Safety and efficacy of sirolimus in hospitalised patients with COVID-19 pneumonia.

BACKGROUND: There is a critical need to develop novel therapies for COVID-19. METHODS: We conducted a phase 2, multicentre, placebo-controlled, double-blind, randomised trial; hospitalised patients with hypoxemic respiratory failure due to COVID-19 and at least one poor prognostic biomarker, were given sirolimus (6 mg on Day 1 followed by 2 mg daily for 14 days or hospital discharge, whichever happens first) or placebo, in a 2:1 randomization scheme favouring sirolimus. Primary outcome was the proportion of patients alive and free from advanced respiratory support measures at Day 28. RESULTS: Between April 2020 and April 2021, 32 patients underwent randomization and 28 received either sirolimus (n = 18) or placebo (n = 10). Mean age was 57 years and 75 % of the subjects were men. Twenty-two subjects had at least one co-existing condition (Diabetes, hypertension, obesity, CHF, or asthma/COPD) associated with worse prognosis. Mean FiO2 requirement was 0.35. There was no difference in the proportion of patients who were alive and free from advanced respiratory support measures in the sirolimus group (n = 15, 83 %) compared with the placebo group (n = 8, 80 %). Although patients in the sirolimus group demonstrated faster improvement in oxygenation and spent less time in the hospital, these differences were not statistically significant. There was no between-group difference in the rate of change in serum biomarkers such as LDH, ferritin, d-dimer or lymphocyte count. There was a decreased risk of thromboembolic complications in patients on sirolimus compared with placebo. CONCLUSIONS: Larger studies are warranted to evaluate the role sirolimus in COVID-19 infection.

Safety and Efficacy of Combined Resveratrol and Sirolimus in Lymphangioleiomyomatosis.

BACKGROUND: A critical need exists to develop remission-inducing therapies for lymphangioleiomyomatosis. RESEARCH QUESTION: Is the addition of resveratrol safe and more efficacious than sirolimus alone in patients with lymphangioleiomyomatosis? STUDY DESIGN AND METHODS: We conducted a phase 2, dose-escalating, open-label trial of resveratrol in patients with lymphangioleiomyomatosis receiving a stable regimen of sirolimus. Resveratrol was started at 250 mg/d and escalated every 8 weeks to maximum dose of 1,000 mg/d over 24 weeks. The primary outcome was ≥ 42% decline in serum vascular endothelial growth factor D (VEGF-D) levels on combined therapy compared with baseline VEGF-D levels on sirolimus. Secondary objectives included an assessment of the safety profile and the effect on lung function and health-related quality of life (HRQOL). Longitudinal change in outcome measures was assessed using linear mixed models. Adverse effects were tabulated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4. RESULTS: Twenty-five patients with lymphangioleiomyomatosis with a median age of 51 years were enrolled. Pulmonary function parameters at study inclusion were: FEV1: median absolute, 1.72 L; 64% predicted; FVC: median absolute, 2.99 L; 96% predicted; and diffusing capacity of the lungs for carbon monoxide: median absolute, 14.68 mL/mm Hg/min; 37% predicted. The median serum VEGF-D value at baseline was 617 pg/mL. Patients entered the study with a median sirolimus dose of 2 mg/d with median trough level of 6.3 ng/mL. Despite some GI side effects, the addition of resveratrol was well tolerated. Although the primary outcome was not met, a statistically significant reduction in serum VEGF-D levels and improvement in HRQOL during the study was found. INTERPRETATION: The addition of resveratrol was safe and well tolerated in patients with lymphangioleiomyomatosis taking sirolimus and was associated with modest improvement in HRQOL. Larger controlled trials of this combination might be warranted to assess definitively the usefulness of resveratrol as an additive therapy in lymphangioleiomyomatosis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03253913; URL: www. CLINICALTRIALS: gov.

Spontaneous pneumothorax and air travel in Pulmonary Langerhans cell histiocytosis: A patient survey.

