Lifelong effect of therapy in young patients with the COL4A5 Alport missense variant p.(Gly624Asp): a prospective cohort study.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEis) have evolved as a first-line therapy for delaying end-stage renal failure (ESRF) in Alport syndrome (AS). The present study tested the hypothesis of a superior nephroprotective potential of an early ACEi intervention, examining a cohort with the COL4A5 missense variant p.(Gly624Asp). METHODS: In this observational cohort study (NCT02378805), 114 individuals with the identical gene variant were explored for age at ESRF and life expectancy in correlation with treatment as endpoints. RESULTS: All 13 untreated hemizygous patients developed ESRF (mean age 48.9 ± 13.7 years), as did 3 very late treated hemizygotes (51.7 ± 4.2 years), with a mean life expectancy of 59.2 ± 9.6 years. All 28 earlier-treated [estimated glomerular filtration rate (eGFR) ≥60 mL/min/1.73 m2] hemizygous patients were still alive and still had not reached ESRF. Therapy minimized the annual loss of their GFR, similar to the annual loss in healthy individuals. Of 65 heterozygotes, 4 untreated individuals developed ESRF at an age of 53.3 ± 20.7 years. None of the treated heterozygous females developed ESRF. CONCLUSIONS: For the first time, this study shows that in AS, early therapy in individuals with missense variants might have the potential to delay renal failure for their lifetime and thus to improve life expectancy and quality of life without the need for renal replacement therapy. Some treated patients have reached their retirement age with still-functioning kidneys, whereas their untreated relatives have reached ESRF at the same or a younger age. Thus, in children with glomerular haematuria, early testing for Alport-related gene variants could lead to timely nephroprotective intervention.

Dendritic Cell Maturation Defines Immunological Responsiveness of Tumors to Radiation Therapy.

Radiation therapy is capable of directing adaptive immune responses against tumors by stimulating the release of endogenous adjuvants and tumor-associated Ags. Within the tumor, conventional type 1 dendritic cells (cDC1s) are uniquely positioned to respond to these signals, uptake exogenous tumor Ags, and migrate to the tumor draining lymph node to initiate cross-priming of tumor-reactive cytotoxic CD8+ T cells. In this study, we report that radiation therapy promotes the activation of intratumoral cDC1s in radioimmunogenic murine tumors, and this process fails to occur in poorly radioimmunogenic murine tumors. In poorly radioimmunogenic tumors, the adjuvant polyinosinic-polycytidylic acid overcomes this failure following radiation and successfully drives intratumoral cDC1 maturation, ultimately resulting in durable tumor cures. Depletion studies revealed that both cDC1 and CD8+ T cells are required for tumor regression following combination therapy. We further demonstrate that treatment with radiation and polyinosinic-polycytidylic acid significantly expands the proportion of proliferating CD8+ T cells in the tumor with enhanced cytolytic potential and requires T cell migration from lymph nodes for therapeutic efficacy. Thus, we conclude that lack of endogenous adjuvant release or active suppression following radiation therapy may limit its efficacy in poorly radioimmunogenic tumors, and coadministration of exogenous adjuvants that promote cDC1 maturation and migration can overcome this limitation to improve tumor control following radiation therapy.

Sexual Dysfunction Among Adolescent and Young Adult Men Diagnosed with Cancer.

Purpose: Adolescent and young adult (AYA) cancer patients frequently demonstrate sexual dysfunction; however, there is a lack of data quantifying the severity and frequency. Methods: Males aged 18-39 years, diagnosed with cancer of any kind and who were scheduled to begin, were actively receiving, or had completed cancer treatment within 6 months, were offered validated surveys during their oncology appointment. These surveys included the International Index of Erectile Function (IIEF-6), Masturbation Erection Index (MEI), 36-Item Short Form Survey, and 5-point Likert scales to assess their desire and ability to engage in sex and masturbation. Results: Forty subjects completed the IIEF survey with a mean score of 17.7 ± 11, erectile dysfunction (ED) prevalence accordingly was 58%. Thirty-eight subjects completed the MEI with a mean score of 25.3 ± 5.3, ED prevalence was again 58%. Age and IIEF scores demonstrated a statistically significant (p < 0.05, n = 38) Pearson's correlation coefficient of 0.40, patients younger than 30 years had an ED prevalence of 72% (mean IIEF 13), whereas patients aged 30 years and older had an ED prevalence of 45% (mean IIEF 22). All treatment modalities had ED rates >30%: chemotherapy demonstrated the highest prevalence at 64% (mean IIEF 17), whereas radiation therapy had the lowest prevalence at 33% (mean IIEF 23). Conclusion: This study demonstrates that the prevalence of sexual dysfunction among male AYA patients undergoing treatment for cancer is high. AYA oncologists should discuss potential sexual health concerns when treating this population. The exact cause of ED (non-organic vs. organic) within this group should be explored further.

