Citations

Background Birt-Hogg-Dubé (BHD) syndrome is a rare genetic syndrome caused by pathogenic or likely pathogenic germline variants in the FLCN gene. Patients with BHD syndrome have an increased risk of fibrofolliculomas, pulmonary cysts, pneumothorax and renal cell carcinoma. There is debate regarding whether colonic polyps should be added to the criteria. Previous risk estimates have mostly been based on small clinical case series. Methods A comprehensive review was conducted to identify studies that had recruited families carrying pathogenic or likely pathogenic variants in FLCN . Pedigree data were requested from these studies and pooled. Segregation analysis was used to estimate the cumulative risk of each manifestation for carriers of FLCN pathogenic variants. Results Our final dataset contained 204 families that were informative for at least one manifestation of BHD (67 families informative for skin manifestations, 63 for lung, 88 for renal carcinoma and 29 for polyps). By age 70 years, male carriers of the FLCN variant have an estimated 19% (95% CI 12% to 31%) risk of renal tumours, 87% (95% CI 80% to 92%) of lung involvement and 87% (95% CI 78% to 93%) of skin lesions, while female carriers had an estimated 21% (95% CI 13% to 32%) risk of renal tumours, 82% (95% CI 73% to 88%) of lung involvement and 78% (95% CI 67% to 85%) of skin lesions. The cumulative risk of colonic polyps by age 70 years old was 21% (95% CI 8% to 45%) for male carriers and 32% (95% CI 16% to 53%) for female carriers. Conclusions These updated penetrance estimates, based on a large number of families, are important for the genetic counselling and clinical management of BHD syndrome.

Mutations that predispose to familial pheochromocytoma and paraganglioma include inherited variants in the four genes ( SDHA , SDHB , SDHC and SDHD ) encoding subunits of succinate dehydrogenase (SDH), an enzyme of the mitochondrial tricarboxylic acid cycle and complex II of the electron transport chain. In heterozygous variant carriers, somatic loss of heterozygosity is thought to result in tumorigenic accumulation of succinate and reactive oxygen species. Inexplicably, variants affecting the SDHB subunit predict worse clinical outcomes. Why? Here we consider two hypotheses. First, relative to SDH A, C and D subunits, the small SDHB subunit might be more intrinsically ‘fragile’ to missense mutations because of its relatively large fraction of amino acids contacting prosthetic groups and other SDH subunits. We show evidence that supports this hypothesis. Second, the natural pool of human SDHB variants might, by chance, be biased toward severe truncating variants and missense variants causing more disruptive amino acid substitutions. We tested this hypothesis by creating a database of known SDH variants and predicting their biochemical severities. Our data suggest that natural SDHB variants are more pathogenic. It is unclear if this bias is sufficient to explain clinical data. Other explanations include the possibility that SDH subcomplexes remaining after SDHB loss have unique tumorigenic gain-of-function characteristics, and/or that SDHB may have additional unknown tumor-suppressor functions.

Despite the proven benefit of stent retrievers, challenges to rapid revascularization of large vessel occlusions (LVO) persist. Current stent retrievers have limited effectiveness for removing organized thrombi. The NeVa device is a novel stent retriever designed with openings in the basket cell structure (“drop zones”) intended to capture organized thrombi within the central scaffold during retrieval. Prospective, multicenter, open label, single arm, FDA-regulated IDE study to evaluate the performance of the NeVa device for recanalizing occluded intracranial vessels including ICA, M1/M2 MCA, and vertebrobasilar arteries, within 8 hours of onset. Primary endpoint was rate of eTICI 2b-3 within 3 NeVa passes, tested for non-inferiority against a performance goal of 72% with a margin of -10%. Additional efficacy endpoints included first pass effect to eTICI 2b-3 (FPE) and 90-day mRS 0-2. Primary safety endpoint was 90-day mortality. (ClinicalTrials.gov NCT04514562) (Site-adjudicated revascularization results are reported here. Final core lab results will be presented at the conference.) From April 1, 2021 to April 28, 2022, 139 subjects were enrolled at 25 centers in the US and Europe. Mean age was 67 ± 13 years; 47% were female. Median NIHSS score was 16 (IQR: 12-20). Occlusions were 14 (10%) ICA, 85 (61%) M1, 38 (27%) M2, 1 (1%) Basilar and 1 (1%) PCA. Mean time to first pass was 19 ± 12 minutes. eTICI 2b-3 within 3 NeVa passes occurred in 87.8% (122/139; CI 81.1%,92.7%; non-inferiority p<0.0001; post hoc superiority p=0.002, tested against performance goal of 72%). FPE (to eTICI 2b-3) was observed in 67.6% (94/139), with first pass to eTICI 2b67-3 in 61.2% (85/139) and to eTICI 2c-3 in 43.9% (61/139). Median number of passes was 1 (IQR 1-2). Final eTICI 2b-3 rate was 94.2% (131/139); final eTICI 2c-3 rate was 65.5% (91/139). Good outcome (90-day mRS 0-2) was seen in 62.6% (87/139) and was 74.4% in patients with FPE (70/94 vs. 17/45 (37.8%) without FPE; p<0.0001). Mortality was 9.4% (13/139) with sICH in 8 (5.8%) subjects. The NeVa device is effective and safe for revascularization of LVO strokes and demonstrates high first pass success in this international multicenter study. First pass reperfusion (eTICI 2b-3) was strongly associated with functional independence.

Abstract Objectives To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). Methods A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. Results Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. Conclusions Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.