BCL2 is an anti-apoptotic protein that allows chronic lymphocytic leukemia cells to survive and a promising pharmacologic target for relapsed chronic lymphocytic leukemia. Previously, drugs like navitoclax showed efficacy to the same target but cross-reacted with other proteins and caused thrombocytopenia. Venetoclax is much more selective and showed efficacy both in vitro and in xenograft models. As a result, phase 1 trials were started on 56 patients with chronic lymphocytic or small lymphocytic leukemia that was either relapsing or refractory. The doses of venetoclax varied from 150 to 2500 milligrams per day. 60 additional patients were treated with weekly increasing doses up to 400 milligrams per day. 89% of the patients in the two groups had indications of a poor prognosis. Overall, there was a 79% response rate and complete remission occurred in 20% of patients. Additionally, a 15-month survival rate without progression was estimated as 69% for those dosed with 400 milligrams per day. However, side effects included mild diarrhea in 52% of patients, infections of the upper respiratory tract in 48% of patients, as well as nausea in 47% of patients and neutropenia (grade 3 or 4) in 41% of patients. To conclude, the results of this phase 1 trial showed venetoclax to have noteworthy efficacy in this group of patients and did not raise any severe safety concerns.
In 20% of at-term births and 40% of preterm births, the amniotic sac membrane ruptures prior to labor. Though it has been shown that if the mother is at-term, immediate delivery has better outcomes than expectant management, this study sought to examine what is best for mothers if this occurs prior to 37 weeks of pregnancy. This study, done at multiple centers in multiple countries, enrolled 1839 women whose membranes ruptured between 34 weeks and 36 weeks and 6 days and randomized them to either immediate birth or expectant management. Sepsis in the neonate was the primary outcome, with secondary outcomes of respiratory distress in the neonate, mechanical ventilation of the neonate, time spent in the neonatal intensive care unit, maternal hemorrhage, intrapartum fever, postpartum antibiotics, and the type of delivery. Sepsis occurred in 2% of neonates that were immediately delivered, but 3% of those who were treated with expectant management (RR 0.8, 95% CI 0.5 to 1.3, p = 0.37). Additionally, mothers with expectant management had a higher rate of hemorrhage, intrapartum fever, and postpartum use of antibiotics. However, morbidity and mortality occurred in the neonate at an 8% rate among those immediately delivered and 7% of mothers that were expectantly managed. Additionally, the rates of mechanical ventilation and respiratory distress were higher for those neonates who were immediately delivered, as compared to management (12% compared to 9% and 8% compared to 5%, respectively), and mothers had a lower rate of Caesarean section. To conclude, in mothers whose membranes rupture between 34 and 37 weeks, expectant management and surveillance procedures should be followed.
Immunosuppression with belatacept has improved kidney transplantation outcomes. However, the long-term results beyond 5 years of the transplant operation, has not been well characterized. This study examined the effects of a drug regimen including belatacept, an immunosuppressive drug designed to improve outcomes of kidney transplants, as compared to regimens that include cyclosporine, a calcineurin inhibitor that also acts as an immunosuppressive drug. In this study, 660 patients were treated, randomized approximately in thirds to a less-intensive regimen including belatacept, a more-intensive regimen including beltacept, and a regimen including cyclosporine. The study then analyzed the patients at 7 years from transplantation. The group was able to re-examine 153 of 219 patients in the group with the more-intensive belatacept treatment, 163 of 226 patients that were treated with the less-intensive beltacept regimen, and 131 of the 215 patients that were given the cyclosporine regimen. Results were encouraging, showing that the belatacept regimens reduced risk of death and/or graft loss by 43%. Additionally, average estimated glomerular filtration rate declined for those treated with the cyclosporine regimen (52.5 to 44.9 mL/minute/m2 from year 1 to year 7) while it was improved for both the less-intensive (66 to 72.1 mL/minute/m2 from year 1 to year 7) and the more-intensive belatacept regimen (67 to 70.4 mL/minute/m2 from year 1 to year 7). Adverse effects did not show significant differences between the groups. To conclude, belatacept was shown to have better long term outcomes for kidney transplants than cyclosporine in terms of glomerular filtration rate and rates of death and transplant failure.
In the past it has been reported that moderate alcohol consumption has led to lower rates of all-cause mortality, as well as cardiovascular disease. However, confounding variables and selection bias are associated with those studies. The exclusion of individuals who stopped drinking due to sickness also introduced bias. The study utilized a Cox regression to look at 24,029 persons over the age of 50 in the United States, adjusting for several variables outside the scope of this study. Occasional drinkers, those who consumed alcohol at least once, but less than once a week, were used as the control group in order to alleviate some of the confounding variables. Drinking level was measured 3 times during a 4-year period and then follow-up was started. For those who consumed alcohol on a regular basis, the hazard ratio for all-cause mortality was increased. It was 1.03 (95% CI 0.94 to 1.11) for those who consumed less than 7 drinks a week, 1.14 (95% CI 1.02 to 1.28) for those who had 7 to 13 drinks per week, 1.13 (95% CI 0.96 to 1.35) for those who had 14 to 20 drinks in a week, and 1.45 (95% CI 1.16 to 1.81) for those who consumed more than 21 drinks in a week. This study did not find that moderate alcohol consumption is associated with a diminished rate of all-cause mortality.
Long-term side effects of childhood cancer therapy have become the leading cause of death in patients 30 years after their cancer diagnosis. A large subset of those side effects is cardiovascular disease. Prior to this study, studies on the adverse effects of childhood cancer treatment had looked at by utilizing self-reporting data, registries, and death certificates. However, in this cross-sectional study of 1853 adults who survived childhood cancer, the group conducted a history and physical, as well as fasting metabolic and lipid panels, echocardiography, electrocardiography, and a six minute walking test. The outcomes that were investigated included valve function, coronary artery disease, rhythm or conduction defects, and cardiomyopathy. In this study of pediatric cancer survivors, 28% had valvular stenosis or regurgitation, 3.8% had coronary artery disease, 4.4% had conduction abnormalities, and 7.4% had cardiomyopathy. Though it was asymptomatic in most patients, those with cardiomyopathy or coronary artery disease had about twice the odds of having abnormal results in the 6 minute walking test. Anthracycline (doses equal to or higher than 250 mg/m2) and heart radiation had increased risks of cardiomyopathy, with odds ratios of 2.7 and 1.9 respectively. Radiation over 1500 cGy and anthracycline exposure was also associated with higher incidence of valve issues. To conclude, in survivors of childhood cancer, cardiovascular diseases are present at significant levels, though the diseases were largely subclinical at the time of follow-up.
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