[Leptomeningeal carcinomatosis as a rare metastatic spreading of BRAF-mutated microsatellite stable colon cancer]. / Meningeosis carcinomatosa als seltener Metastasierungsweg eines BRAF-mutierten Mikrosatelliten-stabilen Kolonkarzinoms.

Leptomeningeal carcinomatosis is a rare but serious complication of solid tumors such as melanoma, breast and lung cancer, as well as gastrointestinal carcinomas. Its clinical manifestation is highly variable, presenting as radicular pain with or without neurological deficits, as well as with headaches and hallucinatory irritation symptoms. Leptomeningeal carcinomatosis is often misdiagnosed, which delays treatment. Here we report a rare case of a patient with BRAF-mutated microsatellite stable colon carcinoma with lymphatic and skeletal metastases, who developed neurological symptoms one month after the initial diagnosis of malignancy. Based on the cytological detection of tumor cells in the cerebrospinal fluid, a leptomeningeal carcinomatosis was diagnosed, despite normal findings on MRI. Intrathecal chemotherapy with methotrexate, combined with intensive systemic immunochemotherapy, resulted in a good partial remission of the underlying malignant disease. However, approximately 8 months after the start of therapy, the patient developed progressive leptomeningeal carcinomatosis and died a few weeks later.

Common genetic variation in vitamin D metabolism is associated with liver stiffness.

UNLABELLED: Recently, genome-wide studies identified genetic variants that affect serum 25-hydroxyvitamin D levels in healthy populations (rs12785878, near dehydrocholesterol reductase, DHCR7; rs10741657, at CYP2R1; and rs7041, at vitamin D binding protein, GC). Because vitamin D deficiency is associated with advanced liver disease, we hypothesized that these variants are associated with 25(OH)-vitamin D levels and liver fibrosis. Overall, 712 Caucasian patients with chronic liver diseases were included. Liver fibrosis was assessed by transient elastography (TE) and/or histology. Serum levels of 25(OH)-vitamin D were correlated with TE and fibrosis stages. Genotypes were determined using TaqMan assays and tested for association with vitamin D and liver stiffness. Serum 25(OH)-vitamin D levels were inversely correlated with liver stiffness and histology (P < 0.001). Homozygous carriers of the rare DHCR7 allele or the common CYP2R1 allele presented with reduced 25(OH)-vitamin D levels (P < 0.05). The variant rs12785878 in the DHCR7 locus was associated with liver stiffness in both patients with TE <7.0 kPa and TE between 7.0 and 9.5 kPa. 25(OH)-vitamin D levels correlated with sunshine hours at the time of inclusion (P < 0.001). CONCLUSION: Common variation in 25(OH)-vitamin D metabolism is associated with liver stiffness in patients presenting with low to moderately increased elasticity. Although the susceptible DHCR7 genotype confers small risk, we speculate that the observed stiffness differences indicate a stronger influence of 25(OH)-vitamin D on initiation rather than progression of hepatic fibrosis.

A common variant in the precursor miR-146a sequence does not predispose to cholangiocarcinoma in a large European cohort.

BACKGROUND: Micro-RNAs (miRNAs) are small, non-coding RNA species considered to fine-tune basic cellular functions by modulating target gene translation and/or mRNA stability. A common G/C polymorphism (rs2910164) in the precursor (pre-) miR-146a gene engaged in NF-κB signaling and apoptosis pathways has been reported to modulate the genetic risk of hepatocellular carcinoma by increased G-allelic production of mature miR-146a. We investigated rs2910164 in a large European-based cholangiocarcinoma (CCA) cohort. METHODS: We recruited 182 CCA patients and 350 controls in three academic medical centers. Genotyping for rs2910164 was performed by PCR-based assays with 5'-nuclease and fluorescence detection. Genotype frequencies were tested for consistency with the Hardy-Weinberg equilibrium using an exact test; allelic and genotypic differences between the patients and controls were assessed by the Chi-square test and Armitage's trend test. Exploratory subgroup analyses included gender, tumor localization (extra- versus intrahepatic CCA) and early-onset CCA. RESULTS: Genotype distributions were consistent with the Hardy-Weinberg equilibrium. No significant differences in either allele or genotype distributions were detected between the CCA and control groups or the respective subgroups investigated. However, there was a trend for a protective effect of the heterozygous single-nucleotide polymorphism state GC, as indicated by an underrepresentation in the CCA group in general (29% vs 35%; P=0.18) and, in particular, for extrahepatic tumor sites (26% vs 35%; OR=0.67; 95% CI, 0.43-1.02; P=0.065). CONCLUSIONS: Our data do not support a prominent contribution of the pre-miR-146a sequence variant in the genetic predisposition to CCA. However, current studies functionally characterizing rs2910164 have proposed that distinct repertoires of target genes are addressed by genotype-specific mature miR-146a species. Given the detected trend towards a potentially protective role of GC heterozygosity, a subtle modulation of genetic CCA risk by the pre-miR-146a GC genotype may exist and should be evaluated further.

