Effect of Prostate Volume and Minimum Tumor Temperature on 4-Year Quality-of-Life After Focal Cryoablation Compared with Active Surveillance in Men with Prostate Cancer.

Background: The purpose of this study is to analyze quality-of-life (QoL) metrics in men treated with focal cryoablation (FC) compared with active surveillance (AS) for localized prostate cancer over a 4-year follow-up period. We further investigated the effect of prostate size and minimum tumor temperature on QoL outcomes. Methods: An Institutional Review Board-approved database was reviewed for patients who underwent FC or AS. QoL questionnaire responses were collected and scores were analyzed for differences between FC and AS, between prostate volume <50 cc and ≥50 cc, and "cold" (<-78°C) and "warm" (≥-78°C) tumor temperatures. Results: One hundred forty-eight AS and 60 FC patients were included. Compared with AS, no significant difference existed in urinary function (UF) measured by Expanded Prostate Cancer Index Composite (EPIC) (p = 0.593) and International Prostate Symptom Score (IPSS) (p = 0.241), bowel habits (p = 0.370), or anxiety (p = 0.672) across time post-FC. FC had significantly worse sexual function (SF) compared with AS measured by EPIC (p < 0.0001) and International Index of Erectile Function (IIEF) (p < 0.0001). Patients with prostate volume <50 cc did not demonstrate differences between AS and FC in UF on EPIC (p = 0.459) or IPSS (p = 0.628), but FC patients had worse SF on EPIC (p < 0.001) and IIEF (p < 0.001). FC patients with a prostate volume ≥50 cc had better UF measured by IPSS (p < 0.05) and similar SF on EPIC (p = 0.162) and IIEF (p = 0.771) compared with AS. UF over time measured by EPIC (0.825) and IPSS (p = 0.658) was the same between AS, "warm," and "cold" FC groups. AS had significantly better SF than the "warm" and "cold" FC groups on EPIC (p < 0.001) and IIEF (p < 0.05). Conclusions: No differences were found in anxiety, urinary, or bowel function between AS and FC. Despite differences in SF, patients with larger prostates had no difference in SF and improved UF compared with AS. Future studies with larger cohorts are needed.

Comparative results of focal-cryoablation and stereotactic body radiotherapy in the treatment of unilateral, low-to-intermediate-risk prostate cancer.

OBJECTIVE: The purpose of this study is to compare oncologic and functional outcomes of men with unilateral, localized PCa treated with stereotactic body radiotherapy (SBRT) versus focal cryoablation (FC). METHODS: Patients from our IRB-approved PCa database who underwent FC or SBRT and were eligible for both treatments were included. Patients with less than 1 year of follow-up or prior PCa treatment were excluded. The primary outcome was treatment failure, defined as salvage treatment or a Gleason group (GG) of ≥ 2 on post-treatment biopsy. Biochemical recurrence (BCR) was evaluated with Phoenix. Functional outcomes were based on EPIC surveys. Complications were categorized with the CTCAE 5.0. Outcomes were compared using descriptive statistics, univariate analyses, and Kaplan-Meier curve for failure-free survival (FFS) and BCR-free survival. P < 0.05 was significant. RESULTS: 68 FC and 51 SBRT patients with a median age of 68 years (48-86) and a median follow-up time of 84 (70-101) months were included in this analysis. There was no difference in tumor risk (p = 0.47), GG (p = 0.20), or PSA (p = 0.70) among the two cohorts at baseline. At 7-year follow-up, no difference in FFS was found between the two cohorts (p = 0.70); however, significantly more FC patients had BCR (p < 0.001). At 48 months, no differences existed in urinary or bowel function; however, SBRT patients had significantly worse sexual function (p = 0.032). CONCLUSION: FC and SBRT are associated with similar oncologic and functional outcomes 7-year post-treatment. These results underscore the utility of FC and SBRT for the management of unilateral low-to-intermediate-risk PCa.

Four-year quality-of-life outcomes in low- to intermediate-risk prostate cancer patients following definitive stereotactic body radiotherapy versus management with active surveillance.

OBJECTIVE: To review quality-of-life (QoL) metrics between patients who underwent definitive stereotactic body radiotherapy (SBRT) versus active surveillance (AS) for management of low- to intermediate-risk prostate cancer (PCa). METHODS: A prospectively maintained PCa database was reviewed containing results of patient-reported QoL surveys. Patients with localized disease who chose AS or SBRT and completed at least one survey within four years of treatment were included. Patients who received salvage therapy were excluded. Survey results were compared across time using mixed-effects repeated measures analysis of covariance models that adjusted for factors significant in univariate analysis. A group x time interaction effect was examined to compare rate of change over time between AS and SBRT. P < 0.05 was significant. RESULTS: 148 AS and 161 SBRT patients were included. Significantly more SBRT patients had intermediate-risk disease (p < 0.0001). AS had significantly worse sexual function compared to SBRT across time. While not significant, bowel function scores were lower for SBRT patients across time points. SBRT patients had significantly lower anxiety than AS patients at 24 months (p < 0.011) and 36 months (p < 0.010). Urinary function though worse in SBRT patients at 12 months in EPIC, was not significantly different in both groups across time points. CONCLUSION: SBRT patients have excellent QoL compared to AS with regard to anxiety post treatment. Though SBRT patients initially have worse urinary and bowel function than AS, scores were eventually similar in both cohorts by 48 months. SBRT patients have significantly worse sexual function post treatment. This study may help facilitate counseling in patients choosing PCa treatment.

Association of mast-cell-related conditions with hypermobile syndromes: a review of the literature.