Number of cores needed to diagnose prostate cancer during MRI targeted biopsy decreases after the learning curve.

INTRODUCTION: We hypothesized that the number of cores needed to detect prostate cancer would decrease with increasing MRI-targeted biopsy (TBx) experience. METHODS: All patients undergoing TBx at our institution from May 2017 to August 2019 were enrolled in a prospectively maintained database. Five biopsy cores were obtained from each lesion ≥3 on PI-RADS v2.0 followed by a systematic 12-core biopsy. To assess learning curve, the study population was divided into quartiles by sequential biopsies. Clinically significant prostate cancer (csPC) was defined as Gleason Grade Group 2 or higher. RESULTS: 377 patients underwent prostate biopsy (533 lesions); 233 lesions (44%) were positive for prostate cancer and 173 lesions (32%) were csPC. There was a significant decline in the number of cores required for diagnosing any cancer (P < 0.001) and csPC (P < 0.05) after the first quartile. There was no difference when stratifying by PI-RADS score or lesion volume. Within the first quartile, limiting the biopsy to 3 cores would miss 16.2% of csPC, decreasing to 6.6% after approximately 100 patients. CONCLUSION: MRI TBx is associated with a learning curve of approximately 100 cases. Four or 5 cores should be considered during the initial experience, but thereafter, 3 cores per lesion is sufficient to detect csPC.

Barriers to receiving testosterone replacement therapy in the community during COVID-19 pandemic.

BACKGROUND: While the etiology for the upsurge in testosterone testing and prescriptions is likely multifactorial, increased direct-to-consumer marketing and the expansion of clinical care centers devoted to testosterone treatment likely play a role. Many of these centers require patients to report, in-person, on a regular basis for their injectable therapy and/or lab studies. The purpose of our study was to investigate barriers of care that patients receiving treatment for testosterone deficiency may be experiencing in the setting of COVID-19. METHODS: Our survey was posted on a closed Facebook support page for males currently receiving testosterone treatment and members of the group were invited to participate. The survey asked participants several questions related to how they received their injections, if they've experienced difficulties obtaining their injections due to COVID-19 restrictions, and about their interest in telemedicine services for their care. RESULTS: The majority of patients were able to receive their treatment despite barriers enforced by the pandemic. Of the 104 participants, almost half received their testosterone prescriptions from an outpatient clinic dedicated to testosterone replacement, while the other half received their therapy from a PCP, endocrinologist, or urologist. Only 5 patients (4.8%) noted difficulties obtaining their injections during this pandemic, 4 of which received their prescriptions from dedicated testosterone clinics, and the other from a PCP. Nearly 90% of respondents self-administered their testosterone therapy. With regards to telemedicine, 57.8% of patients have utilized the technology in some capacity, however 74.4% said that they would prefer to use telemedicine video services with a urologist or APP with expertise in andrology over in-person services. CONCLUSIONS: In our survey, the majority of the respondents have been able to receive their injectable testosterone therapy despite the ongoing pandemic. The majority of respondents self-administer their treatments, which may explain the lack of barriers. This study is the first of its kind to investigate the effect of a pandemic on the receipt of care for those being treated for testosterone deficiency with injectable testosterone.

The additive impact of the distal ureteral diameter ratio in predicting early breakthrough urinary tract infections in children with vesicoureteral reflux.

