Kristin Delfino

Immune Characterization of the Programmed Death Receptor Pathway in High Risk Prostate Cancer

Micro‐Abstract The objective of this study was to determine the expression of programmed cell death‐1 (PD‐1) and programmed cell death ligand‐L1 (PD‐L1) in high‐grade prostate cancer tissues, and correlate the expression with disease and patient characteristics. Of the 25 samples, 2 (8%) scored high for PD‐1 expression, 2 (8%) scored high for PD‐L1 expression, and 18 (72%) scored high for CD3 expression. Background: Programmed cell death‐1 (PD‐1), a T‐cell inhibitory receptor, and its ligand, PD‐L1, have been reported to be expressed in many tumor types, and this expression has led to the development of many drugs targeting the PD‐1 pathway. The objective of this study was to determine the expression of PD‐1 and PD‐L1 in high‐grade prostate cancer tissues, and correlate the expression with disease and patient characteristics. Materials and Methods: Immunohistochemistry for PD‐1 (CD279), PD‐L1 (B7‐H1), and CD3 was performed and scored from 0 to 5 on prostatectomy/biopsy tissue samples taken from 25 men with high‐grade prostate cancer. Charts were then retrospectively reviewed for numerous patient and disease characteristics. Statistical analyses were done to investigate the association of these patient and disease characteristics with PD‐1, PD‐L1, and CD3 expression. Results: A score of 3 to 5 on the semiquantitative 0 to 5 score was deemed “high” expression whereas a score of 0 to 2 was deemed “low” expression. Of the 25 samples, 2 (8%) scored high for PD‐1 expression, 2 (8%) scored high for PD‐L1 expression, and 18 (72%) scored high for CD3 expression. There was no statistically significant difference between high and low expression groups of PD‐1, PD‐L1, or CD3 for any of the variables we collected. Conclusion: An overall low expression of PD‐1 and PD‐L1, and a concurrent high expression of CD3+ T cells was found in high‐risk prostate cancer tissue. No significant association was found between expression of PD‐1, PD‐L1, or CD3, and patient or disease characteristics. Because of this, one might be able to question the role of PD‐L1 in local immune suppression in prostate cancer.

Single nucleotide variant in Nucleoporin 107 may be predictive of sensitivity to chemotherapy in patients with ovarian cancer

Background Alterations in nuclear pore complex (NPC) genes have been previously associated with response to chemotherapy. Using agnostic exome sequencing, we envisioned that new alleles in NPC genes, predictive of sensitivity to platinum treatment, could be discovered. Methods Twenty-two platinum-sensitive and six platinum-resistant ovarian cancer patients were tested. Platinum sensitivity was defined as disease-free survival greater than 6 months. Next-generation sequencing of exomes was used to compare platinum-sensitive and platinum-resistant patients. Single nucleotide variants (SNVs) associated with platinum sensitivity in NPC genes (n=30 genes) were identified. Results SNVs in three NPC genes were associated with response to platinum on univariate analysis. SNV rs79419059 (10T>C) in Nucleoporin 107 (Nup107) was associated with platinum resistance (P=0.0061), whereas rs2302811 (3662-4A>G) in Nucleoporin 188 (Nup188) and rs77246077 (3420-67T>A) in Nucleoporin 214 (Nup214) were associated with platinum sensitivity (P=0.0483 and 0.0091, respectively). Controlling for other confounders, multivariate age-adjusted Cox proportional hazard analysis showed rs79419059 to be significantly associated with platinum resistance (odds ratio: 4.519, 95% confidence interval: 1.317–15.501, P=0.0457). Conclusion We identified a variant in the 3′-UTR region Nup107 unique to sensitivity to platinum in ovarian cancer. With validation of this variant, it is possible that a new marker predictive of patient response may be identified.

Engaging rural communities in genetic research: challenges and opportunities

Statistical analyses of health and disease in rural communities is frequently limited by low sample counts. Still, some studies indicate increased risk for some diseases even after adjustment for known risk factors. It has been hypothesized that the context of community formation in rural areas facilitates the propagation of genetic founder effects—potentially impacting disease susceptibility. However, outright examination of genetic diversity in such communities has not been performed. Our objective was to engage otherwise research-inexperienced rural communities of largely European descent in genomic research in the context of cancer susceptibility. From September 2015 to February 2016, we implemented a systematic process of progressive community engagement. This iterative method sought project buy-in from first the town mayor, then village council. If approved by both, a focus group of community members examined how residents might view the research, informed consent and specimen collection, and issues of privacy. We were successful in engaging three of the four communities approached for the research project. There was universal enthusiasm for the project by all mayors and village councils. The focus groups’ main point of discussion involved wording in the informed consent, with little concern regarding the research question or privacy. Perhaps contrary to popular thought, we found each community we approached to be both welcoming and enthusiastic about collaborating in research on genomic diversity. The systematic method of engagement did much to preserve community respect and autonomy and facilitated buy-in.

