Causality and functional relevance of BRCA1 and BRCA2 pathogenic variants in non-high-grade serous ovarian carcinomas

The identification of causal BRCA1/2 pathogenic variants (PVs) in epithelial ovarian carcinoma (EOC) aids the selection of patients for genetic counselling and treatment decision-making. Current recommendations therefore stress sequencing of all EOCs, regardless of histotype. Although it is recognised that BRCA1/2 PVs cluster in high-grade serous ovarian carcinomas (HGSOC), this view is largely unsubstantiated by detailed analysis. Here, we aimed to analyse the results of BRCA1/2 tumour sequencing in a centrally revised, consecutive, prospective series including all EOC histotypes. Sequencing of n = 946 EOCs revealed BRCA1/2 PVs in 125 samples (13%), only eight of which were found in non-HGSOC histotypes. Specifically, BRCA1/2 PVs were identified in high-grade endometrioid (3/20; 15%), low-grade endometrioid (1/40; 2.5%), low-grade serous (3/67; 4.5%), and clear cell (1/64; 1.6%) EOCs. No PVs were identified in any mucinous ovarian carcinomas tested. By re-evaluation and using loss of heterozygosity and homologous recombination deficiency analyses, we then assessed: (1) whether the eight ‘anomalous’ cases were potentially histologically misclassified and (2) whether the identified variants were likely causal in carcinogenesis. The first ‘anomalous’ non-HGSOC with a BRCA1/2 PV proved to be a misdiagnosed HGSOC. Next, germline BRCA2 variants, found in two p53-abnormal high-grade endometrioid tumours, showed substantial evidence supporting causality. One additional, likely causal variant, found in a p53-wildtype low-grade serous ovarian carcinoma, was of somatic origin. The remaining cases showed retention of the BRCA1/2 wildtype allele, suggestive of non-causal secondary passenger variants. We conclude that likely causal BRCA1/2 variants are present in high-grade endometrioid tumours but are absent from the other EOC histotypes tested. Although the findings require validation, these results seem to justify a transition from universal to histotype-directed sequencing. Furthermore, in-depth functional analysis of tumours harbouring BRCA1/2 variants combined with detailed revision of cancer histotypes can serve as a model in other BRCA1/2-related cancers. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.     

Atacicept in relapsed/refractory multiple myeloma or active Waldenstr?m's macroglobulinemia: a phase I study

Background:

Advanced multiple myeloma (MM) and Waldenström''s macroglobulinemia (WM) are incurable B-cell malignancies. This is the first full clinical report of atacicept, a fusion protein that binds to and neutralises the B-cell survival factors, B-lymphocyte stimulator (BLyS) and A proliferation-inducing ligand (APRIL), in MM and WM.

Methods:

In this open-label phase-I study, 16 patients with advanced disease (12 MM, 4 WM) received one cycle of five once-weekly subcutaneous injections of atacicept (2, 4, 7 or 10 mg kg⁻¹). Patients with stable disease after cycle 1 entered an extension study (either two additional cycles (2, 4 and 7 mg kg⁻¹ cohorts) or 15 consecutive weekly injections of atacicept 10 mg kg⁻¹).

Results:

Atacicept was well tolerated, systemically and locally; the maximum tolerated dose was not identified. Of 11 patients with MM who completed initial treatment, five patients were progression-free after cycle 1 and four patients were progression-free after extended therapy. Of four patients with WM, three patients were progression-free after cycle 1. Consistent with atacicept''s mechanism of action, polyclonal immunoglobulin isotypes and total B cells were reduced. Bone-marrow density, myeloma cell numbers and plasma concentrations of soluble CD138 also decreased.

Conclusion:

Atacicept is well tolerated in patients with MM and WM, and shows clinical and biological activity consistent with its mechanism of action.     

白首乌化学成分的研究

自白首乌主要品种耳叶牛皮消(Cynanchum auriculatum Royle ex Wight)根中首次分得三个已知甾体酯型甙元:告达亭(caudatin),开德甙元(kidjolanin),萝藦甙元(Metaplexigenin)和一种新的二苯酮衍生物(Ⅳ),经光谱分析推定其结构为2,6,2′,5′-四羟基,3-乙酰基,6′-甲基二苯酮,命名白首乌二苯酮。     

白首乌化学成分的研究

自白首乌主要品种耳叶牛皮消(Cynanchum auriculatum Royle ex Wight)根中首次分得三个已知甾体酯型甙元:告达亭(caudatin),开德甙元(kidjolanin),萝藦甙元(Metaplexigenin)和一种新的二苯酮衍生物(Ⅳ),经光谱分析推定其结构为2,6,2′,5′-四羟基,3-乙酰基,6′-甲基二苯酮,命名白首乌二苯酮。     

Lung abscesses in children: diagnostic and therapeutic needle aspiration

Three children aged 17 months to 17 years developed right-sided peripheral lung abscesses. Clinical signs were fever and cough. Laboratory cultures were negative, and the patients did not respond to appropriate antibiotic coverage. Under fluoroscopic guidance, purulent material was removed from the abscesses by needle aspiration. The patients became afebrile within 24 hours; none suffered complications of bleeding or pneumothorax. Cultures of the aspirate were positive for microorganisms sensitive to the prescribed treatments. A simple aspiration technique is described and proposed as useful for selected patients when surgical drainage is recommended. There was no morbidity in our cases, and recovery from a typically prolonged course was shortened by the procedure.     

功能性消化不良者胃排空功能和体表胃电变化的研究

以ＳＰＥＣＴ胃排空检测技术和ＷＣＤＦ－４Ｂ胃电分析仪检测了１２例ＦＤ患者液、固体食物胃排空和体表胃电图的变化。结果显示：ＦＤ患者的液体胃排空与对照组无明显差异，仅在摄食后比对照组更多地分布于远端胃内：固体食物的排模式发生变化，表现为初始排空较快，继后的排空延缓，７例半排空时间延长。