tumor characteristics, response to neoadjuvant RCTX and overall survival (OS). CTC were detected in the blood using CK20 RT-PCR. RESULTS: Sixty-three patients were treated with neoadjuvant RCTX. In 46.8% of the patients receiving neoadjuvant RCTX CTC were detected, which was significantly higher than in the group without RCTX (p=0.002). Histopathologic regression after RCTX was evident in 27.8% of the patients. In the subgroup of responders after RCTX we found CTC at a significantly lower rate than in non-responders (p=0.03). No significant association was found between CTC detection and tumor characteristics and OS. The OS was significantly improved for responders compared to non-responders (p=0.007). CONCLUSIONS: Responders after neoadjuvant RCTX had a lower incidence of CTC compared to non-responders, which might be a result of effective systemic and local treatment prior to surgery. Interestingly, detection of CTC did not correlate with tumor stage and OS, which is in contrast to previous reports of patients with colon cancer.

Lifestyle factors and health-related quality of life in colorectal cancer survivors.

PURPOSE: This study investigates the association between a postdiagnosis lifestyle score and health-related quality of life (HrQol) in long-term colorectal cancer (CRC) survivors. METHODS: A cross-sectional study of 1,389 long-term CRC survivors in Northern Germany was analyzed. On average 7.2 years after CRC diagnosis, HrQol was assessed with the EORTC QLQ-C30, and lifestyle factors, including weight, height, diet, physical activity, and smoking were obtained using self-administered questionnaires. A lifestyle score (BMI <30 kg/m², healthy diet, recreationally active, and not smoking) was applied. Participants were categorized in adhering to at most one, two, three, or all recommended lifestyle factors, categorizing unfavorable behaviors with 0 and favorable with 1 point. Multivariable logistic regression models were used to investigate the association between the lifestyle score and HrQol as a binary variable. RESULTS: Approximately 10 % had at most one, 30 % two, 38 % three, and 23 % all favorable factors. Compared to participants with one or zero factors, the odds ratio (OR) for a low global HrQol (gHrQol) decreased with stronger adherence to the score. The OR (95% CI) for a low gHrQol was 0.50 (0.33-0.76) for participants with all favorable lifestyle factors compared to participants with one or zero. Clinical and socio-demographic factors had little impact on these associations, with exception of living arrangement which showed a statistically significant interaction. Associations were stronger for functioning domains, representing mobility rather than mental health. CONCLUSIONS: Favorable lifestyle behaviors might be associated with HrQol in CRC long-term survivors. More research in prospective studies is needed.