Ehlers-Danlos syndrome (EDS) is a group of related connective tissue disorders consisting of 13 subtypes, each with its own unique phenotypic and genetic variation. The overlap of symptoms and multitude of EDS variations makes it difficult for patients to achieve a diagnosis early in the course of their disease. The most common form, hypermobile type EDS (hEDS) and its variant, hypermobile spectrum disorder (HSD), are correlated with rheumatologic and inflammatory conditions. Evidence is still needed to determine the pathophysiology of hEDS; however, the association among these conditions and their prevalence in hEDS/HSD may be explained through consideration of persistent chronic inflammation contributing to a disruption of the connective tissue. Aberrant mast cell activation has been shown to play a role in disruption of connective tissue integrity through activity of its mediators including histamine and tryptase which affects multiple organ systems resulting in mast cell activation disorders (MCAD). The overlap of findings associated with MCAD and the immune-mediated and rheumatologic conditions in patients with hEDS/HSD may provide an explanation for the relationship among these conditions and the presence of chronic inflammatory processes in these patients. It is clear that a multidisciplinary approach is required for the treatment of patients with EDS. However, it is also important for clinicians to consider the summarized symptoms and MCAD-associated characteristics in patients with multiple complaints as possible manifestations of connective tissue disorders, in order to potentially aid in establishing an early diagnosis of EDS.

Simple graphical approach to investigate differences in transepithelial paracellular leak pathway permeability.

Although many studies have reported differences in epithelial paracellular Leak Pathway permeability following genetic manipulations and treatment with various agents, the basis for these differences remains mostly unclear. Two primary mechanisms which could underlie differences in Leak Pathway permeability are differences in the density of Leak Pathway openings and differences in the opening size. Using a computational approach, we demonstrate that these two possibilities can be readily distinguished graphically by comparing the apparent paracellular permeabilities of a size panel of solutes measured across different cell layers. Using this approach, we demonstrated that depletion of ZO-1 protein in MDCK Type II renal epithelial cells decreased Leak Pathway opening size and increased opening density. Depletion of ZO-2 protein either had no effect or minimally decreased opening size and did not markedly change opening density. Comparison of MDCK Type II cells with MDCK Type I cells revealed that Type I cells exhibited a substantially smaller Leak Pathway permeability than did Type II cells. This lower permeability was due to a decrease in opening density with little or no change in opening size. These results demonstrate the utility of this approach to provide insights into the basis for observed differences in epithelial Leak Pathway permeability. This approach has wide applications including analysis of the molecular basis for Leak Pathway permeability, the effects of specific manipulations on Leak Pathway permeability properties, and the effects of permeation enhancers on Leak Pathway permeability properties.

The Epithelial Cell Leak Pathway.

The epithelial cell tight junction structure is the site of the transepithelial movement of solutes and water between epithelial cells (paracellular permeability). Paracellular permeability can be divided into two distinct pathways, the Pore Pathway mediating the movement of small ions and solutes and the Leak Pathway mediating the movement of large solutes. Claudin proteins form the basic paracellular permeability barrier and mediate the movement of small ions and solutes via the Pore Pathway. The Leak Pathway remains less understood. Several proteins have been implicated in mediating the Leak Pathway, including occludin, ZO proteins, tricellulin, and actin filaments, but the proteins comprising the Leak Pathway remain unresolved. Many aspects of the Leak Pathway, such as its molecular mechanism, its properties, and its regulation, remain controversial. In this review, we provide a historical background to the evolution of the Leak Pathway concept from the initial examinations of paracellular permeability. We then discuss current information about the properties of the Leak Pathway and present current theories for the Leak Pathway. Finally, we discuss some recent research suggesting a possible molecular basis for the Leak Pathway.

Cellulose Acetate Phthalate and Antiretroviral Nanoparticle Fabrications for HIV Pre-Exposure Prophylaxis.

To adequately reduce new HIV infections, development of highly effective pre-exposure prophylaxis (PrEP) against HIV infection in women is necessary. Cellulose acetate phthalate (CAP) is a pH sensitive polymer with HIV-1 entry inhibitory properties. Dolutegravir (DTG) is an integrase strand transfer inhibitor with potent antiretroviral activity. DTG delivered in combination with CAP may significantly improve current PrEP against HIV. In the present study the development of DTG-loaded CAP nanoparticles incorporated in thermosensitive (TMS) gel at vaginal pH 4.2 and seminal fluid pH 7.4 is presented as proof-of-concept for improved PrEP. Water-oil-in-water homogenization was used to fabricate DTG-loaded CAP nanoparticles (DTG-CAP-NPs). Size, polydispersity, and morphological analyses illustrate that DTG-CAP-NPs were smooth and spherical, ≤200 nm in size, and monodispersed with a polydispersity index PDI ≤ 0.2. The drug encapsulation (EE%) and release profile of DTG-CAP-NPs was determined by HPLC analysis. The EE% of DTG in DTG-CAP-NPs was evaluated to be ∼70%. The thermal sensitivity of the TMS gel was optimized and the pH dependency was evaluated by rheological analysis. DTG release studies in TMS gel revealed that DTG-CAP-NPs were stable in TMS gel at pH 4.2 while DTG-CAP-NPs in TMS gel at pH 7.4 rapidly release DTG (≥80% release within 1 h). Cytotoxicity studies using vaginal cell lines revealed that DTG-CAP-NPs were relatively non-cytotoxic at concentration <1 µg/mL. Confocal microscopic studies illustrate that ≥98% cells retained DTG-CAP-NPs intracellularly over seven days. Antiretroviral drug loaded nanocellulose fabrications in TMS gel delivered intravaginally may enhance both microbicidal and antiretroviral drug efficacy and may present a novel option for female PrEP against HIV.