ABCC8 variants in MODY12: Review of the literature and report of a case with severe complications.

More than 1000 variants of the ATP-binding cassette transporter subfamily C member 8 (ABCC8) gene have been reported in neonatal diabetes mellitus. Up to now only 55 ABCC8 variants were associated with Maturity-Onset Diabetes of the Young 12 (MODY12). We present a c.3544C>T p.(Arg1182Trp) ABCC8 variant in a 35-year-old women who had pronounced microvascular diabetic complications and a charcot arthropathy necessitating a lower limb amputation. The unusual severity of the disease course prompted us to perform a systematic review of all genetic variants in MODY12. The present mutation has mostly been associated with neonatal diabetes and in only three papers reporting a MODY12. The 55 MODY12 variants show a large clinical heterogeneity, even in relatives with the same mutation, ranging from mild impaired glucose tolerance to severe insulin-dependent diabetes mellitus. HbA1c at diagnosis ranged from 5% to 14% and age at diagnosis ranged from 2 to 53 years. However, several case reports lack documentation of diabetic complications. Hence, more detailed reports remain necessary to improve insight in MODY12 pathophysiology and outcome. In this article current data regarding therapeutic management are provided, and key points to consider for the individual patient affected by MODY12 are presented.

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma.

BACKGROUND: B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes. METHODS: We performed a database search using the terms "BCMA," "CAR," and "multiple myeloma" for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332). RESULTS: Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0-88.2); 10.5% (6.8-16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3-26.7; I2 = 45%) versus 2.8% (1.3-6.1; I2 = 0%) (p < 0.0001). The pooled overall response rate was 80.5% (73.5-85.9); complete responses (CR) were observed in 44.8% (35.3-54.6). A pooled CR rate of 71.9% (62.8-79.6; I2 = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5-41.1; I2 = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4-17.4) months, which compared favorably to the expected PFS of 1.9 (1.5-3.7) months (HR 0.14; p < 0.0001). CONCLUSIONS: Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

Chimeric Antigen Receptor-Modified T Cell Therapy in Multiple Myeloma: Beyond B Cell Maturation Antigen.

Chimeric antigen receptor (CAR)-modified T cell therapy is a rapidly emerging immunotherapeutic approach that is revolutionizing cancer treatment. The impressive clinical results obtained with CAR-T cell therapy in patients with acute lymphoblastic leukemia and lymphoma have fueled the development of CAR-T cells targeting other malignancies, including multiple myeloma (MM). The field of CAR-T cell therapy for MM is still in its infancy, but remains promising. To date, most studies have been performed with B cell maturation antigen (BCMA)-targeted CARs, for which high response rates have been obtained in early-phase clinical trials. However, responses are usually temporary, and relapses have frequently been observed. One of the major reasons for relapse is the loss or downregulation of BCMA expression following CAR-T therapy. This has fostered a search for alternative target antigens that are expressed on the MM cell surface. In this review, we provide an overview of myeloma target antigens other than BCMA that are currently being evaluated in pre-clinical and clinical studies.

Cardiac sarcoidosis: a diagnostic and therapeutic challenge.

OBJECTIVE: Cardiac involvement in sarcoidosis can present in various ways, with atrioventricular (AV) block and ventricular arrhythmias being the most common signs. Because of initial non-specific findings, diagnosis can be a challenge. Very few data can support treatment decisions as cardiac manifestations of this systemic disorder are rare. METHODS AND RESULTS: We reviewed current guidelines, cohort studies, and expert opinions concerning diagnosis and treatment of cardiac sarcoidosis. CONCLUSIONS: Longitudinal follow-up studies are necessary to improve the diagnostic process and risk stratification of cardiac sarcoidosis. The optimal dose of steroids, indications for internal cardioverter-defibrillator (ICD), and technique and optimal timing of ablation are still under debate.