We assessed the safety and efficacy of cabozantinib and nivolumab (CaboNivo) and CaboNivo plus ipilimumab (CaboNivoIpi) in patients with metastatic urothelial carcinoma (mUC) and other genitourinary ...(GU) malignances.
Patients received escalating doses of CaboNivo or CaboNivoIpi. The primary objective was to establish a recommended phase II dose (RP2D). Secondary objectives included objective response rate (ORR), progression-free survival (PFS), duration of response (DoR), and overall survival (OS).
Fifty-four patients were enrolled at eight dose levels with a median follow-up time of 44.6 months; data cutoff was January 20, 2020. Grade 3 or 4 treatment-related adverse events (AEs) occurred in 75% and 87% of patients treated with CaboNivo and CaboNivoIpi, respectively, and included fatigue (17% and 10%, respectively), diarrhea (4% and 7%, respectively), and hypertension (21% and 10%, respectively); grade 3 or 4 immune-related AEs included hepatitis (0% and 13%, respectively) and colitis (0% and 7%, respectively). The RP2D was cabozantinib 40 mg/d plus nivolumab 3 mg/kg for CaboNivo and cabozantinib 40 mg/d, nivolumab 3 mg/kg, and ipilimumab 1 mg/kg for CaboNivoIpi. ORR was 30.6% (95% CI, 20.0% to 47.5%) for all patients and 38.5% (95% CI, 13.9% to 68.4%) for patients with mUC. Median DoR was 21.0 months (95% CI, 5.4 to 24.1 months) for all patients and not reached for patients with mUC. Median PFS was 5.1 months (95% CI, 3.5 to 6.9 months) for all patients and 12.8 months (95% CI, 1.8 to 24.1 months) for patients with mUC. Median OS was 12.6 months (95% CI, 6.9 to 18.8 months) for all patients and 25.4 months (95% CI, 5.7 to 41.6 months) for patients with mUC.
CaboNivo and CaboNivoIpi demonstrated manageable toxicities with durable responses and encouraging survival in patients with mUC and other GU tumors. Multiple phase II and III trials are ongoing for these combinations.
Patients with moderate to severe psoriasis often require systemic immunomodulatory medications that place them at risk for infection. Vaccination is a proven strategy to reduce infections. However, ...vaccination rates among patients with inflammatory autoimmune conditions, including psoriasis, remain low. We review the literature regarding vaccine-preventable illness and vaccinations commonly used in the United States in patients older than 18 years on immunosuppressive therapies that are used in the treatment of psoriasis. The medical board of the National Psoriasis Foundation recommends that dermatologists counsel patients on updating vaccinations in accordance with recommendations of the Advisory Committee for Immunization Practices as any measures taken to prevent infection can increase the safety of immunomodulatory therapies.
Active transportation (AT), or walking or bicycling for transportation, represents one way individuals can achieve recommended physical activity (PA) levels. This study describes AT prevalence and ...temporal trends, and examines associations between AT levels and measured CVD risk factors (hypertension, hypercholesterolemia, low high-density HDL cholesterol, diabetes, and obesity) among U.S. adults.
National Health and Nutrition Examination Survey (NHANES) 2007–2016 data (analyzed in 2017) were used to conduct overall trend analyses of reported AT in a typical week none (0–9 min/week); low (10–149 min/week); or high (≥150 min/week). Logistic regression was used to examine associations between AT level and each CVD risk factor from NHANES 2011–2016 (n = 13,943). Covariates included age, sex, race/Hispanic origin, education, income, smoking, survey cycle, non-transportation PA, and urbanization level.
U.S. adults who engaged in high AT levels increased from 13.1% in 2007–2008 to 17.9% in 2011–2012, and then decreased to 10.6% in 2015–2016 (p for quadratic trend = 0.004). Over the same period, the quadratic trend for low AT was not significant. During 2011–2016, 14.3% of adults engaged in high AT, 11.4% in low AT, and 74.4% in no AT. High AT levels were associated with decreased odds of each CVD risk factor assessed, compared to no AT. Low AT (versus no AT) was associated with decreased odds of hypertension (aOR = 0.77, 95% CI 0.64, 0.91) and diabetes (aOR = 0.68, 95% CI 0.54, 0.85).
AT prevalence among adults has fluctuated from 2007 to 2016. Despite favorable associations between AT and CVD risk factors, most U.S. adults do not engage in any AT.
