Association of gBRCA1/2 mutation locations with ovarian cancer risk in Japanese patients from the CHARLOTTE study

Whether germline (g) breast cancer susceptibility gene (BRCA) mutations are located within or outside the ovarian cancer cluster region (OCCR) (1380‐4062 bp for gBRCA1, and between 3249‐5681 bp and 6645‐7471 bp for gBRCA2) may influence risk variations for ovarian cancers. This ad hoc analysis of the CHARLOTTE epidemiological study in Japan assessed the distribution of gBRCA1/2 mutations in patients with newly diagnosed ovarian cancer, and investigated an association between gBRCA1/2 mutation locations and ovarian cancer risk. Differences in patient background and clinical characteristics in subgroups stratified by gBRCA1/2 mutation locations were also evaluated. We analyzed the data of 93 patients (14.7%) from the CHARLOTTE study who were positive for gBRCA1/2 mutations. After excluding 16 cases with L63X founder mutation, 28 (65.1%) of gBRCA1 mutations were within the OCCR. Of 30 gBRCA2 mutations, 15 (50.0%) were within the OCCR. Of 27 patients (one patient excluded for unknown family history) with gBRCA1 mutations located in the OCCR, 11 (40.7%) had a family history of ovarian cancer; the proportion of patients with a family history of ovarian cancer and gBRCA1 mutations outside the OCCR was lower (13.3%). Sixty percent of patients with gBRCA1 mutations outside the OCCR had a family history of breast cancer; the proportion of patients with a family history of breast cancer and gBRCA1 mutations within the OCCR was relatively lower (33.3%). Understanding the mutation locations may contribute to more accurate risk assessments of susceptible individuals and early detection of ovarian cancer among gBRCA mutation carriers.     

Systemic capillary leak syndrome triggered by anti-programmed death 1 checkpoint inhibitor in psoriasis

Programmed death 1 (PD-1) inhibitors are increasingly used for the treatment of malignancies. Despite the clinical benefits, unpredictable and potentially fatal side-effects may occur. We report a psoriatic patient who developed systemic capillary leak syndrome (SCLS) after starting a PD-1 checkpoint inhibitor. In order to determine which factors could trigger the development of SCLS in a patient with stable psoriasis after starting anti-PD-1 therapy, serum cytokines were serially measured before and after the development of SCLS in this patient. We also retrospectively reviewed 28 previously reported patients presenting clinical exacerbations of pre-existing psoriasis or the de novo induction of psoriasis after anti-PD-1 therapy. In 16 of the 28 patients (57.1%), the interval between last anti-PD-1 therapy and exacerbations of pre-existing psoriasis or the de novo induction of psoriasis was less than 28 days. The timing of the onset of SCLS in this patient was coincident with the increase in lymphocyte counts and at 22 days after last anti-PD-1 therapy. In 75%, however, anti-PD-1 therapy was able to be restarted and was tolerated well. Increased levels of interleukin (IL)-2, IL-6, interferon-γ and tumor necrosis factor-α, in addition to a persistent increase in vascular endothelial growth factor (VEGF), were detected at onset of SCLS. An increase in pro-inflammatory cytokines and VEGF, when combined with a rapid and sequential recovery of neutrophils and lymphocytes after anti-PD-1 therapy, would predict the development of SCLS. Clinicians need to be aware that patients with psoriasis are at risk of a potentially fatal disease, SCLS, when anti-PD-1 therapy is started.