BACKGROUND: The optimal approach for management of spontaneous pneumothoraces (SPs) and the safety of air travel in patients with pulmonary Langerhans cell histiocytosis (PLCH) are not well established. METHODS: Patients with PLCH were recruited from the Rare Lung Diseases Clinic Network and the Histiocytosis Association, and surveyed about disease manifestations and safety of air travel. RESULTS: A total of 94 patients completed the survey. Median age at diagnosis of PLCH was 40 years (range: 15-67 years). Average interval between symptom onset and diagnosis was 2.9 years (range: -4 to 31 years). Twenty-two patients (23%) had at least one SP, of which 14 (64%) had at least one additional SP that showed either an ipsilateral recurrence (10 patients; 45%) or a contralateral recurrence (8 patients; 36%). Mean age at the time of first SP was 29 years. SP was the presenting manifestation that led to the diagnosis of PLCH in 19% of patients, typically after the second episode. Surgical pleurodesis reduced the recurrence rate of SP by half in comparison with conservative management (29% vs. 65%, p = 0.025). Two patients experienced an episode of SP during air travel, consistent with an air travel-related pneumothorax rate of 2.4% per patient and 0.27% per flight. CONCLUSIONS: SP is a common manifestation of PLCH, can be seen in approximately one-fourth of the patients, and has a high recurrence risk. Surgical pleurodesis leads to a substantial reduction in the SP recurrence risk. The risk of an air travel-related SP in patients with PLCH is about 2-3 per thousand flights. TRIAL REGISTRY CLINICALTRIALS.GOV: NCT03052101.

Proton pump induced thrombocytopenia: A case report and review of literature.

Proton pump inhibitors (PPIs) are not widely recognized as a cause of drug-induced thrombocytopenia. Literature is mainly confined to case reports and has been insufficient to explore the possibility that this adverse event may be attributed to a class effect of PPI therapy. We present a case where platelet counts dropped from 177 (×10(3) per mm(3)) to 47 (×10(3) per mm(3)) within 6 days after the patient was switched from omeprazole to pantoprazole. There have been case reports of thrombocytopenia caused by PPIs; however, this is noted to be extremely rare. In our case, the patient developed thrombocytopenia on two separate occasions of exposure to pantoprazole, which resolved after stopping the medicine, thus providing definite proof of pantoprazole causing thrombocytopenia. Moreover, the patient did not have thrombocytopenia with omeprazole, thus suggesting that thrombocytopenia with PPIs might be an individual drug effect rather than a class effect. This occurrence has been reported in three other case reports as well. From the nine case reports that we have reviewed, direct causal relationship was found in a few reports only. It has been hypothesized that this adverse effect may be immune mediated, but further investigations are still needed to identify the exact pathogenesis.

Effect of type II diabetes mellitus on outcomes in patients with acute respiratory distress syndrome.

PURPOSE: The acute respiratory distress syndrome (ARDS) is a life-threatening condition, whereas the presence of diabetes has been shown to be protective in its development. We undertook this study to assess the association of type II diabetes mellitus with clinical outcomes in patients with ARDS. MATERIALS AND METHODS: We retrospectively examined the medical records of consecutive series of patients with ARDS requiring mechanical ventilation from January 2008 to March 2011. Patients with type I diabetes were excluded from the study. Clinical outcomes such as ventilator-free days, mortality, length of stay in the hospital and intensive care unit (ICU), and reintubations were compared based on the presence of diabetes. Multivariate regression model was used to find if the presence of type II diabetes mellitus predicts ventilator-free days at day 28. RESULTS: Two hundred forty-nine patients with ARDS were admitted to the ICU during the study period. Fifty (20%) subjects had type II diabetes mellitus. Differences in ventilator-free days, in-hospital mortality, reintubation rate, and length of stay in the hospital or ICU were not statistically significant between diabetic and nondiabetic patients with ARDS. Acute Physiologic and Chronic Health Evaluation II, ICU specialty, use of vasopressors, and the need for reintubation were predictors of ventilator-free days at day 28. The presence of type II diabetes mellitus and its adjustment by body mass index did not show association with ventilator-free days at day 28. CONCLUSIONS: The presence of type II diabetes mellitus is not associated with clinical outcomes in ARDS, even when its presence is adjusted by body mass index.

