A dual role for Caspase8 and NF-κB interactions in regulating apoptosis and necroptosis of ovarian cancer, with correlation to patient survival.

Ovarian cancer is a deadly disease characterized by primary and acquired resistance to chemotherapy. We previously associated NF-κB signaling with poor survival in ovarian cancer, and functionally demonstrated this pathway as mediating proliferation, invasion and metastasis. We aimed to identify cooperating pathways in NF-κB-dependent ovarian cancer cells, using genome-wide RNA interference as a loss-of-function screen for key regulators of cell survival with IKKß inhibition. Functional genomic screen for interactions with NF-κB in ovarian cancer showed that cells depleted of Caspase8 died better with IKKß inhibition. Overall, low Caspase8 was associated with shorter overall survival in three independent gene expression data sets of ovarian cancers. Conversely, Caspase8 expression was markedly highest in ovarian cancer subtypes characterized by strong T-cell infiltration and better overall prognosis, suggesting that Caspase8 expression increased chemotherapy-induced cell death. We investigated the effects of Caspase8 depletion on apoptosis and necroptosis of TNFα-stimulated ovarian cancer cell lines. Inhibition of NF-κB in ovarian cancer cells switched the effects of TNFα signaling from proliferation to death. Although Caspase8-high cancer cells died by apoptosis, Caspase8 depletion downregulated NF-κB signaling, stabilized RIPK1 and promoted necroptotic cell death. Blockage of NF-κB signaling and depletion of cIAP with SMAC-mimetic further rendered these cells susceptible to killing by necroptosis. These findings have implications for anticancer strategies to improve outcome for women with low Caspase8-expressing ovarian cancer.

Deleterious BRCA1/2 mutation is an independent risk factor for carboplatin hypersensitivity reactions.

BACKGROUND: We tested the hypothesis that BRCA1/2 mutation carriers with ovarian cancer are at higher risk of carboplatin hypersensitivity reactions (HSRs). METHODS: Medical records of women enrolled in two carboplatin+olaparib clinical trials (NCT01237067/NCT01445418) were reviewed. A maximum of eight cycles containing carboplatin were administered. RESULTS: All women (N=87) had good performance status and end-organ function. Incidences of carboplatin HSR before enrolment and on study were 17% and 21%, respectively. Most patients who developed carboplatin HSR had a deleterious BRCA1/2 mutation (93%) vs 50% in patients without HSR (P<0.0001). Multivariable analysis accounting for potential confounding variables including age, history of allergies, and cumulative prior carboplatin cycles confirmed deleterious BRCA1/2 mutation as an independent risk factor for carboplatin HSR (odds ratio 13.1 (95% confidence interval 2.6-65.4), P=0.0017). Mutation carriers had onset of carboplatin HSR at lower cumulative exposure (P=0.003). No significant difference in outcome was observed on our study between patients with and without a history of HSR. CONCLUSION: Deleterious BRCA1/2 mutation increased susceptibility and shortened time to carboplatin HSR, independently of other reported factors. These data suggest that at-risk women should be counselled regarding likelihood, symptoms, and potential earlier onset of carboplatin HSRs.

Frequency and outcome of neoplastic brachial plexopathy: single institution experience.

Symptomatic neoplastic brachial plexopathy (NBP) is estimated to occur in about 0.4% of all patients with cancer. The aim of this review was to determine the incidence of NBP occurring in patients referred for magnetic resonance imaging (MRI). A retrospective review over a 5 year period revealed that a total of sixty-six MRls of brachial plexus were performed. Twenty-nine were performed for assessment of suspected traumatic injuries. Eighteen MRIs were performed in patients with a known cancer diagnosis, one was performed in a patient with a benign thymoma, one with a neurofibroma and the remaining seventeen MRIs were ordered for other conditions. In total, thirteen MRls were positive for brachial plexopathy (seven traumatic, five due to cancer, one neurofibroma). Of the twenty MRIs performed in patients with neoplasms, six (30%) confirmed a diagnosis of NBRP. Twenty seven point eight per cent (5/18) of patients with a diagnosis of cancer had NBP.

Occupational contact urticaria: Australian data.

BACKGROUND: Over the last 30 years there has been increasing recognition of the clinical entity contact urticaria (CU) and the related diagnosis, protein contact dermatitis. However, there are relatively few reports of the occupational relevance of this condition. OBJECTIVES: To describe relevant characteristics of patients diagnosed with occupational CU (OCU) in a tertiary level specialist occupational dermatology clinic in Australia. METHODS: We performed a retrospective analysis of all patients diagnosed with OCU at an occupational dermatology clinic in Melbourne between 1 January 1993 and 31 December 2004. We identified 151 cases of CU diagnosed over the 12-year period. RESULTS: OCU was diagnosed in 8.3% (143 of 1720) of the total number of patients with occupational skin disease. Natural rubber latex accounted for the majority of all cases of OCU. Other common causes were foodstuffs and ammonium persulphate utilized as hairdressing bleach. The most commonly affected sites were the hands, followed by the arms and face. The most frequently affected occupations were healthcare workers, food handlers and hairdressers. All cases of CU in patients with hand symptoms were assessed to be work related. Atopy was a significant risk factor for both latex-related and nonlatex-related OCU. CONCLUSIONS: Radioallergosorbent tests and skin prick testing, including to patients' own food samples, should be part of the routine assessment of patients in high-risk occupations for OCU, particularly if the hands are affected, there is a history of atopy and there is exposure to urticants. We emphasize the importance of both determining the role of occupation in the causation of CU and recognizing all contributory factors in complex cases of occupational contact dermatitis of the hands.