Faculty Bibliography

Background/UNASSIGNED:Effective therapies to combat coronavirus 2019 (COVID-19) are urgently needed. Hydroxychloroquine (HCQ) has in vitro antiviral activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the clinical benefit of HCQ in treating COVID-19 is unclear. Randomized controlled trials are needed to determine the safety and efficacy of HCQ for the treatment of hospitalized patients with COVID-19. Methods/UNASSIGNED:We conducted a multicenter, double-blind randomized clinical trial of HCQ among patients hospitalized with laboratory-confirmed COVID-19. Subjects were randomized in a 1:1 ratio to HCQ or placebo for 5 days and followed for 30 days. The primary efficacy outcome was a severe disease progression composite end point (death, intensive care unit admission, mechanical ventilation, extracorporeal membrane oxygenation, and/or vasopressor use) at day 14. Results/UNASSIGNED: = .350). There were no significant differences in COVID-19 clinical scores, number of oxygen-free days, SARS-CoV-2 clearance, or adverse events between HCQ and placebo. HCQ was associated with a slight increase in mean corrected QT interval, an increased D-dimer, and a trend toward an increased length of stay. Conclusions/UNASSIGNED:In hospitalized patients with COVID-19, our data suggest that HCQ does not prevent severe outcomes or improve clinical scores. However, our conclusions are limited by a relatively small sample size, and larger randomized controlled trials or pooled analyses are needed.

BACKGROUND:Targeted therapies and checkpoint blockade therapy (CBT) have shown efficacy for patients with Hodgkin lymphoma (HL) in the relapsed and refractory (R/R) setting, but once discontinued owing to progression or side effects, it is unclear how successful further therapies will be. Moreover, there are no data on optimal sequencing of these treatments with standard therapies and other novel agents. In a multicenter, retrospective analysis, we investigated whether exposure to CBT could sensitize HL to subsequent therapy. MATERIALS AND METHODS/METHODS:Seventeen centers across the U.S. and Canada retrospectively queried medical records for eligible patients. The primary aim was to evaluate the overall response rate (ORR) to post-CBT treatment using the Lugano criteria. Secondary aims included progression-free survival (PFS), duration of response, and overall survival (OS). RESULTS:Eighty-one patients were included. Seventy-two percent had stage III-IV disease, and the population was heavily pretreated with a median of four therapies before CBT. Most patients (65%) discontinued CBT owing to progression. The ORR to post-CBT therapy was 62%, with a median PFS of 6.3 months and median OS of 21 months. Post-CBT treatment regimens consisted of chemotherapy (44%), targeted agents (19%), immunotherapy (15%), transplant conditioning (14%), chemotherapy/targeted combination (7%), and clinical trials (1%). No significant difference in OS was found when stratified by post-CBT regimen. CONCLUSION/CONCLUSIONS:In a heavily pretreated R/R HL population, CBT may sensitize patients to subsequent treatment, even after progression on CBT. Post-CBT regimen category did not impact OS. This may be a novel treatment strategy, which warrants further investigation in prospective clinical trials. IMPLICATIONS FOR PRACTICE/CONCLUSIONS:Novel, life-prolonging treatment strategies in relapsed and refractory (R/R) Hodgkin lymphoma (HL) are greatly desired. The results of this multicenter analysis concur with a smaller, earlier report that checkpoint blockade therapy (CBT) use in R/R HL may sensitize patients to their subsequent treatment. This approach may potentially enhance therapeutic options or to bridge patients to transplant. Prospective data are warranted prior to practice implementation. As more work is done in this area, we may also be able to optimize sequencing of CBT and novel agents in the treatment paradigm to minimize treatment-related toxicity and thus improve patient quality of life.

BACKGROUND:Palbociclib is highly active in oestrogen-receptor positive (ER+) metastatic breast cancer, but neutropenia is dose limiting. The goal of this study was to determine whether early neutropenia is associated with disease response to single-agent palbociclib. METHODS:Blood count and disease-response data were analysed from two Phase 2 clinical trials at different institutions using single-agent palbociclib: advanced solid tumours positive for retinoblastoma protein and advanced liposarcoma. The primary endpoint was PFS. The primary exposure variable was the nadir absolute neutrophil count (ANC) during the first two cycles of treatment. RESULTS:One hundred and ninety-six patients (61 breast, 135 non-breast) were evaluated between the two trials. Development of any grade neutropenia was significantly associated with longer median PFS in both the breast cancer (HR 0.29, 95% CI 0.11-0.74, p = 0.010) and non-breast cancer (HR 0.57, 95% CI 0.38-0.85, p = 0.006) cohorts. Grade 3-4 neutropenia was significantly associated with prolonged PFS in the non-breast cohort (HR 0.57, 95% CI 0.38-0.85, p = 0.006) but not in the breast cohort (HR 0.87, 95% CI 0.51-1.47, p = 0.596). Multivariate analysis yielded similar results. CONCLUSIONS:Treatment-related neutropenia in the first two cycles was significantly and independently associated with prolonged PFS, suggesting that neutropenia may be a useful pharmacodynamic marker to guide individualised palbociclib dosing. CLINICAL TRIALS REGISTRATION INFORMATION/UNASSIGNED:Basket Trial: NCT01037790; Sarcoma Trial: NCT01209598.

