Physical activity, body size and composition, and risk of ovarian cancer

Objectives: We examined the association between risk of ovarian cancer and physical activity and anthropometry (body mass index, height, waist, fat, and fat-free mass) in the Melbourne Collaborative Cohort Study. Methods: This prospective cohort study included 18,700 women aged 26-76 years old at recruitment between 1990 and 1994. Participants were interviewed about their physical activity, including frequency and intensity. Body measurements were taken directly; fat mass and fat-free mass were calculated from bioelectrical impedance analysis. During an average of 10.2 years of follow-up, 113 ovarian cancers were ascertained. Cox regression was used to estimate hazard ratios. Results: After adjusting for potential confounders, compared with no physical activity, the hazard ratios for levels of total physical activity were 1.56 (95% CI: 0.81, 3.00) for low level, 1.92 (1.07, 3.45) for medium level, and 2.21 (1.16, 4.24) for high level (test for trend, p = 0.01). The hazard ratio for ovarian cancer in relation to BMI was 1.22 (95% CI: 1.00, 1.48; p-trend, 0.06) per 5 kg/m2 increment, and for fat mass, 1.23 (95% CI: 1.01, 1.49; p-trend, 0.04) per 10 kg increment. Conclusions: This study found some evidence for a possible relationship between higher levels of physical activity and body size and increased ovarian cancer risk. © 2010 Springer Science+Business Media B.V

Ante-mortem diagnosis of localized invasive esophageal aspergillosis in a patient with acute myeloid leukemia

Opportunistic infection with invasive aspergillosis (IA) is increasingly frequent in immunocompromised patients, particularly in those with hematological malignancies. In this setting, IA typically involves the lung, with extra-pulmonary involvement usually occurring in the setting of disseminated infection. We report a case of localized gastrointestinal IA complicating induction chemotherapy for acute myeloid leukemia (AML). Oral voriconazole was successful as primary treatment, with no evidence of progressive infection despite further myelosuppressive chemotherapy. A review of the literature suggests that although localized gastrointestinal IA is rare, involvement of the gastrointestinal tract is not uncommon in disseminated infection. Thus, in patients with hematological malignancies who develop significant gastrointestinal symptoms, we recommend that endoscopic investigations and biopsies are performed to exclude IA as a potential cause

Author Correction : DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis

The Original Article was published on 29 January 201

DUSP5 is methylated in CIMP-high colorectal cancer but is not a major regulator of intestinal cell proliferation and tumorigenesis

Abstract The ERK signalling pathway regulates key cell fate decisions in the intestinal epithelium and is frequently dysregulated in colorectal cancers (CRCs). Variations in the dynamics of ERK activation can induce different biological outcomes and are regulated by multiple mechanisms, including activation of negative feedback loops involving transcriptional induction of dual-specificity phosphatases (DUSPs). We have found that the nuclear ERK-selective phosphatase DUSP5 is downregulated in colorectal tumours and cell lines, as previously observed in gastric and prostate cancer. The DUSP5 promoter is methylated in a subset of CRC cell lines and primary tumours, particularly those with a CpG island methylator phenotype (CIMP). However, this epigenetic change alone could not account for reduced DUSP5 expression in CRC cells. Functionally, DUSP5 depletion failed to alter ERK signalling or proliferation in CRC cell lines, and its transgenic overexpression in the mouse intestine had minimal impact on normal intestinal homeostasis or tumour development. Our results suggest that DUSP5 plays a limited role in regulating ERK signalling associated with the growth of colorectal tumours, but that methylation the DUSP5 gene promoter can serve as an additional means of identifying CIMP-high colorectal cancers

BCL-XL inhibitors enhance the apoptotic efficacy of BRAF inhibitors in BRAF V600E colorectal cancer

Abstract Metastatic BRAF V600E colorectal cancer (CRC) carries an extremely poor prognosis and is in urgent need of effective new treatments. While the BRAFV600E inhibitor encorafenib in combination with the EGFR inhibitor cetuximab (Enc+Cet) was recently approved for this indication, overall survival is only increased by 3.6 months and objective responses are observed in only 20% of patients. We have found that a limitation of Enc+Cet treatment is the failure to efficiently induce apoptosis in BRAF V600E CRCs, despite inducing expression of the pro-apoptotic protein BIM and repressing expression of the pro-survival protein MCL-1. Here, we show that BRAF V600E CRCs express high basal levels of the pro-survival proteins MCL-1 and BCL-XL, and that combining encorafenib with a BCL-XL inhibitor significantly enhances apoptosis in BRAF V600E CRC cell lines. This effect was partially dependent on the induction of BIM, as BIM deletion markedly attenuated BRAF plus BCL-XL inhibitor-induced apoptosis. As thrombocytopenia is an established on-target toxicity of BCL-XL inhibition, we also examined the effect of combining encorafenib with the BCL-XL -targeting PROTAC DT2216, and the novel BCL-2/BCL-XL inhibitor dendrimer conjugate AZD0466. Combining encorafenib with DT2216 significantly increased apoptosis induction in vitro, while combining encorafenib with AZD0466 was well tolerated in mice and further reduced growth of BRAF V600E CRC xenografts compared to either agent alone. Collectively, these findings demonstrate that combined BRAF and BCL-XL inhibition significantly enhances apoptosis in pre-clinical models of BRAF V600E CRC and is a combination regimen worthy of clinical investigation to improve outcomes for these patients

Genomic Profiling of Biliary Tract Cancer Cell Lines Reveals Molecular Subtypes and Actionable Drug Targets

Biliary tract cancers (BTCs) currently have no approved targeted therapies. Although genomic profiling of primary BTCs has identified multiple potential drug targets, accurate models are needed for their evaluation. Genomic profiling of 22 BTC cell lines revealed they harbor similar mutational signatures, recurrently mutated genes, and genomic alterations to primary tumors. Transcriptomic profiling identified two major subtypes, enriched for epithelial and mesenchymal genes, which were also evident in patient-derived organoids and primary tumors. Interrogating these models revealed multiple mechanisms of MAPK signaling activation in BTC, including co-occurrence of low-activity BRAF and MEK mutations with receptor tyrosine kinase overexpression. Finally, BTC cell lines with altered ERBB2 or FGFRs were exquisitely sensitive to specific targeted agents, whereas surprisingly, IDH1-mutant lines did not respond to IDH1 inhibitors in vitro. These findings establish BTC cell lines as robust models of primary disease, reveal specific molecular disease subsets, and highlight specific molecular vulnerabilities in these cancers