Venetoclax or placebo in combination with bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma (BELLINI): a randomised, double-blind, multicentre, phase 3 trial.

BACKGROUND: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma. METHODS: In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597. FINDINGS: Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6-21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3-not estimable) with venetoclax versus 11·5 months (9·6-15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44-0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related. INTERPRETATION: The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option. FUNDING: AbbVie and Genentech.

Identification and Determination of the Seminiferous Epithelium Stages and Spermatid Development in the Testis of Aceh Bull (Bos indicus).

This study was conducted to describe the stages of seminiferous epithelium (SE), determine the relative frequency of the stages, and identify the steps of spermatid development during spermatogenesis in the testicular tissue of Aceh bull. Seven pairs of the testicular organs of Aceh bull (Bos indicus) were used and then processed in a histological manner for staining using haematoxylin and eosin (H&E) and periodic acid-Schiff-haematoxylin (PAS-H). The stages of seminiferous tubules were examined using a tubular morphology method while spermatid development was observed based on the acrosome formation during spermatid development. Eight stages (stages I to VIII) of SE were found in the testicular seminiferous tubules of Aceh bull. Furthermore, the percentage of the relative frequency of each stage was 25.48, 15.38, 12.92, 4.74, 14.97, 10.69, 10.74, and 5.08%, respectively, with the relative frequency of premeiotic, meiotic, and postmeiotic phases being 53.78, 4.74, and 41.48%, respectively. Spermatid development from round to elongated spermatids occurred in 14 steps. Steps 1 to 7 were observed in stage I, steps 8 and 9 in stage II, steps 10 and 11 in stage III, step 12 in stage IV, step 13 in stages V and VI, and step 14 in stages VII and VIII. These findings can be used as a basis for further studies, particularly in evaluating the abnormality of the cellular composition of the seminiferous tubule in each stage of spermatogenesis and also in determining daily sperm production in Aceh bull.

Epidemiology of COVID-19 cases and vaccination coverage in Seremban District, Malaysia, 2021.

Objective: Malaysia's first case of coronavirus disease (COVID-19) was reported in January 2020, with the first case in the state of Negeri Sembilan diagnosed on 17 February 2020. The National COVID-19 Immunization Programme commenced in early March 2021 in Negeri Sembilan. This study describes the COVID-19 cases and vaccination coverage in Seremban District, Negeri Sembilan, during 2021. Methods: The demographic and clinical characteristics of COVID-19 cases and the district's vaccination coverage were described. Vaccination coverage was plotted against COVID-19 cases on the epidemic curve. The χ2 test was used to examine the differences between the vaccination status of COVID-19 cases and severity category, hospitalization status and mortality. Results: In Seremban District, there were 65 879 confirmed cases of COVID-19 in 2021. The data revealed that the 21-30-year age group had the highest proportion of cases (16 365; 24.8%), the majority of cases were male (58.3%), and most cases were from the subdistrict of Ampangan (23.1%). The majority of cases were Malaysian. Over half (53.5%) were symptomatic, with fever (29.8%) and cough (22.8%) being the most frequently reported symptoms. COVID-19 vaccination status was significantly associated with severity category, hospitalization and mortality (P < 0.001 for all categories). Discussion: This is the first study to describe two-dose vaccination coverage and the trend in COVID-19 cases in Seremban District. It was observed that COVID-19 cases had been reduced following more than 60.0% vaccination coverage.

Statin-induced Mitochondrial Priming Sensitizes Multiple Myeloma Cells to BCL2 and MCL-1 Inhibitors.

The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia and acute myeloid leukemia. However, multiple myeloma cells are frequently more dependent on MCL-1 for survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome resistance to venetoclax in multiple myeloma cell lines and primary cells. In addition, statins sensitize to apoptosis induced by MCL-1 inhibitor, S63845. In retrospective analysis of venetoclax clinical studies in multiple myeloma, background statin use was associated with a significantly enhanced rate of stringent complete response and absence of progressive disease. Statins sensitize multiple myeloma cells to venetoclax by upregulating two proapoptotic proteins: PUMA via a p53-independent mechanism and NOXA via the integrated stress response. These findings provide rationale for prospective testing of statins with venetoclax regimens in multiple myeloma. SIGNIFICANCE: BH3 mimetics including venetoclax hold promise for treatment of multiple myeloma but rational combinations are needed to broaden efficacy. This study presents mechanistic and clinical data to support addition of pitavastatin to venetoclax regimens in myeloma. The results open a new avenue for repurposing statins in blood cancer.

