Obinutuzumab Effectively Depletes Key B-cell Subsets in Blood and Tissue in End-stage Renal Disease Patients.

The THEORY study evaluated the effects of single and multiple doses of obinutuzumab, a type 2 anti-CD20 antibody that induces antibody-dependent cell-mediated cytotoxicity and direct cell death, in combination with standard of care in patients with end-stage renal disease. Methods: We measured B-cell subsets and protein biomarkers of B-cell activity in peripheral blood before and after obinutuzumab administration in THEORY patients, and B-cell subsets in lymph nodes in THEORY patients and an untreated comparator cohort. Results: Obinutuzumab treatment resulted in a rapid loss of B-cell subsets (including naive B, memory B, double-negative, immunoglobulin D+ transitional cells, and plasmablasts/plasma cells) in peripheral blood and tissue. This loss of B cells was associated with increased B cell-activating factor and decreased CXCL13 levels in circulation. Conclusions: Our data further characterize the mechanistic profile of obinutuzumab and suggest that it may elicit greater efficacy in indications such as lupus where B-cell targeting therapeutics are limited by the resistance of pathogenic tissue B cells to depletion.

Letermovir and tacrolimus interaction effects in hematopoietic cell transplantation recipients receiving moderate cytochrome P450 3A4 inhibitors for antifungal prophylaxis.

INTRODUCTION: Letermovir inhibits cytomegalovirus replication and is approved for the prevention of cytomegalovirus infection in cytomegalovirus seropositive hematopoietic cell transplantation recipients. Studies have found that letermovir coadministration has minimal effect on tacrolimus levels prior to the start of voriconazole, a strong cytochrome P450 (CYP) 3A4 inhibitor. However, data are lacking for hematopoietic cell transplantation recipients receiving letermovir and tacrolimus with moderate CYP 3A4 inhibitors as antifungal prophylaxis. METHODS: In this retrospective single-center analysis, we reviewed the charts of 92 consecutive adult allogeneic hematopoietic cell transplantation recipients receiving letermovir, tacrolimus, and moderate CYP3A4 inhibitors for antifungal prophylaxis. RESULTS: Tacrolimus concentration/dose (C/D) ratios were evaluated for the first 7 days pre-letermovir and for the first and second 7-day periods after letermovir. The tacrolimus mean C/D ratios [(ng/mL)/(mg/kg/day)] increased significantly with the addition of letermovir: 172.99 (95% confidence interval (CI): 158.2-187.78) pre-letermovir, 268.66 (95% CI: 244.34-292.98) first-week letermovir, and 312.19 (95% CI: 279.39-344.99) second-week letermovir (P < 0.001). The average dosages (mg/kg) of tacrolimus also decreased significantly across the three-time intervals (P < 0.001). Only four patients experienced clinically significant cytomegalovirus reactivation which required systemic treatment. CONCLUSION: These results demonstrate a reduction in tacrolimus dosing requirements for patients receiving tacrolimus and letermovir with concomitant moderate CYP3A4 inhibitors. The results of this interaction suggest that frequent monitoring of tacrolimus trough levels is warranted when starting letermovir and that empiric reduction of tacrolimus dosing upon letermovir initiation should be considered.

The efficacy and safety of cardio-protective therapy in patients with 5-FU (Fluorouracil)-associated coronary vasospasm.

BACKGROUND: Coronary vasospasm is a known side effect of 5-FU (fluorouracil) therapy. Beyond switching to non-5FU-based chemotherapy, there are no established treatments for 5-FU associated coronary vasospam. Our objective was to assess the safety and efficacy of re-challenge with 5-FU after pre-treatment with calcium channel blockers (CCBs) and long-acting nitrates among patients 5-FU associated coronary vasospasm. METHODS: We conducted a retrospective study of patients with 5-FU coronary vasospasm at a single academic center. By protocol, those referred to cardio-oncology received pre-treatment with either combination [nitrates and CCBs] or single-agent therapy [nitrates or CCBs]) prior to re-challenge with 5-FU. Our primary outcome was overall survival. Other important outcomes included progression-free survival and safety. RESULTS: Among 6,606 patients who received 5-FU from January 2001 to Dec 2020, 115 (1.74%) developed coronary vasospasm. Of these 115 patients, 81 patients continued 5-FU therapy, while 34 stopped. Of the 81 who continued, 78 were referred to cardio-oncology and prescribed CCBs and/or nitrates prior to subsequent 5-FU, while the remaining 3 continued 5-FU without cardiac pre-treatment. Of the 78, 56.4% (44/78) received both nitrates and CCBs, 19.2% (15/78) received CCBs alone, and 24.4% (19/78) received nitrates alone. When compared to patients who stopped 5-FU, those who continued 5-FU after pre-treatment (single or combination therapy) had a decreased risk of death (HR 0.42, P = 0.005 [95% CI 0.23-0.77]) and a trend towards decreased cancer progression (HR 0.60, P = 0.08 [95% CI 0.34-1.06]). No patient in the pre-treatment group had a myocardial infarct after re-challenge; however, chest pain (without myocardial infarction) recurred in 19.2% (15/78) among those who received cardiac pre-treatment vs. 66.7% (2/3) among those who did not (P = 0.048). There was no difference in efficacy or the recurrence of vasospasm among patients who received pre-treatment with a single agent (nitrates or CCBs) or combination therapy (14.7% (5/34) vs. 25.0% (11/44), P = 0.26). CONCLUSION: Re-challenge after pre-treatment with CCBs and nitrates guided by a cardio-oncology service was safe and allowed continued 5-FU therapy.