Feasibility and safety of long-term photodynamic therapy (PDT) in the palliative treatment of patients with hilar cholangiocarcinoma.

BACKGROUND AND AIM: PDT is an important palliative option for patients with unresectable extrahepatic cholangiocarcinoma (CC). However, the results published to date reported on studies with no more than 6 (mostly up to 4) PDT procedures. Furthermore, the clinical experience of PDT in combination with chemotherapy is limited. The purpose of this retrospective analysis was to evaluate the feasibility and safety of multiple (4 to 14) settings of PDT, combined with biliary drainage, and (in some cases) with chemotherapy. - METHODS: Ten patients with unresectable extrahepatic CC were treated with biliary stenting and at least 4 PDT procedures in our department between 10/2005 and 08/2010. - RESULTS: Ten patients (male/female = 5/5), mean age 68.8 years (range, 54 - 81 years) who received at least 4 PDT procedures were analyzed. All patients underwent endoscopic biliary drainage. Nine patients received metallic stents and one patient a plastic stent. In 4 patients (40%) bilateral metal stenting (JoStent SelfX®) was performed. The mean number of PDT sessions was 7.9 ± 3.9 (range: 4 - 14). Eight patients had elevated bilirubin levels with a mean bilirubin at admission of 9.9 ± 11.3 mg/dL, which had decreased to an average minimum of 1.2 ± 0.9 mg/dL after 3 months. No severe toxicity was noted. Two patients received concomitant chemotherapy (GEMCIS as 1st line, GEMOX plus cetuximab as 2nd line). The median overall survival has not been reached, whereas the estimated survival of all patients was 47.6 months, 95% CI 25.9 - 48.1. - CONCLUSION: Long-term PDT in patients with extrahepatic CC is feasible and effective and is accompanied - at least in this cohort- by a survival time of more than 2 years.

Genetics of biliary tract diseases: new insights into gallstone disease and biliary tract cancers.

PURPOSE OF REVIEW: Chronic biliary diseases are due to complex interactions between environmental and genetic factors. Here we summarize the current knowledge of genetic factors that contribute to common biliary diseases, focusing on gallstones and carcinogenesis, and review the recent association studies. RECENT FINDINGS: Since most studies were based on small sample sizes, replication of the findings is mandatory. Recently a large twin study confirmed a genetic predisposition to gallstones and a genome-wide association scan identified the hepatocanalicular cholesterol transporter ABCG8 as the common susceptibility factor for gallstone disease. Genetic studies in patients with cholangiocarcinoma indicate that genes controlling the metabolism and transport of xenobiotics or modulating chronic inflammation may determine individual susceptibility. SUMMARY: Genetic studies have identified the first susceptibility factors for gallstones and biliary tract cancers, but most results have yet to be replicated. In the future, genome-wide studies in different populations are likely to identify the entire set of genes contributing to chronic biliary diseases. Since the disease phenotypes result from the manifestation of susceptibility factors under the influence of environmental triggers, the discovery of these genes will open avenues to control environmental challenges and lead to novel strategies for risk assessment ('gene signatures') and prevention.

Evidence for PTGER4, PSCA, and MBOAT7 as risk genes for gastric cancer on the genome and transcriptome level.

Genetic associations between variants on chromosome 5p13 and 8q24 and gastric cancer (GC) have been previously reported in the Asian population. We aimed to replicate these findings and to characterize the associations at the genome and transcriptome level. We performed a fine-mapping association study in 1926 GC patients and 2012 controls of European descent using high dense SNP marker sets on both chromosomal regions. Next, we performed expression quantitative trait locus (eQTL) analyses using gastric transcriptome data from 143 individuals focusing on the GC associated variants. On chromosome 5p13 the strongest association was observed at rs6872282 (P = 2.53 × 10-04 ) and on chromosome 8q24 at rs2585176 (P = 1.09 × 10-09 ). On chromosome 5p13 we found cis-eQTL effects with an upregulation of PTGER4 expression in GC risk allele carrier (P = 9.27 × 10-11 ). On chromosome 8q24 we observed cis-eQTL effects with an upregulation of PSCA expression in GC risk allele carrier (P = 2.17 × 10-47 ). In addition, we found trans-eQTL effects for the same variants on 8q24 with a downregulation of MBOAT7 expression in GC risk allele carrier (P = 3.11 × 10-09 ). In summary, we confirmed and refined the previously reported GC associations at both chromosomal regions. Our data point to shared etiological factors between Asians and Europeans. Furthermore, our data imply an upregulated expression of PTGER4 and PSCA as well as a downregulated expression of MBOAT7 in gastric tissue as risk-conferring GC pathomechanisms.

Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma.

BACKGROUND: Primary sclerosing cholangitis confers risk of cholangiocarcinoma. Here, we assessed the primary sclerosing cholangitis-associated variant rs3197999 in the MST1 gene, coding for RON receptor tyrosine kinase ligand macrophage stimulating protein, in a large European cholangiocarcinoma cohort. MATERIALS AND METHODS: 223 cholangiocarcinoma patients including three primary sclerosing cholangitis individuals and 355 cancer- and primary sclerosing cholangitis-free controls were genotyped for MST1 rs3197999. RESULTS: The cancer group departed from Hardy-Weinberg equilibrium (p = 0.022) and exhibited a trend for rs3197999 [A] overrepresentation (31% vs. 26%: p = 0.10). Homozygous rs3197999 [AA] carrier status significantly increased overall (OR = 1.97; p = 0.023) and primary sclerosing cholangitis-unrelated biliary tract cancer risk (OR = 1.84; p = 0.044), relative to homozygous common allele carriers. The association was most pronounced in patients with extrahepatic tumours. This finding was robust to multivariate analysis (p < 0.05), validating the [AA] genotype as an independent cholangiocarcinoma risk factor. CONCLUSIONS: These results suggest that the [AA] genotype of the common MST1 variant rs3197999 enhances genetic risk of sporadic extrahepatic cholangiocarcinoma irrespective of primary sclerosing cholangitis status, presumably by modulating inflammatory responses and/or altered MSP/RON signalling.

Potential genotype-specific single nucleotide polymorphism interaction of common variation in p53 and its negative regulator mdm2 in cholangiocarcinoma susceptibility.

Aberrant cell cycle control and apoptosis deregulation are involved in biliary carcinogenesis. The tumor suppressor gene p53 and its key negative regulator murine double minute 2 (mdm2) cooperate in modulating these basic cell functions and germline p53 alteration promotes cholangiocarcinoma (CCA) formation in animal models. The potential association between common functional genetic variation in p53 (SNP72 G/C) and mdm2 (SNP309 T/G) and susceptibility to bile duct cancer, however, has not been studied. p53/SNP72 G/C (rs1042522) and mdm2/SNP309 T/G (rs2279744) were genotyped in 182 Caucasian CCA patients and 350 controls using TaqMan assays. Allelic and genotypic differences, including exploratory data analyses (according to gender, tumor localization, early onset and genotypic interactions) were compared in contingency tables using the χ(2) and Fisher's exact tests. The overall comparison of allele and genotype frequencies yielded no significant association between either SNP and CCA susceptibility. Similarly, gender- and localization-specific analyses did not reveal deviations in allelic or genotypic distributions. In carriers of the low-apoptotic p53 genotype CC, the mdm2 SNP309 T allele conferred borderline significant CCA risk [P=0.049; odds ratio (OR), 4.36; 95% CI, 0.92-20.77]. Power analysis confirmed adequate statistical power to exclude major SNP effects (each >97% for OR 1.7). Collectively, the results we obtained from the largest European CCA cohort do not support the hypothesis of a prominent role of common p53 and mdm2 variation in the genetic susceptibility to bile duct cancer. However, epistatic effects may modulate genetic CCA risk in individual subsets.

Pancreatic cancer risk variant ABO rs505922 in patients with cholangiocarcinoma.

The aim of this study was to investigate an association between the development of cholangiocarcinoma (CCA) and the ABO variant rs505922 (known to increase pancreatic cancer risk) in a large cohort of European individuals with CCA. In total, 180 individuals with CCA and 350 CCA-free controls were included. The ABO variant rs505922 was genotyped using a polymerase chain reaction-based assay. Association between this single nucleotide polymorphism (SNP) and CCA was tested in contingency tables. Neither allele distributions nor association tests and regression analysis provided evidence for an increased risk of CCA among carriers of the ABO variant (all P > 0.05). Nevertheless, we documented a deviation from Hardy-Weinberg equilibrium in the entire CCA cohort (P = 0.028) and for patients with intrahepatic (P = 0.037) but not extrahepatic tumor localization (P > 0.05). The association tests did not provide evidence for a prominent role of the investigated SNP in the genetic risk of CCA. However, Hardy-Weinberg disequilibrium in the entire cohort and the intrahepatic CCA subgroup warrants future studies investigating a potential CCA risk modulation by individual blood groups.