Immunotherapy for metastatic renal cell carcinoma: A brief history, current trends, and future directions.

Recent innovations in systemic therapy for metastatic renal cell carcinoma (mRCC) have occurred at a break-neck pace. In the 1980s, nontargeted cytokine-mediated immunotherapy was the systemic therapy of choice. Based on improvements in tolerability and patient outcomes, targeted antiangiogenic agents supplanted cytokines in the early 2000s. During the last decade, the most recent innovation has come in the form of immune-checkpoint inhibitors (ICIs), a form of immunotherapy that enhances immune-mediated tumor cell destruction. ICIs improve on all prior iterations of systemic therapies and have become the first-line therapy for many mRCC indications. ICIs have been shown to increase overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and complete response rate (CRR) in mRCC patients. We reviewed the recent trends associated with ICI management of mRCC, their immune-related adverse events, and cost implications.

Association between chronic kidney disease and COVID-19-related mortality in New York.

PURPOSE: To evaluate mortality risk of CKD patients infected with COVID-19, and assess shared characteristics associated with health disparities in CKD outcome. METHODS: We extracted the data from a case series of 7624 patients presented at Mount Sinai Health System, in New York for testing between 3/28/2020 and 4/16/2020. De-identified patient data set is being produced by the Scientific Computing department and made available to the Mount Sinai research community at the following website: https://msdw.mountsinai.org/ . RESULTS: Of 7624 COVID-19 patients, 7.8% (n = 597) had CKD on hospital admission, and 11.2% (n = 856) died of COVID-19 infection. CKD patients were older, more likely to have diabetes, hypertension, and chronic obstructive pulmonary disease (COPD), were current or former smokers, had a longer time to discharge, and had worse survival compared to non-CKD patients (p < 0.05). COVID-19 mortality rate was significantly higher in CKD patients (23.1% vs 10.2%) with a 1.51 greater odds of dying (95% CI: 1.19-1.90). Controlling for demographic, behavioral, and clinical covariates, the logistic regression analysis showed significant and consistent effects of CKD, older age, male gender, and hypertension with mortality (p < 0.05). CONCLUSION: CKD was a significant independent predictor of COVID-19 mortality, along with older age, male gender, and hypertension. Future research will investigate the effects of COVID-19 on long-term renal function.

Repurposing of α1-Adrenoceptor Antagonists: Impact in Renal Cancer.

Renal cancer ranks twelfth in incidence among cancers worldwide. Despite improving outcomes due to better therapeutic options and strategies, prognosis for those with metastatic disease remains poor. Current systemic therapeutic approaches include inhibiting pathways of angiogenesis, immune checkpoint blockade, and mTOR inhibition, but inevitably resistance develops for those with metastatic disease, and novel treatment strategies are urgently needed. Emerging molecular and epidemiological evidence suggests that quinazoline-based α1-adrenoceptor-antagonists may have both chemopreventive and direct therapeutic actions in the treatment of urological cancers, including renal cancer. In human renal cancer cell models, quinazoline-based α1-adrenoceptor antagonists were shown to significantly reduce the invasion and metastatic potential of renal tumors by targeting focal adhesion survival signaling to induce anoikis. Mechanistically these drugs overcome anoikis resistance in tumor cells by targeting cell survival regulators AKT and FAK, disrupting integrin adhesion (α5ß1 and α2ß1) and engaging extracellular matrix (ECM)-associated tumor suppressors. In this review, we discuss the current evidence for the use of quinazoline-based α1-adrenoceptor antagonists as novel therapies for renal cell carcinoma (RCC) and highlight their potential therapeutic action through overcoming anoikis resistance of tumor epithelial and endothelial cells in metastatic RCC. These findings provide a platform for future studies that will retrospectively and prospectively test repurposing of quinazoline-based α1-adrenoceptor-antagonists for the treatment of advanced RCC and the prevention of metastasis in neoadjuvant, adjuvant, salvage and metastatic settings.

Blood pressure extremes and severe IVH in preterm infants.

BACKGROUND: The optimal upper and lower limits of blood pressure in preterm infants are not known. Exceeding these thresholds may contribute to intraventricular hemorrhage (IVH). METHODS: Preterm infants born ≤30 weeks GA were identified. Infants had continuous measurement of mean arterial blood pressure (MABP) for 7 days and cranial ultrasound imaging. IVH was classified as severe IVH (grade 3/4), no severe IVH (no IVH; grade 1/2), or no IVH. Mean ± SEM MABP values from hours 1-168 were calculated and sorted into bins 2 mm Hg wide. The normalized proportion of each recording spent in each bin was then calculated. Candidate limits were identified by comparison of MABP distribution in those with severe IVH vs. those without severe IVH. RESULTS: Eighty-five million measurements were made from 157 infants. Mean EGA was 25.2 weeks; mean BW was 749 g; 65/157 female; inotrope use in 59/157; grade 3/4 IVH in 29/157. Infants with severe IVH spent significantly more time with extreme MABP measurements (<23 mm Hg or >46 mm Hg) compared to those without severe IVH (12% vs. 8% of recording, p = 0.02). CONCLUSIONS: Infants who developed severe IVH had substantially more unstable MABP and spent a significantly greater period of time with MABP outside of the optimal range.

Progressive anemia of prematurity is associated with a critical increase in cerebral oxygen extraction.

BACKGROUND: Elevated cerebral fractional tissue oxygen extraction (cFTOE) is an adaptation to anemia of prematurity (AOP). cFTOE ≥0.4 is associated with brain injury in infants ≤30 weeks. This longitudinal study sought to investigate the utility of cFTOE in the evaluation of AOP. METHODS: Infants ≤30 weeks estimated gestational age (EGA) underwent weekly hemoglobin, cerebral saturation, and pulse oximetry recordings from the second through 36 weeks post-menstrual age (PMA). Recordings were excluded if they were under 1 h or if hemoglobin was not measured within 7 days of recording. Mean cFTOE was calculated for each recording. Statistical analysis used linear mixed-effects modeling and receiver operating characteristic analysis. RESULTS: 144 recordings from 39 infants (mean EGA 27.6 ±â€¯2.2 weeks, BW 1139 ±â€¯286 g) were included of whom 39% (15/39) were transfused. The mean recording length was 2.8 ±â€¯1.3 h. There was a significant negative correlation between hemoglobin and cFTOE (R = -0.423, p ≤.001). In a multivariate model, adjusting for EGA, PMA, and patent ductus arteriosus treatment the AUC was 0.821. A critical increase in cFTOE occurred at a hemoglobin level of 9.6 g/dL. CONCLUSIONS: AOP is associated with a critical increase in cFTOE that occurs at a significantly higher hemoglobin level than standard clinical thresholds for transfusion.