INTRODUCTION: Many factors influence patient and provider decisions to surgically correct vesicoureteral reflux (VUR), including risk of breakthrough febrile urinary tract infections and likelihood of spontaneous resolution. Ureteral diameter ratio has been shown in several studies to be more predictive than reflux grade with regard to breakthrough urinary tract infection (UTI). We developed and investigated the accuracy of a computational model for predicating febrile breakthrough urinary tract infection within 13 months of starting prophylactic antibiotics in children with VUR. OBJECTIVE: The aim of this study was to validate a model for evaluating the impact of distal ureteral diameter ratio (UDR) in predicting early breakthrough urinary tract infections in children with VUR. STUDY DESIGN: Following a retrospective review, we recorded patient demographics, presenting symptoms, VUR grade, laterality, VUR during filling or voiding, initial bladder volume at the onset of VUR, ureteral duplication, voiding dysfunction, distal ureteral diameter ratio, and number of UTIs prior to VUR diagnosis. NeUROn++, a set of C++ programs, was used to model each data set using logistic regression and neural networks with different architectures. RESULTS: After exclusions, 136 children (93 girls and 43 boys) diagnosed with primary VUR had detailed VCUG and UDR data available. Fourteen children (10.3%) experienced breakthrough febrile UTI events within 13 months of VUR diagnosis. There was a significant association with UDR and breakthrough UTI (p = 0.008). Various computational prediction models for the outcome of breakthrough UTI were developed and evaluated. The computational model that fit best was a model using all variables with an ROC of 0.802. DISCUSSION AND CONCLUSIONS: Clinicians and parents often opt for intervention based on likelihood of spontaneous resolution of VUR as well as clinical course, thereby placing an emphasis on the ability to predict likelihood of breakthrough UTI infections. Our statistical analysis and prediction models further confirm UDR as an important variable predictive of breakthrough UTIs within the first 13 months of beginning prophylactic antibiotics. Furthermore, we developed a neural network model incorporating UDR and grade with an ability to yield the greatest accuracy of any breakthrough UTI predictive calculator to date at 80%.

Tumor cure by radiation therapy and checkpoint inhibitors depends on pre-existing immunity.

Radiation therapy is a source of tumor antigen release that has the potential to serve as an endogenous tumor vaccination event. In preclinical models radiation therapy synergizes with checkpoint inhibitors to cure tumors via CD8 T cell responses. To evaluate the immune response initiated by radiation therapy, we used a range of approaches to block the pre-existing immune response artifact initiated by tumor implantation. We demonstrate that blocking immune responses at tumor implantation blocks development of a tumor-resident antigen specific T cell population and prevents tumor cure by radiation therapy combined with checkpoint immunotherapy. These data demonstrate that this treatment combination relies on a pre-existing immune response to cure tumors, and may not be a solution for patients without pre-existing immunity.

Evaluation of Explant Responses to STING Ligands: Personalized Immunosurgical Therapy for Head and Neck Squamous Cell Carcinoma.

Surgeons have unique in situ access to tumors enabling them to apply immunotherapies to resection margins as a means to prevent local recurrence. Here, we developed a surgical approach to deliver stimulator of interferon genes (STING) ligands to the site of a purposeful partial tumor resection using a gel-based biomaterial. In a range of head and neck squamous cell carcinoma (HNSCC) murine tumor models, we demonstrate that although control-treated tumors recur locally, tumors treated with STING-loaded biomaterials are cured. The mechanism of tumor control required activation of STING and induction of type I IFN in host cells, not cancer cells, and resulted in CD8 T-cell-mediated cure of residual cancer cells. In addition, we used a novel tumor explant assay to screen individual murine and human HNSCC tumor responses to therapies ex vivo We then utilized this information to personalize the biomaterial and immunotherapy applied to previously unresponsive tumors in mice. These data demonstrate that explant assays identify the diversity of tumor-specific responses to STING ligands and establish the utility of the explant assay to personalize immunotherapies according to the local response.Significance: Delivery of immunotherapy directly to resection sites via a gel-based biomaterial prevents locoregional recurrence of head and neck squamous cell carcinoma. Cancer Res; 78(21); 6308-19. ©2018 AACR.