Time trends for drug specific adverse events in patients on sunitinib; implications for remote monitoring.

INTRODUCTION: Sunitinib is a multi-targeted receptor tyrosine kinase inhibitor used to treat metastatic renal cell carcinoma (mRCC). Patients on sunitinib do require regular in-person appointments to monitor for adverse events (AEs). Given the Covid-19 pandemic, regular in-person visits expose patients to an increased risk of infection in addition to potentially preventable travel costs. This study investigated the feasibility of implementing a remote monitoring strategy for patients being treated with sunitinib for mRCC by examining the time trends of AEs. MATERIALS AND METHODS: In this retrospective chart review of patients with a diagnosis of mRCC, 167 patients received sunitinib during their treatment. The time between initiation of treatment and the first AE was recorded. The AEs were categorized according to the Common Terminology Criteria for Adverse Events (CTCAE), version 5. Survival analysis was used to calculate the time-to-AE. RESULTS: Of the 167 patients identified, 145 experienced an AE (86.8%). Hypertension was the most common AE with 80% of AEs were ≤ Grade 2. Incidence of AE dropped by 91% after 3 months follow up and a further 36% after 6 months. The cumulative incidence of AEs were 87.8%, 94.6% and 98.0%, at 3, 6 and 9 months respectively. The severity of AEs observed were 39.3%, 38.6%, 20.7%, 1.4%,0% of Grade 1-5 events respectively. A trend of grade migration to less severe grades was also shown over time, with percentage of Grade ≥ 3 toxicity dropping from 22% between 0-3 months to 14% beyond 6 months follow up. CONCLUSIONS: The role of remote monitoring for mRCC patients on sunitinib remains relevant now with new waves of the Covid-19 pandemic, triggered by novel variants. The majority of AEs observed were of low severity ≤ Grade 2, with a trend of reduced AE frequency and severity most prevalent beyond 3 months of follow up. This data appears to support the implementation of a remote monitoring strategy 3 months after initiation of treatment.

The prognostic value of urinary cytology after trimodal therapy (TMT) for muscle-invasive bladder cancer.

BACKGROUND: Urine cytology and cystoscopy are routinely employed during follow-up of patients after trimodal therapy (TMT) for muscle-invasive bladder cancer (MIBC). The significance of positive or equivocal cytology without visible disease recurrence on cystoscopy during follow-up is unknown, and studies informing outcomes in this scenario are lacking. This study aims to investigate the temporal trends of positive/equivocal cytology in the absence of visible disease recurrence and the association with bladder cancer recurrence and survival outcomes. METHODS: One hundred and twenty-nine patients with available post-TMT cytology data and negative cystoscopy from a single academic institution between 2002 and 2017 with a median follow-up of 3.4 (range 0.1-14.2) years were analyzed. Cytology results, first post-TMT cytology positive/equivocal (CP) and negative (CN), were evaluated for association with disease recurrence and survival. Kaplan. Meier and competing risks methods were used to assess time-to-negative cytology in CP patients with ≥2 interval post-TMT cytology results (n = 33), time-to-recurrence, and disease-specific mortality (DSM) stratified by first post-TMT cytology result. RESULTS: At first follow-up (6-8 weeks post-TMT completion), CP was observed in 41 (32%) and CN in 88 (68%) of patients. With further follow-up of CP patients with ≥2 interval post-TMT cytology results, the probability of developing negative cytology was 57% (95% CI 42, 77) at 6 months post-TMT, and the median time-to-negative cytology was 3.2 months (95% CI 2.99, 5.80). The median time-to-recurrence was reduced in CP patients compared to CN (24.3 vs. 78.1 months, p = 0.1), corresponding with an apparent increase in the cumulative incidence of recurrence rate at 3 years in the CP vs. CN group (62% vs. 42%, p = 0.1). No significant difference was observed in the 3-year DSM rates. On univariable analysis, the hazards of recurrence and DSM for patients with CP were 1.5 (95% CI 0.9, 2.5, p = 0.1) and 2.1 (95% CI 0.9, 4.7, p = 0.07) respectively. CONCLUSION: This is the first study to investigate the significance of a positive/equivocal cytology without visible disease following TMT for MIBC. Positive cytology is common and does not preclude subsequent negative cytology supporting a watchful waiting approach rather than proceeding immediately to biopsy. However, cytology that remains positive at subsequent follow-up may be associated with adverse recurrence and survival outcomes.

Time trends of drug-specific actionable adverse events among patients on androgen receptor antagonists: Implications for remote monitoring.