INTRODUCTION/BACKGROUND:Perceived stress is linked to poor sexual and reproductive health, but its relationship with sexually transmitted infections (STIs) is less clear. The elevated burden of stress and STI among Black women suggests a need to examine racial differences in the associations on additive and multiplicative scales. METHODS:Using data from Black and White female participants from wave IV of the National Longitudinal Study of Adolescent to Adult Health (n = 4744), we examined the association of high stress (scores ≥6 on the Perceived Stress Scale-4) with self-reported past-year chlamydia diagnosis, combined curable STI, and lifetime pelvic inflammatory disease using modified Poisson regression with robust variance to estimate prevalence ratios and prevalence differences. Models included a race-stress product-interaction term and adjusted for sociodemographic variables, prior trauma and stressors, and mental health factors. RESULTS:In unadjusted analyses, stress was associated with STI among Black and White women. Adjusted associations were attenuated among White women; among Black women, stress remained associated with chlamydia (adjusted prevalence ratio, 2.22; 95% confidence interval, 1.30-3.79) and curable STI (adjusted prevalence ratio, 1.59; 95% confidence interval, 1.05-2.40), corresponding to approximately 5 excess cases of each. Among White women, poverty and personality traits were the strongest confounders; among Black women, poverty, trauma, and neurotic personality traits were the strongest confounders for chlamydia, although no factors seemed to confound the association with curable STI. CONCLUSIONS:Stress is independently linked to STI, particularly among Black women. Additional research with longitudinal data is needed to understand the role of stress on STI and address a significant health disparity.

The dynamics of viral load (VL) of the 2019 novel coronavirus (severe acute respiratory syndrome coronavirus 2) and its association with different clinical parameters remain poorly characterized in the US patient population. Herein, we investigate associations between VL and parameters, such as severity of symptoms, disposition (admission versus direct discharge), length of hospitalization, admission to the intensive care unit, length of need for oxygen support, and overall survival in a cohort of 205 patients from a tertiary care center in New York City. VL was determined using quantitative PCR and log10 transformed for normalization. Univariate and multivariate regression models were used to test these associations. We found that diagnostic viral load is significantly lower in hospitalized patients than in patients not hospitalized (log10 VL = 3.3 versus 4.0; P = 0.018) after adjusting for age, sex, race, body mass index, and comorbidities. Higher VL was associated with shorter duration of the symptoms in all patients and hospitalized patients only and shorter hospital stay (coefficient = -2.02, -2.61, and -2.18; P < 0.001, P = 0.002, and P = 0.013, respectively). No significant association was noted between VL, admission to intensive care unit, length of oxygen support, and overall survival. Our findings suggest a higher shedding risk in less symptomatic patients, an important consideration for containment strategies in severe acute respiratory syndrome coronavirus 2. Furthermore, we identify a novel association between viral load and history of cancer. Larger studies are warranted to validate our findings.

OBJECTIVE:D-cycloserine (DCS) promotes consolidation of extinction learning. This study extends earlier work by examining whether DCS can enhance cognitive behavioral therapy (CBT) for delusions. METHODS:Adults reporting moderate or greater delusions were randomly assigned to receive 50 mg of DCS or placebo prior to 10 weekly CBT sessions. The primary outcome was change in severity of delusions measured with the Psychotic Symptom Rating Scale delusion subscale (PSYRATS-D). Secondary outcomes included persistence of response at 3 and 6 month follow-up and the effects of DCS on memory consolidation and cognitive flexibility. Fifty-eight participants were randomized and 44 completed the trial. RESULTS:The DCS and placebo groups did not differ in change from baseline to end of CBT on PSYRATS-D, nor did DCS improve memory consolidation or cognitive flexibility compared to placebo. However, at the 3 month follow-up visit (week 24), 47% of participants who completed treatment with DCS reported a 20% or greater decrease on PSYRATS-D compared to 15% in the placebo group (p = .04). Change in distress across CBT sessions interacted with treatment group to predict change from baseline to week 24 in PSYRATS-D total score (p = .03) such that response at week 24 was greatest in DCS-treated participants who experienced a decrease in distress during CBT sessions. CONCLUSIONS:DCS augmentation of CBT did not improve delusions compared to placebo during treatment; however, DCS was associated with a higher response rate at 3-month follow-up. DCS may produce a delayed therapeutic effect, associated with successful CBT sessions, but this finding requires replication.

The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.ajpath.2020.07.001. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal.

Sixteen million caregivers currently provide care to more than 5 million persons living with dementia (PLWD) in the United States. Although this population is growing and highly complex, evidence-based management remains poorly integrated within healthcare systems. Therefore, the National Institute on Aging IMPACT Collaboratory was formed to build the nation's ability to conduct embedded pragmatic clinical trials (ePCTs) for PLWD and their caregivers. The pilot core of the IMPACT Collaboratory seeks to provide funds for upward of 40 pilots for ePCTs to accelerate the testing of nonpharmacologic interventions with the goal that these pilots lead to full-scale ePCTs and eventually the embedding of evidence-based care into healthcare systems. The first two challenges for the pilot core in building the pilot study program were (1) to develop a transparent, ethical, and open nationwide process for soliciting, reviewing, and selecting pilot studies; and (2) to begin the process of describing the necessary components of a pilot study for an ePCT. During our initial funding cycle, we received 35 letters of intent, of which 17 were accepted for a full proposal and 14 were submitted. From this process we learned that investigators lack knowledge in ePCTs, many interventions lack readiness for an ePCT pilot study, and many proposed studies lack key pragmatic design elements. We therefore have set three key criteria that future pilot studies must meet at a minimum to be considered viable. We additionally discuss key design decisions investigators should consider in designing a pilot study for an ePCT. J Am Geriatr Soc 68:S14-S20, 2020.