Sulindac targets nuclear β-catenin accumulation and Wnt signalling in adenomas of patients with familial adenomatous polyposis and in human colorectal cancer cell lines

Nonsteroidal anti-inflammatory drugs (NSAIDs) have chemopreventive potential against colorectal carcinomas (CRCs). Inhibition of cyclooxygenase (COX)-2 underlies part of this effect, although COX-2-independent mechanisms may also exist. Nonsteroidal anti-inflammatory drugs appear to inhibit the initial stages of the adenoma-carcinoma sequence, suggesting a link to the APC/beta-catenin/TCF pathway (Wnt-signalling pathway). Therefore, the effect of the NSAID sulindac on nuclear (nonphosphorylated) beta-catenin and beta-catenin/TCF-mediated transcription was investigated. Nuclear #946;-catenin expression was assessed in pretreatment colorectal adenomas and in adenomas after treatment with sulindac from five patients with familial adenomatous polyposis (FAP). Also, the effect of sulindac sulphide on beta-catenin/TCF-mediated transcription was studied. Adenomas of FAP patients collected after treatment with sulindac for up to 6 months showed less nuclear beta-catenin expression compared to pretreatment adenomas of the same patients. Sulindac sulphide abrogated beta-catenin/TCF-mediated transcription in the CRC cell lines DLD1 and SW480, and decreased the levels of nonphosphorylated beta-catenin. As a result, the protein levels of the positively regulated TCF targets Met and cyclin D1 were downregulated after sulindac treatment. This study provides in vivo and in vitro evidence that nuclear beta-catenin localisation and beta-catenin/TCF-regulated transcription of target genes can be inhibited by sulindac. The inhibition of Wnt-signalling provides an explanation for the COX-2-independent mechanism of chemoprevention by NSAID

Letter to the editor: a response to Ming’s study on machine learning techniques for personalized breast cancer risk prediction

A recent paper [1] compared two well-known breast cancer risk prediction models (BCRAT and BOADICEA) with eight different machine learning (ML) methods. The authors found a striking improvement in cancer prediction with ML. While their comparative assessment against more classical approaches is timely, we are skeptical about the results presented

Uptake of genetic testing by the children of Lynch syndrome variant carriers across three generations

Many Lynch syndrome (LS) carriers remain unidentified, thus missing early cancer detection and prevention opportunities. Tested probands should inform their relatives about cancer risk and options for genetic counselling and predictive gene testing, but many fail to undergo testing. To assess predictive testing uptake and demographic factors influencing this decision in LS families, a cross-sectional registry-based cohort study utilizing the Finnish Lynch syndrome registry was undertaken. Tested LS variant probands (1184) had 2068 children divided among three generations: 660 parents and 1324 children (first), 445 and 667 (second), and 79 and 77 (third). Of children aged 418 years, 801 (67.4%), 146 (43.2%), and 5 (23.8%), respectively, were genetically tested. Together, 539 first-generation LS variant carriers had 2068 children and grandchildren (3.84 per carrier). Of the 1548 (2.87 per carrier) eligible children, 952 (61.5%) were tested (1.77 per carrier). In multivariate models, age (OR 1.08 per year; 95% CI 1.06-1.10), family gene (OR 2.83; 1.75-4.57 for MLH1 and 2.59; 1.47-4.56 for MSH2 compared with MSH6), one or more tested siblings (OR 6.60; 4.82-9.03), no siblings (OR 4.63; 2.64-8.10), and parent under endoscopic surveillance (OR 5.22; 2.41-11.31) were independent predictors of having genetic testing. Examples of parental adherence to regular surveillance and genetically tested siblings strongly influenced children at 50% risk of LS to undergo predictive gene testing. High numbers of untested, adult at-risk individuals exist even among well-established cohorts of known LS families with good adherence to endoscopic surveillance.Peer reviewe

Impact of BRAF, MLH1 on the incidence of microsatellite instability high colorectal cancer in populations based study