INTRODUCTION: In light of COVID-19, reducing patient exposure via remote monitoring is desirable. Patients prescribed abiraterone/ enzalutamide are scheduled for monthly in-person appointments to screen for adverse events (AEs). We determined time trends of drug-specific actionable AEs among users of abiraterone/enzalutamide to assess the safety of remote monitoring. METHODS: A chart review was conducted on 828 prostate cancer patients prescribed abiraterone and/or enzalutamide. Data were collected to determine time to actionable first AEs, including hypertension, elevated liver enzymes (aspartate transaminase [AST], alanine transaminase [ALT]), hyperbilirubinemia, and hypokalemia. Survival analysis was used to determine time to AEs. RESULTS: In this study, 425 and 403 patients received enzalutamide and abiraterone, respectively. In total, 25.6% of those who took enzalutamide experienced an AE, compared to 28.8% of patients on abiraterone. For patients using abiraterone and experiencing an AE, cumulative incidence of AEs at three, six, nine, and 12 months were: 67.2%, 81.9%, 90.5%, and 93.9%, respectively. Among enzalutamide users experiencing an AE, cumulative incidence of AEs at three, six, nine, and 12 months were 51.4%, 70.7%, 82.6%, and 88.1%, respectively. The AEs associated with enzalutamide were hypertension and liver dysfunction (77.1% and 22.9%, respectively). In the abiraterone group, associated AEs were liver dysfunction (47.4%), hypertension (47.4%), and hypokalemia (5.2%). CONCLUSIONS: Attaining AEs secondary to abiraterone/enzalutamide decreases over time and tends to occur within the first six months of therapy. Most actionable AEs can be remotely monitored. Given COVID-19, remote monitoring after six months of initiating abiraterone or enzalutamide appears appropriate.

Looking on the Bright Side Reduces Worry in Pregnancy: Training Interpretations in Pregnant Women.

Background: Recent evidence suggests that anxiety is more common than depression in the perinatal period, however there are few interventions available to treat perinatal anxiety. Targeting specific processes that maintain anxiety, such as worry, may be one potentially promising way to reduce anxiety in this period. Given evidence that negative interpretation bias maintains worry, we tested whether interpretation bias could be modified, and whether this in turn would lead to less negative thought (i.e., worry) intrusions, in pregnant women with high levels of worry. Method: Participants (N = 49, at least 16 weeks gestation) were randomly assigned to either an interpretation modification condition (CBM-I) which involved training in accessing positive meanings of emotionally ambiguous scenarios, or an active control condition in which the scenarios remained ambiguous and unresolved. Results: Relative to the control condition, participants in the CBM-I condition generated significantly more positive interpretations and experienced significantly less negative thought intrusions. Conclusions: Our findings indicate that worry is a modifiable risk factor during pregnancy, and that it is possible to induce a positive interpretation bias in pregnant women experiencing high levels of worry. Although preliminary, our findings speak to exciting clinical possibilities for the treatment of worry and the prevention of perinatal anxiety.

MyD88 acts as an adaptor protein for inflammatory signalling induced by amyloid-ß in macrophages.

Neuroinflammation is the complex innate immune response of neural tissue to control infection, and Toll-like receptors (TLRs), a major family of pattern recognition receptors (PRRs), have a key role in Alzheimer's disease (AD) progression. Innate immune cells, including macrophages, govern tailored inflammatory gene expression to regulate inflammatory responses, however the role of macrophages in AD pathogenesis is not clear. All TLRs, with the exception of TLR3, recruit the MyD88 adaptor, and evidence indicates a role for this adaptor in inflammatory and cognitive changes in mouse AD models, in addition to amyloid-beta (Aß)-induced inflammatory signalling at a cellular level. In the present study, we employed the use of Aß to induce inflammatory signalling in immortalized macrophages. Data presented herein demonstrate that Aß promoted the nuclear sequestration of NF-κB, and polarized macrophages to an M1 phenotype with downstream consequences on pro-inflammatory cytokine expression. Importantly, Aß-induced TNF-α production was exacerbated in macrophages lacking MyD88, while MyD88 deficiency promoted NF-κB activation, enhanced M1 and M2 polarization, and compromised macrophage viability. We demonstrate that in the absence of MyD88, mitogen-activated protein kinase (MAPKs) act as upstream signalling intermediates targeted by Aß in the cascade leading to TNF-α expression. Our findings offer a new role for MyD88 in cellular mechanisms underlying AD pathogenesis, indicating that MyD88 adaptors are key in regulating Aß-induced inflammatory signalling in macrophages.