•Trends in active transportation prevalence in U.S. adults fluctuated in 2007–2016.•The majority of U.S. adults do not engage in any active transportation.•Active transportation was inversely associated with CVD risk in recent years.
Background/Objectives
Epidermolysis bullosa (EB) comprises a group of inherited skin blistering diseases. There is currently no cure, and management includes skin protection and prevention of ...infection. To date, there has been no systematic investigation of home skin care practices among EB patients on a multicenter scale.
Methods
This cross‐sectional, observational study included data collected from patients with EB enrolled in the Epidermolysis Bullosa Characterization and Clinical Outcomes Database (EBCCOD) who provided answers to a patient‐directed questionnaire between January 1, 2017, and December 31, 2017.
Results
Of 202 respondents, 130 (64.4%) had dystrophic EB, 51 (25.2%) had EB simplex, 21 (7.4%) had junctional EB, 3 (1.5%) had Kindler syndrome, and 3 (1.5%) had an unspecified subtype. Seventy‐eight patients reported cleansing in plain water only (39%). Of those who used an additive in their cleansing water, 75 (57%) added salt, 71 (54%) added bleach, 36 (27%) added vinegar, and 34 (26%) endorsed the use of an “other” additive (multiple additives possible). Reported concentrations of additives ranged widely from 0.002% sodium hypochlorite and 0.002% acetic acid solutions, which are thought to have negligible effects on microbes, to 0.09% sodium hypochlorite and 0.156% acetic acid, concentrations shown to be cytotoxic. One hundred eighty‐eight patients answered questions regarding topical product use (93%). Of those, 131 reported topical antimicrobial use (70%). Mupirocin and bacitracin were the most commonly reported topical antibiotics (59, 58 31.4%, 30.9%, respectively).
Conclusions
These findings highlight the variety of skin care routines and frequent use of topical antimicrobials among EB patients and have potential implications for antibiotic resistance. The reported range of bleach and vinegar additives to cleansing water, including cytotoxic concentrations, emphasizes the need for clear and optimized skin cleansing recommendations.
Febrile infection‐related epilepsy syndrome (FIRES) is a subset of new onset refractory status epilepticus (NORSE) that involves a febrile infection prior to the onset of the refractory status ...epilepticus. It is unclear whether FIRES and non‐FIRES NORSE are distinct conditions. Here, we compare 34 patients with FIRES to 30 patients with non‐FIRES NORSE for demographics, clinical features, neuroimaging, and outcomes. Because patients with FIRES were younger than patients with non‐FIRES NORSE (median = 28 vs. 48 years old, p = .048) and more likely cryptogenic (odds ratio = 6.89), we next ran a regression analysis using age or etiology as a covariate. Respiratory and gastrointestinal prodromes occurred more frequently in FIRES patients, but no difference was found for non‐infection‐related prodromes. Status epilepticus subtype, cerebrospinal fluid (CSF) and magnetic resonance imaging findings, and outcomes were similar. However, FIRES cases were more frequently cryptogenic; had higher CSF interleukin 6, CSF macrophage inflammatory protein‐1 alpha (MIP‐1a), and serum chemokine ligand 2 (CCL2) levels; and received more antiseizure medications and immunotherapy. After controlling for age or etiology, no differences were observed in presenting symptoms and signs or inflammatory biomarkers, suggesting that FIRES and non‐FIRES NORSE are very similar conditions.
Circulating tumor cells (CTC) are under investigation as a minimally invasive liquid biopsy that may improve risk stratification and treatment selection. CTCs uniquely allow for digital pathology of ...individual malignant cell morphology and marker expression. We compared CTC features and T-cell counts with survival endpoints in a cohort of patients with metastatic genitourinary cancer treated with combination immunotherapy.
Markers evaluated included pan-CK/CD45/PD-L1/DAPI for CTCs and CD4/CD8/Ki-67/DAPI for T cells. ANOVA was used to compare CTC burden and T-cell populations across timepoints. Differences in survival and disease progression were evaluated using the maximum log-rank test.