Incidence of supraventricular arrhythmias during autologous peripheral blood stem cell transplantation.

Arrhythmias, especially supraventricular arrhythmias, often complicate the clinical course during autologous hematopoietic cell transplantation (AHCT). We wanted to determine the incidence and risk factors for cardiac arrhythmias during AHCT. The study included 983 patients (median age, 58 years [range, 19 to 77]; 61% male) who underwent AHCT between August 2006 and December 2010 at a single institution and for whom all relevant medical records were available for review. AHCT was done for plasma cell disorders in 58% patients and for lymphoma or leukemia in the remaining. Overall, 92 patients (9.4%) developed a supraventricular tachyarrhythmia at a median of 9 days posttransplantation (range, 0 to 18) and with a median duration of less than 1 day (range, <1 to 17 days). Atrial fibrillation was the most common and seen in 71 patients (7%), followed by atrial flutter and supraventricular tachycardia in 12 (1%) and 8 (1%) patients, respectively. In multivariate analysis, age older than 63 years, presence of premature supraventricular complexes or atrioventricular conduction delay on pretransplantation electrocardiogram, and history of any prior arrhythmia increased the risk of arrhythmia. Development of arrhythmia resulted in longer outpatient follow-up after AHCT, with the median follow-up for those developing an arrhythmia of 22 days compared with 19 days for the rest; P < .001. In conclusion, 9% of patients undergoing ASCT developed supraventricular arrhythmias posttransplantation, and this risk was elevated among older patients, those with a prior history of arrhythmias, and those with pretransplantation electrocardiographic abnormalities.

Personalizing cardiovascular disease prevention among breast cancer survivors.

PURPOSE OF REVIEW: With the advancement of breast cancer therapies, most women diagnosed with breast cancer in the United States are now expected to survive their disease, and management of competing comorbidities, particularly cardiovascular disease (CVD), is crucial. RECENT FINDINGS: Recent studies have suggested that CVD is the most common cause of death for women diagnosed with ductal carcinoma in situ or stage I disease and for women aged more than 80 years with stage II disease. Various breast cancer therapies, including targeted therapies, can accentuate CVD risk; referrals for cardiology opinion are not uncommon at the time at which treatment options are under consideration. The use of less cardiotoxic alternatives, such as liposomal doxorubicin, and intensity-modulated radiation therapy should be considered when appropriate. Doppler myocardial imaging and cardiac MRI might allow early recognition of cardiotoxicity. SUMMARY: It is important to weigh both the risk of CVD and that of breast cancer recurrence in a breast cancer survivor. Certain interventions for the primary prevention of CVD, including diet, physical activity, smoking cessation and aspirin, can reduce breast cancer risk as well. The management of CVD risk factors is of increasing importance in the management of breast cancer survivors.

Current advances in non-proteasome inhibitor-based approaches to the treatment of relapsed/refractory multiple myeloma.

In the past decade, immunomodulatory drugs have been approved by the US Food and Drug Administration for the treatment of multiple myeloma (MM)-and a number of emerging agents that target the cellular pathways or proteins involved in the pathophysiology of MM are currently in development. Lenalidomide (Revlimid) and pomalidomide induce apoptosis and sensitize MM cells while demonstrating superior efficacy and better tolerability than thalidomide (Thalomid). Several novel classes of drugs, including the histone deacetylase (HDAC) inhibitors, heat shock protein (HSP) inhibitors, and monoclonal antibodies have been shown to have activity in myeloma in early-stage clinical trials. HDAC inhibitors, including vorinostat (Zolinza), panobinostat, and romidepsin (Istodax) are thought to affect multiple pathways involved in MM and correct the deregulation of genes involved in apoptosis and cell cycle arrest, thus potentially sensitizing MM cells to apoptosis. HSP inhibitors (eg, tanespimycin) decrease MM proliferation and suppress the long-term replicative potential of MM cells; they may also sensitize MM cells to other anticancer agents. The humanized monoclonal antibody elotuzumab induces antibody-dependent cell cytotoxicity-mediated apoptosis. It is likely that in the near future the treatment armamentarium for MM will undergo significant expansion as some of these additional target pathways become validated.