A Review of the FAERS Data on 5-Alpha Reductase Inhibitors: Implications for Postfinasteride Syndrome

OBJECTIVE To quantify reports made to the Food and Drug Administration Adverse Event Reporting System (FAERS), create a demographic of patient reports, and examine the cluster of symptoms to correlate consistency of postfinasteride syndrome (PFS) complaints. PFS is a provisional diagnosis encompassing a cluster of sexual, physical, and psychological and/or neurologic symptoms associated with 5-alpha reductase inhibitor use that emerge or continue after discontinuation of medication. MATERIALS AND METHODS FAERS dataset of 5-alpha reductase inhibitors from April 2011 to October 2014 was obtained. Each FAERS report had 16 categories for completion, but not every report was fully completed. Statistical analysis compared variables of interest between the 2 doses of finasteride (1 mg vs 5 mg). RESULTS From FAERS, 2048 monotherapy cases were identified: 1581 of finasteride 1 mg, 240 of finasteride 5 mg, and 226 of unreported doses. Possibly related to labeling changes, from 2011 to 2014, there was a significant increase in adverse events (AEs) reported involving 1 mg dosing. Finasteride use was reported with many sexual AEs including diminished libido, erectile dysfunction, and ejaculatory complaints. Other common AEs included dermatologic, metabolic, and psychological and/or neurologic complaints. There were more AE reports with the 1 mg dose than the 5 mg dose. One case of dutasteride reported back pain, not generally attributed to PFS. CONCLUSION FAERS data suggests that finasteride exposure is reported with a diverse collection of symptoms, particularly in younger men on 1 mg dosage compared to older men on 5 mg. Many of these complaints fall well out of the realm of previously established AEs from long-term controlled studies.

Deletion of Nrip1 Extends Female Mice Longevity, Increases Autophagy, and Delays Cell Senescence

Using age of female sexual maturation as a biomarker, we previously identified nuclear receptor interacting protein 1 (Nrip1) as a candidate gene that may regulate aging and longevity. In the current report, we found that the deletion of Nrip1 can significantly extend longevity of female mice (log-rank test, p = .0004). We also found that Nrip1 expression is altered differently in various tissues during aging and under diet restriction. Remarkably, Nrip1 expression is elevated with aging in visceral white adipose tissue (WAT), but significantly reduced after 4 months of diet restriction. However, in gastrocnemius muscle, Nrip1 expression is significantly upregulated after the diet restriction. In mouse embryonic fibroblasts, we found that the deletion of Nrip1 can suppress fibroblast proliferation, enhance autophagy under normal culture or amino acid starvation conditions, as well as delay oxidative and replicative senescence. Importantly, in WAT of old animals, the deletion of the Nrip could significantly upregulate autophagy and reduce the number of senescent cells. These results suggest that deleting Nrip1 can extend female longevity, but tissue-specific deletion may have varying effects on health span. The deletion of Nrip1 in WAT may delay senescence in WAT and extend health span.

MP27-20 CONVECTIVE RADIOFREQUENCY WATER VAPOR ENERGY PROSTATE ABLATION (REZUM®) EFFECTIVELY TREATS URINARY RETENTION

INTRODUCTION AND OBJECTIVES: New minimally invasive surgical therapies (MIST) for lower urinary tract symptoms due to benign prostatic hyperplasia (LUTS/BPH) such as prostatic urethral lift and convective radiofrequency water vapor energy prostate ablation (WaVE) have shown promising intermediate-term results in improving voiding symptoms. However, the initial trials excluded men in urinary retention; thus the ability of these new technologies to achieve catheter independence has not been evaluated. This study investigated outcomes of patients with urinary retention at baseline treated with WaVE. METHODS: Patients in urinary retention who underwent WaVE were retrospectively identified. Urinary retention was defined as dependence on an indwelling catheter or performance of clean intermittent catheterization (CIC) for bladder emptying. Age, duration of catheter dependence, prostate size, baseline IPSS and PVR, and number of treatments per procedure were recorded. For subjects with successful trials without catheter (TWOC), time to catheter independence and post-procedure PVR and IPSS were recorded. Baseline characteristics between subjects with successful TWOC and unsuccessful TWOC were compared using Mann Whitney U test and T-test for continuous variables and Chi-square test and Fisher0s exact test for non-continuous variables. RESULTS: 30 patients were identified with urinary retention who underwent WaVE. 22 subjects had an indwelling catheter, 8 subjects performed clean intermittent catheterization (CIC). Mean age was 76 years. Relevant baseline measures included (mean): duration of catheter dependence (6.9mo), prostate size (64.3 ml), PVR (538 mL), and number of treatments per procedure (6.4). 28/30 subjects had middle lobe treatment (1 treatment per procedure). 23 of 30 subjects (77%) achieved successful TWOC post-procedure. Mean time to catheter independence was 29 days post-procedure with mean post-procedure PVR 84 mL and post-procedure IPSS 9. There were no differences between subjects with or without successful TWOC in age, duration of catheter dependence, prostate size, baseline PVR, baseline IPSS, number of treatments per procedure, or treatment of median lobe. CONCLUSIONS: WaVE can effectively treat patients with urinary retention and successfully render patients catheter independent, including patients with a median lobe. Longer-term follow up is necessary to evaluate the durability of this technology.

Involvement of DNA mismatch repair in the maintenance of heterochromatic DNA stability in Saccharomyces cerevisiae

Heterochromatin contains a significant part of nuclear DNA. Little is known about the mechanisms that govern heterochromatic DNA stability. We show here that in the yeast Saccharomyces cerevisiae (i) DNA mismatch repair (MMR) is required for the maintenance of heterochromatic DNA stability, (ii) MutLα (Mlh1-Pms1 heterodimer), MutSα (Msh2-Msh6 heterodimer), MutSβ (Msh2-Msh3 heterodimer), and Exo1 are involved in MMR at heterochromatin, (iii) Exo1-independent MMR at heterochromatin frequently leads to the formation of Pol ζ-dependent mutations, (iv) MMR cooperates with the proofreading activity of Pol ε and the histone acetyltransferase Rtt109 in the maintenance of heterochromatic DNA stability, (v) repair of base-base mismatches at heterochromatin is less efficient than repair of base-base mismatches at euchromatin, and (vi) the efficiency of repair of 1-nt insertion/deletion loops at heterochromatin is similar to the efficiency of repair of 1-nt insertion/deletion loops at euchromatin.