From December 2016 to January 2019, 183 samples from 81 patients were tested. CTCs were found in 75% of patients at baseline. CTC burden was associated with shorter overall survival (OS) at baseline (
= 0.022), but not on-therapy. Five morphologic subtypes were detected, and the presence of two specific subtypes with unique cellular features at baseline and on-therapy was associated with worse OS (0.9-2.3 vs. 28.2 months;
< 0.0001-0.013). Increasing CTC heterogeneity on-therapy had a trend toward worse OS (
= 0.045). PD-L1
CTCs on-therapy were associated with worse OS (
< 0.01, cycle 2). Low baseline and on-therapy CD4/CD8 counts were also associated with poor OS and response category.
Shorter survival may be associated with high CTC counts at baseline, presence of specific CTC morphologic subtypes, PD-L1
CTCs, and low %CD4/8 T cells in patients with metastatic genitourinary cancer. A future study is warranted to validate the prognostic utility of CTC heterogeneity and detection of specific CTC morphologies.
Following nerve stimulation, there are two distinct phases of Ca.sup.2+ -dependent neurotransmitter release: a fast, synchronous release phase, and a prolonged, asynchronous release phase. Each of ...these phases is tightly regulated and mediated by distinct mechanisms. Synaptotagmin 1 is the major Ca.sup.2+ sensor that triggers fast, synchronous neurotransmitter release upon Ca.sup.2+ binding by its C.sub.2 A and C.sub.2 B domains. It has also been implicated in the inhibition of asynchronous neurotransmitter release, as blocking Ca.sup.2+ binding by the C.sub.2 A domain of synaptotagmin 1 results in increased asynchronous release. However, the mutation used to block Ca.sup.2+ binding in the previous experiments (aspartate to asparagine mutations, syt.sup.D-N) had the unintended side effect of mimicking Ca.sup.2+ binding, raising the possibility that the increase in asynchronous release was directly caused by ostensibly constitutive Ca.sup.2+ binding. Thus, rather than modulating an asynchronous sensor, syt.sup.D-N may be mimicking one. To directly test the C.sub.2 A inhibition hypothesis, we utilized an alternate C.sub.2 A mutation that we designed to block Ca.sup.2+ binding without mimicking it (an aspartate to glutamate mutation, syt.sup.D-E). Analysis of both the original syt.sup.D-N mutation and our alternate syt.sup.D-E mutation at the Drosophila neuromuscular junction showed differential effects on asynchronous release, as well as on synchronous release and the frequency of spontaneous release. Importantly, we found that asynchronous release is not increased in the syt.sup.D-E mutant. Thus, our work provides new mechanistic insight into synaptotagmin 1 function during Ca.sup.2+ -evoked synaptic transmission and demonstrates that Ca.sup.2+ binding by the C.sub.2 A domain of synaptotagmin 1 does not inhibit asynchronous neurotransmitter release in vivo.
•Asymptomatic infection is common.•Bimodal age distribution of coronavirus disease 2019 (COVID-19) was observed at the University of the Philippines–Philippine General Hospital.•Universal testing ...impacts infection control measures in resource-limited settings.•Further blood testing is likely to be unnecessary for mild and asymptomatic cases of COVID-19.•Symptom-based isolation protocol reduces length of hospitalization.
To describe the clinical profile and outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19) across the spectrum of disease severity.
This retrospective study included adult patients with confirmed COVID-19 infection admitted to a referral hospital. Descriptive statistics, tests for trend, Kaplan–Meier curve and log-rank test were used to compare characteristics and outcomes across disease severity categories.
Of 1500 patients with COVID-19, 14.8% were asymptomatic, 13.5% had mild disease, 36.6% had moderate disease, 12.3% had severe disease and 22.7% had critical disease. Asymptomatic patients were admitted for a concurrent condition or for isolation. Patients aged >60 years, male gender and with co-morbidities had more severe disease. Fever, cough, shortness of breath, malaise, gastrointestinal symptoms and decreased sensorium were more common in patients with severe disease. Bilateral pulmonary infiltrates were common (51.1%), with sicker patients having more abnormal findings. The overall mortality rate was 15.1%. Adopting a symptom-based strategy reduced the length of hospitalization from a median of 13 interquartile range (IQR) 7–21 days to 9 (IQR 5–14) days.
The clinical profile and outcomes for this cohort of patients with COVID-19 was consistent with published reports. Asymptomatic infection was common, and universal testing may be a valuable strategy in the correct context, given the implications for infection control. A symptom-based strategy was found to reduce the length of hospitalization considerably.
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