The Incidence, Risk Factors, and Outcomes With 5-Fluorouracil-Associated Coronary Vasospasm.

BACKGROUND: Coronary vasospasm is a recognized side effect of 5-FU (fluorouracil). There are limited and conflicting data on the incidence, risk factors and prognostic effect of 5-FU associated vasospasm. OBJECTIVES: To assess the incidence, risk factors and prognostic implications of 5-FU coronary vasospasm among patients receiving 5-FU regimens at a single tertiary care center. METHODS: We conducted a retrospective analysis of all patients who received 5-FU at a single academic center from January 2009 to July 2019. Vasospasm was defined as the occurrence of a typical chest pain syndrome in the presence of 5-FU. The presence of associated electrocardiogram (ECG) changes and/or elevated biomarkers was used to further confirm the diagnosis. Patients with vasospasm were compared to patients treated with 5-FU without vasospasm in a 1:2 ratio. Data regarding demographics, medical history, and follow-up were collected by manual chart review. RESULTS: From approximately 4019 individual patients who received 5-FU from 2009 to 2019 at a single center, 87 (2.16%) developed vasospasm. Patients who developed vasospasm were younger (58±13 vs. 64±13 years, P = 0.001), and were less likely to have any cardiovascular risk factors (70.1% vs. 84.5%, P = 0.007). Patients with vasospasm and patients without vasospasm were otherwise similar in terms of types of cancer, stage of cancer, sex, and race. There was no significant difference in progression-free survival, overall mortality or cancer specific mortality between patients who developed vasospasm versus those who did not. CONCLUSION: In a large, single-center report of 5-FU associated vasospasm, patients who developed vasospasm were younger, had lower rates of traditional cardiovascular risk factors and had no significant difference in progression-free or overall survival compared to those who did not develop vasospasm.

Outcomes with enoxaparin dose reductions during thrombocytopenia in patients with hematopoietic stem cell transplantation (HSCT).

INTRODUCTION: Appropriate dosing of therapeutic anticoagulation during periods of thrombocytopenia remains uncertain for patients undergoing hematopoietic stem cell transplants (HSCT). There is a paucity of literature on treatment outcomes for HSCT patients treated with non-prophylactic, but reduced doses of therapeutic anticoagulation during thrombocytopenia. The primary objective was to determine the incidence of major bleeding events during thrombocytopenia when reduced-dose enoxaparin was administered. METHODS: This is a retrospective review of patients with a venous thromboembolic event (VTE) who underwent HSCT and received reduced-dose enoxaparin during thrombocytopenia at the Massachusetts General Hospital (MGH) from April 1, 2016 to August 31, 2018. Incidence of recurrent VTE and bleeding events for up to one month were investigated. Rates of recurrent VTE and enoxaparin dose adjustments (0.5 mg/kg twice daily vs 1 mg/kg daily) were also reviewed. RESULTS: Out of 172 patients reviewed, 27 patients met inclusion criteria. There were no recurrent VTEs within one month of initial enoxaparin dose reduction. There was one major bleeding episode that occurred while a patient was on full-dose enoxaparin; believed to be related to cyclophosphamide cardiopulmonary toxicity and resulted in death. There were six non-major bleeding episodes, only one of which was clinically significant and resulted in the discontinuation of enoxaparin. CONCLUSION: Our evaluation of therapeutic enoxaparin dose reductions for thrombocytopenia in the HSCT patient population found this practice to be effective in reducing the recurrence of VTE with no major bleeding adverse events. However, the rate of non-significant minor bleeds should be monitored while on reduced-dose enoxaparin.

Bug off! Severe toxicity following inhalational exposure to N, N-diethyl-meta-toluamide (DEET).

N, N-diethyl-meta-toluamide (DEET) is an insect repellent currently used by millions of people since 1956. DEET has an excellent safety profile and has remarkable protection against mosquitoes, ticks and various other arthropods. Toxicity is unusual, and is generally associated with incorrect, or overuse of the product. We report a patient with severe toxicity following inhalational exposure to a "bug bomb". containing 98% DEET.

Soluções químicas para uso tópico bucal - classificação e advertências / Chemical buccal solutions for topic use - classification and warnings

Soluções químicas para uso bucal são usadas em diversas situações clínicas. Tamanha disponibilidade e indiscriminação nas vendas dificultam a prescrição, comprometem a segurança da higiene bucal e predispõem à automedicação, favorecendo o aparecimento de efeitos colaterais e riscos à saúde. Algumas das soluções disponíveis no mercado acham-se classificadas conforme sua composição/indicação, enquanto efeitos colaterais e advertências são ressaltados. Busca-se despertar o interesse dos cirurgiões-dentistas para esse valioso recurso, esperando que a supervisão por profissionais possa influenciar na qualidade dos produtos químicos destinados à cavidade bucal, evitando-se que sejam adquiridos como artigo de perfumaria.