We have identified an alternative pathway of tumorigenesis in sporadic colon cancer, involving microsatellite instability due to mismatched repair methylation, which may be driven by mutations in the BRAF gene (V600E). Colorectal cancer (CRC) is the most common cancer in the world, and African Americans show a higher incidence than other populations in the United States. We analyzed sporadic CRCs in Omani (of African origin, N = 61), Iranian (of Caucasian origin, N = 53) and African American (N = 95) patients for microsatellite instability, expression status of mismatched repair genes (hMLH1, hMSH2) and presence of the BRAF (V600E) mutation. In the Omani group, all tumors with BRAF mutations were located in the left side of the colon, and for African Americans, 88% [7] of tumors with BRAF mutations were found in the right side of the colon. In African Americans, 31% of tumors displayed microsatellite instability at two or more markers (MSI-H), while this rate was 26% and 13% for tumors in the Iranian and Omani groups, respectively. A majority of these MSI-H tumors were located in the proximal colon (right side) in African American and Iranian subjects, whereas most were located in the distal colon (left side) in Omani subjects. Defects in hMLH1 gene expression were found in 77% of MSI-H tumors in both African Americans and Iranians and in 38% of tumors in Omanis. BRAF mutations were observed in all subjects: 10% of tumors in African Americans (8/82), 2% of tumors in Iranians (1/53), and 19% of tumors in Omanis (11/59). Our findings suggest that CRC occurs at a younger age in Omani and Iranian patients, and these groups showed a lower occurrence of MSI-H than did African American patients. Our multivariate model suggests an important and significant role of hMLH1 expression and BRAF mutation in MSI-H CRC in these populations. The high occurrence of MSI-H tumors in African Americans may have significant implications for treatment, since patients with MSI-H lesions display a different response to chemotherapeutic agents such as 5-fluorouracil

External validation and clinical utility assessment of PREDICT breast cancer prognostic model in young, systemic treatment-naïve women with node-negative breast cancer

Background: The validity of the PREDICT breast cancer prognostic model is unclear for young patients without adjuvant systemic treatment. This study aimed to validate PREDICT and assess its clinical utility in young women with node-negative breast cancer who did not receive systemic treatment. Methods: We selected all women from the Netherlands Cancer Registry who were diagnosed with node-negative breast cancer under age 40 between 1989 and 2000, a period when adjuvant systemic treatment was not standard practice for women with node-negative disease. We evaluated the calibration and discrimination of PREDICT using the observed/expected (O/E) mortality ratio, and the area under the receiver operating characteristic curve (AUC), respectively. Additionally, we compared the potential clinical utility of PREDICT for selectively administering chemotherapy to the chemotherapy-to-all strategy using decision curve analysis at predefined thresholds. Results: A total of 2264 women with a median age at diagnosis of 36 years were included. Of them, 71.2% had estrogen receptor (ER)-positive tumors and 44.0% had grade 3 tumors. Median tumor size was 16 mm. PREDICT v2.2 underestimated 10-year all-cause mortality by 33% in all women (O/E ratio:1.33, 95%CI:1.22–1.43). Model discrimination was moderate overall (AUC10-year:0.65, 95%CI:0.62–0.68), and poor for women with ER-negative tumors (AUC10-year:0.56, 95%CI:0.51–0.62). Compared to the chemotherapy-to-all strategy, PREDICT only showed a slightly higher net benefit in women with ER-positive tumors, but not in women with ER-negative tumors. Conclusions: PREDICT yields unreliable predictions for young women with node-negative breast cancer. Further model updates are needed before PREDICT can be routinely used in this patient subset.</p

Intragastric gastric band migration: erosion: an analysis of multicenter experience on 177 patients

BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has proven to be a safe and effective surgical treatment for morbid obesity. It can be a simple, fast, reversible, anatomy-preserving procedure. Despite these advantages, its long-term efficacy came into question by the occurrence of complications such as intragastric band migration. Consistent information regarding this complication is still lacking. Treatment for migration is still being debated as well. Most of the inconsistencies of these data stem from the very low number of patients reported in single-center experiences or case reports. Lack of multicenter experience is evident. The aim of this study was to perform a retrospective analysis of data on intragastric migration in a large multicenter cohort of patients who underwent LAGB. METHODS: A retrospective multicenter study on LAGB patients was performed. Data had been entered into a prospective database of the Italian Group for LapBand(®) (GILB) since January 1997. Pars flaccida and perigastric positioning were considered along with different kinds of gastric bands by the same manufacturer. Time of diagnosis, mean body mass index (BMI), presentation symptoms, and conservative and surgical therapy of intragastric migration were considered. RESULTS: From January 1997 to December 2009, a total of 6,839 patients underwent LAGB and their data were recorded [5,660 females, 1,179 males; mean age 38.5 ± 18.2 years (range 21-62 years); mean BMI = 46.7 ± 7.7 kg/m(2) (range 37.3-68.3); excess weight (EW) 61.8 ± 25.4 kg (range 36-130); %EW 91.1 ± 32.4 % (range 21-112 %)]. A total of 177 of 6,839 (2.5 %) intragastric erosions were observed. According to the postoperative time of follow-up, the diagnosis of intragastric migration was made in 74 (41.8 %), 14 (7.9 %), 38 (21.4 %), 40 (22.6 %), 6 (3.4 %), and 4 (2.2 %) banded patients at 6-12, 24, 36, 48, 60, and 72 months after banding, respectively. Most of intragastric band migration during the first 2 years occurred in bands with no or a few milliliters of filling. In patients with late erosion, the bands were adjusted several times; no band was overfilled but one was filled to the maximum or submaximum with a maximum of two adjustments. Erosions diagnosed during the first 24 months were related to the experience of the surgical staff, while late erosions were not. CONCLUSIONS: Intragastric band migration or band erosion is a rare, disturbing, and usually not life-threatening complication of gastric banding. Its pathogenesis is probably linked to different mechanisms in early (technical failure in retrogastric passage) or late (band management) presentation. It is usually asymptomatic and there is no pathognomonic presentation. A wide range of therapeutic options are available, from simple endoscopic or laparoscopic removal to early or late band replacement or other bariatric procedure. More experience and more studies are needed to lower its presentation rate and definitively clarify its pathogenesis to address the right therapeutic option

Improvement in health-related quality of life in first year after laparoscopic adjustable gastric banding

BACKGROUND: We analyzed the health-related quality of life (HRQOL) and its determinants in the first year after laparoscopic adjustable gastric banding (LAGB). The setting was 10 Italian public and private bariatric surgery centers. METHODS: Data collected in an ongoing, prospective, 3-year multicenter Italian study on the changes in HRQOL after LAGB were used. HRQOL was investigated using the Medical Outcomes Study Short-Form 36 questionnaire. Hunger, satiety, and the self-perceived effects of LAGB were recorded. RESULTS: A total of 334 patients were enrolled. The follow-up rate was 92.2%. The percentage of excess weight loss was 39.6% \ub1 25.8%, with very few side effects or complications. Hunger in the morning (0-10 scale) was 4.5 \ub1 2.7 before surgery and 3.8 \ub1 2.4 after 1 year (P <.001). Satiety after a meal (0-10 scale) was 7.1 \ub1 2.7 before surgery and 8.2 \ub1 1.9 at 1 year (P <.001). The self-perceived effect of LAGB on caloric intake (0-10 scale) was 8.4 \ub1 1.9 after 1 year. The scores for the 8 Medical Outcomes Study Short-Form 36 subscales were significantly improved after surgery. The physical component summary score was 52.6 \ub1 11.9 at baseline and 79.1 \ub1 15.6 after 1 year (P <.001). The corresponding mental component summary scores were 52.2 \ub1 12.3 and 76.5 \ub1 17.2 (P <.001). Greater physical component summary improvement was independently associated with a low initial physical component summary (P <.001), high satiety (P = .002), a high percentage of excess weight loss (P = .013), and a high self-perceived effect of the LAGB (P = .026). Greater mental component summary improvement was associated with a low initial mental component summary (P <.001), high satiety (P <.001), a low frequency of heartburn (P = .004), and a high percentage of excess weight loss (P = .012). CONCLUSIONS: Significant improvements in HRQOL were observed in the first year after LAGB. A poor baseline HRQOL, a high efficacy of the banding in eating control, and better weight loss might influence HRQOL change

LKB1/KRAS mutant lung cancers constitute a genetic subset of NSCLC with increased sensitivity to MAPK and mTOR signalling inhibition

LKB1/STK11 is a multitasking tumour suppressor kinase. Germline inactivating mutations of the gene are responsible for the Peutz-Jeghers hereditary cancer syndrome. It is also somatically inactivated in approximately 30% of non-small-cell lung cancer (NSCLC). Here, we report that LKB1/KRAS mutant NSCLC cell lines are sensitive to the MEK inhibitor CI-1040 shown by a dose-dependent reduction in proliferation rate, whereas LKB1 and KRAS mutations alone do not confer similar sensitivity. We show that this subset of NSCLC is also sensitised to the mTOR inhibitor rapamycin. Importantly, the data suggest that LKB1/KRAS mutant NSCLCs are a genetically and functionally distinct subset and further suggest that this subset of lung cancers might afford an opportunity for exploitation of anti-MAPK/mTOR-targeted therapies