EC-IC Bypass: "Learning Curve" Experiences of Initial 100 Bypasses in Bangladesh / Bypass EC-CI: Experiências de "curva de aprendizado" de desvios iniciais em Bangladesh

Objectives Extracranial to intracranial (EC-IC) bypass is an important part of the armamentarium of a neurosurgeon in managing different vascular and neoplastic pathologies. Here, we report our initial experiences of EC-IC bypasses as experiences in the 'learning curve', including preparation and training of the surgeon, getting cases, patient selection, imaging, operative skills and microtechniques, complications, follow-up, and outcome. Lessons learned from the 'learning curve experiences' can be very useful for young vascular neurosurgeons who are going to start EC-IC bypass or have already started to perform and find themselves in the learning curve. Methods From July 2009 to September 2018, 100 EC-IC bypasses were performed. We looked back to these cases of EC-IC bypass as our initial or 'learning curve' experiences. The recorded data of patient management (EC-IC bypass patient) were reviewed retrogradely. Our preparation for EC-IC bypass was described briefly. Case selection, indications, preparation of the patient for operation, techniques and technical experiences, preoperative difficulties and challenges, postoperative follow-up, complications, patency status of the bypass, and ultimate results were reviewed and studied. Result A total of 100 bypasses were performed in 83 patients, of which 43 were male and 40 were female. The age range was from 04 to 72 years old (average 32 years old). Eleven patients were lost to follow-up postoperatively after 3 months and they were not even available for telephone follow-up. The follow-up period ranged from 3 to 120 months (average of18.4 months). Eight bypasses were high flow bypasses, whereas the number of low flow STA-MCA bypasses was 92. Indication of bypass were (in 83 cases):1. Arterial stenosis/occlusion/dissection causing cerebral ischemia (middle cerebral artery [MCA] stenosis/occlusion-05, MCA dissection-04, internal carotid artery [ICA] occlusion-19); 2. Intracranial aneurysm-30; 3. Moya-Moya disease-21; and 4. Direct carotid cavernous fistula [CCF]-04. Common clinical presentation was hemiparesis & dysphasia in ischemic group with history of transient ischemic attack (H/O TIA) (including Moya Moya disease). Features of subarachnoid hemorrhage (SAH) were the presenting symptoms in intracranial aneurysm group. The average ischemic time, due to clamping of recipient artery, was 28 minutes (range: 20­60 minutes). There was no clamp-related infarction. Two anastomoses were found thrombosed intraoperatively. One preoperatively ambulant patient deteriorated neurologically in the postoperative period. She developed hemiplegia but improved later. Here, the cause seemed to be hyperperfusion. Headache resolved in all cases. TIA and seizures were also gone postoperatively. Ophthalmoplegia recovered in all cases in which it was present, except in one CCF, in which abducent nerve palsy persisted. Complete unilateral total blindness developed in one patient postoperatively (due to ophthalmic artery occlusion), where high flow bypass with ICA occlusion were performed. Red eye and proptosis were cured in CCF cases. Motor and sensory dysphasia improved in all cases in which it was present, except for one case in which preoperative global aphasia converted to sensory aphasia in the postoperative period. Three patients died in the postoperative period. The rest of the patients improved postoperatively. All patients were ambulant with static neurostatus and without new stroke/TIA until the last follow-up. All bypasses were patent until the last follow-up. Conclusion The initial experiences of 100 cases of EC-IC bypass revealed even in inexperienced hand mortality and morbidity in properly indicated cases were low and result were impressive according to the pathological group and aim of bypass. Lessons learned from these experiences can be very helpful for new and beginner bypass neurosurgeons.

Cytotoxic chalcones and flavanones from the tree bark of Cryptocarya costata.

A new flavanone, 7-hydroxy-5,6-dimethoxyflavanone (1), together with three other flavonoids, didymocarpin (2), 2',4'-dihydroxy-5',6'-dimethoxychalcone (3), and isodidymocarpin (4), had been isolated from the methanol extract of the tree bark of Cryptocarya costata. The structures of these compounds were determined based on spectral evidence, including UV, IR, 1-D and 2-D NMR, and mass spectra. Cytotoxic properties of compounds 1-4 were evaluated against murine leukemia P-388 cells. The chalcones 3 and 4 were found to have substantial cytotoxicity with IC50 of 5.7 and 11.1 microM, respectively.