The BRCA1-Δ11q Alternative Splice Isoform Bypasses Germline Mutations and Promotes Therapeutic Resistance to PARP Inhibition and Cisplatin.

Breast and ovarian cancer patients harboring BRCA1/2 germline mutations have clinically benefitted from therapy with PARP inhibitor (PARPi) or platinum compounds, but acquired resistance limits clinical impact. In this study, we investigated the impact of mutations on BRCA1 isoform expression and therapeutic response. Cancer cell lines and tumors harboring mutations in exon 11 of BRCA1 express a BRCA1-Δ11q splice variant lacking the majority of exon 11. The introduction of frameshift mutations to exon 11 resulted in nonsense-mediated mRNA decay of full-length, but not the BRCA1-Δ11q isoform. CRISPR/Cas9 gene editing as well as overexpression experiments revealed that the BRCA1-Δ11q protein was capable of promoting partial PARPi and cisplatin resistance relative to full-length BRCA1, both in vitro and in vivo Furthermore, spliceosome inhibitors reduced BRCA1-Δ11q levels and sensitized cells carrying exon 11 mutations to PARPi treatment. Taken together, our results provided evidence that cancer cells employ a strategy to remove deleterious germline BRCA1 mutations through alternative mRNA splicing, giving rise to isoforms that retain residual activity and contribute to therapeutic resistance. Cancer Res; 76(9); 2778-90. ©2016 AACR.

Anaesthetic injection versus ischemic compression for the pain relief of abdominal wall trigger points in women with chronic pelvic pain.

BACKGROUND: Chronic pelvic pain is a common condition among women, and 10 to 30 % of causes originate from the abdominal wall, and are associated with trigger points. Although little is known about their pathophysiology, variable methods have been practiced clinically. The purpose of this study was to evaluate the efficacy of local anaesthetic injections versus ischemic compression via physical therapy for pain relief of abdominal wall trigger points in women with chronic pelvic pain. METHODS: We conducted a parallel group randomized trial including 30 women with chronic pelvic pain with abdominal wall trigger points. Subjects were randomly assigned to one of two intervention groups. One group received an injection of 2 mL 0.5 % lidocaine without a vasoconstrictor into a trigger point. In the other group, ischemic compression via physical therapy was administered at the trigger points three times, with each session lasting for 60 s, and a rest period of 30 s between applications. Both treatments were administered during one weekly session for four weeks. Our primary outcomes were satisfactory clinical response rates and percentages of pain relief. Our secondary outcomes are pain threshold and tolerance at the trigger points. All subjects were evaluated at baseline and 1, 4, and 12 weeks after the interventions. The study was conducted at a tertiary hospital that was associated with a university providing assistance predominantly to working class women who were treated by the public health system. RESULTS: Clinical response rates and pain relief were significantly better at 1, 4, and 12 weeks for those receiving local anaesthetic injections than ischemic compression via physical therapy. The pain relief of women treated with local anaesthetic injections progressively improved at 1, 4, and 12 weeks after intervention. In contrast, women treated with ischemic compression did not show considerable changes in pain relief after intervention. In the local anaesthetic injection group, pain threshold and tolerance improved with time in the absence of significant differences between groups. CONCLUSION: Lidocaine injection seems to be better for reducing the severity of chronic pelvic pain secondary to abdominal wall trigger points compared to ischemic compression via physical therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT00628355. Date of registration: February 25, 2008.

Abdominal myofascial pain syndrome must be considered in the differential diagnosis of chronic pelvic pain.

Chronic pelvic pain is lower abdominal pain lasting at least 6 months, occurring continuously or intermittently and not associated exclusively with menstruation or intercourse. The involvement of the musculoskeletal system in chronic pelvic pain has been increasingly demonstrated. However, few studies exclusively examining abdominal myofascial pain syndrome as a cause of chronic pelvic pain in women are available. Therefore the objective of this manuscript is to describe the association between abdominal myofascial pain syndrome and chronic pelvic pain in women, and comment on methods for diagnosis and therapeutic options. There is evidence that the musculoskeletal system is compromised in some way in most women with chronic pelvic pain and that in 15% of these cases chronic pelvic pain is associated with abdominal myofascial pain syndrome but the scarcity of published data impairs the definition of protocols for the diagnosis and treatment of this disease. Abdominal myofascial pain syndrome is a highly prevalent disease associated with CPP, and because of this physicians should get used to make a precise and early diagnosis in order to avoid additional and unnecessary investigation.