RAS/TP53 Co-mutation is Associated With Worse Survival After Concurrent Resection of Colorectal Liver Metastases and Extrahepatic Disease.

OBJECTIVE: To determine if tumor genetics are associated with overall survival (OS) after concurrent resection of colorectal liver metastases (CLM) and extrahepatic disease (EHD). SUMMARY BACKGROUND DATA: The prognosis for patients who undergo concurrent resection of CLM/EHD is unclear and the impact of somatic mutations has not been reported. METHODS: Patients undergoing concurrent resection of CLM and EHD from 2007 to 2017 were identified from 2 academic centers. From 1 center, patients were selected from a pre-existing database of patients undergoing cytore-ductive surgery with hyperthermic intraperitoneal chemotherapy. The Kaplan-Meier method was used to construct survival curves, compared using the log-rank test. Multivariable Cox analysis for OS was performed. RESULTS: One hundred nine patients were included. Most common EHD sites included lung (33 patients), peritoneum (32), and portal lymph nodes (14). TP53 mutation was the most common mutation, identified in 75 patients (69%), and RAS/TP53 co-mutation was identified in 31 patients (28%). The median OS was 49 months (interquartile range, 24-125), and 3- and 5-year OS rates were 66% and 44%, respectively. Compared to patients without RAS/ TP53 co-mutation, patients with RAS/TP53 co-mutation had lower median OS: 39 vs. 51 months ( P = 0.02). On multivariable analysis, lung EHD [hazard ratio (HR), 0.7; 95% confidence intervals (CI), 0.3-1.4], peritoneal EHD (HR, 2.2; 95% CI, 1.1-4.2) and RAS/TP53 co-mutation (HR, 2.8; 95% CI, 1.1-7.2) were independently associated with OS. CONCLUSIONS: RAS/TP53 co-mutation is associated with worse OS after concurrent CLM/EHD resection. Mutational status and site of EHD should be included in the evaluation of patients considered for concurrent resection.

Differential expression of PTEN gene correlates with phenotypic heterogeneity in three cases of patients showing clinical manifestations of PTEN hamartoma tumour syndrome.

Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS) and proteus syndrome are disorders known as PTEN hamartoma tumour syndrome (PHTS), that can show remarkable clinical overlap and are all caused by germline PTEN mutations. We here present two families, one affected by CS and the other affected by BRRS, both carriers of specific pathogenetic missense mutation in exon 5 of PTEN gene, within the catalitic domain. Both PHTS families exhibited extremely variable phenotypes, showing inter- and intra- familial variability. One of the two characterised mutations, the c.320A- > T; p.107Asp- > Val, identified in the CS family, was not previously described in the literature. Furthermore, the BRRS family, carrier of the c.406 T- > C; p.136Cys- > Arg mutation, shows a substantial alteration of PTEN protein expression that well correlates with intra-familial phenotypic variability. Finally, we describe an apparently sporadic case of an 80-year-old man, with a very low level of PTEN mRNA and protein expression, both in healthy and tumour colon mucosa, associated with a very atypical phenotype. He developed a metastatic colorectal carcinoma, macrocephaly and pheochromocytoma. According to literature data, our observations confirm that PTEN mutations of catalytic domain can cause different syndromes. We suggest that PTEN expression could represent one of the mechanisms involved in the remarkable heterogeneity of the clinical PHTS manifestations within affected families. Furthermore, constitutive strong decrease of PTEN expression in colon normal mucosa could be associated with late onset of colorectal cancer.

Effectiveness of a new long cytology brush in the evaluation of malignant biliary obstruction: a prospective study.

BACKGROUND: Cancer detection rates with biliary brush sampling remain disappointingly low. A low cellular yield is often the limiting factor in making a diagnosis of malignancy. The new Cytolong brush (Cook Endoscopy, Winston-Salem, NC) is 3 mm in diameter, 5 cm long, with stiffer bristles oriented at 45 degrees on a 7F sheath. We hypothesized that this new brush might improve cancer detection rates by increasing cellular yield. METHODS: Patients found to have a biliary stricture suspicious for neoplasia on ERCP were randomized to undergo brush sampling for cytology with a standard Geenen brush (GB; Cook Endoscopy, Winston-Salem, NC) [3 mm in diameter, 1.5 cm long, bristles oriented at 90 degrees on a 6F sheath] or the Cytolong brush (CB). Repeat sampling was then performed with the other brush. Stricture dilation was not performed prior to brushing. Specimen results were considered normal, atypical (considered benign), highly atypical (suspicious for cancer), or malignant. All specimens were assigned a cellularity score (0 to 3, insufficient to excellent). Final diagnosis was based on cytologic results plus surgery, EUS, autopsy, or clinical follow-up. RESULTS: From November 2001 to July 2003, 102 patients had specimens obtained from 94 malignancies (47% pancreatic cancer). The cancer detection rate was 25 of 94 (27%) using CB and 28 of 94 (30%) with GB (p = NS). No patient had positive cytology results with CB and negative cytology results with GB. The yield of the two brushes combined was 28 of 94 (30%). Cancer detection rates of 28% (18 of 64) and 31% (20 of 64) were found for CB and GB, respectively, in distal biliary strictures, and 23% (7 of 30) and 27% (8 of 30) in proximal strictures (p = NS). Insufficient or limited cellularity was seen less frequently with CB (11 of 98) than with GB (17 of 98), and the mean cellular yield was greater with CB than GB (2.6 vs 2.4, p = 0.006). SUMMARY: Despite improved cellularity, cancer detection rates were not improved by using the larger Cytolong brush in this study. There was no statistical difference between the brushes in both proximal and distal biliary strictures. CONCLUSIONS: The yield of biliary brush cytology at ERCP remains low. Increasing brush size and bristle stiffness does not increase detection rates. Newer devices and processing techniques are required to allow detection rates to approach those attained in other GI tract malignancies.