The Microbial Metabolite Butyrate Stimulates Bone Formation via T Regulatory Cell-Mediated Regulation of WNT10B Expression.

Nutritional supplementation with probiotics can prevent pathologic bone loss. Here we examined the impact of supplementation with Lactobacillus rhamnosus GG (LGG) on bone homeostasis in eugonadic young mice. Micro-computed tomography revealed that LGG increased trabecular bone volume in mice, which was due to increased bone formation. Butyrate produced in the gut following LGG ingestion, or butyrate fed directly to germ-free mice, induced the expansion of intestinal and bone marrow (BM) regulatory T (Treg) cells. Interaction of BM CD8+ T cells with Treg cells resulted in increased secretion of Wnt10b, a bone anabolic Wnt ligand. Mechanistically, Treg cells promoted the assembly of a NFAT1-SMAD3 transcription complex in CD8+ cells, which drove expression of Wnt10b. Reducing Treg cell numbers, or reconstitution of TCRß-/- mice with CD8+ T cells from Wnt10b-/- mice, prevented butyrate-induced bone formation and bone mass acquisition. Thus, butyrate concentrations regulate bone anabolism via Treg cell-mediated regulation of CD8+ T cell Wnt10b production.

Microwave vs radiofrequency ablation for small renal masses: perioperative and oncological outcomes.

OBJECTIVE: To conduct a comprehensive comparison of microwave ablation (MWA) vs radiofrequency ablation (RFA) outcomes in the treatment of small renal masses (SRMs), specifically: TRIFECTA ([i] complete ablation, [ii] absence of Clavien-Dindo Grade ≥III complications, and [iii] absence of ≥30% decrease in estimated glomerular filtration rate) achievement, operative time (OT), and local recurrence rate (LRR). PATIENTS AND METHODS: We retrospectively analysed 531 patients with SRMs (clinical T1a-b) treated with MWA or RFA at a single centre (2008-2022). First, multivariable logistic regression models were used for testing TRIFECTA achievement. Second, multivariable Poisson regression models were used to evaluate variables associated with longer OT. Finally, Kaplan-Meier plots depicted LRR over time. All analyses were repeated after 1:1 propensity score matching (PSM). RESULTS: Of 531 patients with SRMs, 373/531 (70.2%) underwent MWA and 158/531 (29.8%) RFA. MWA demonstrated superior TRIFECTA achievement (314/373 [84.2%]) compared to RFA (114/158 [72.2%], P = 0.001). These differences were driven by higher rates of complete ablation in MWA- vs RFA-treated patients (348/373 [93.3%] vs 137/158 [86.7%], P < 0.001). In multivariable logistic regression models, MWA was associated with higher TRIFECTA achievement, compared to RFA, before (odds ratio [OR] 1.92, P = 0.008) and after PSM (OR 1.99, P = 0.023). Finally, the median OT was shorter for MWA vs RFA (105 vs 115 min; P = 0.002). At Poisson regression analyses, MWA predicted shorter OT before (incidence rate ratio [IRR] 0.86, P < 0.001) and after PSM (IRR 0.85, P < 0.001). Local recurrence occurred in 17/373 (4.6%) MWA-treated patients and 21/158 (13.3%) RFA-treated patients (P = 0.29) after a median (interquartile range) follow-up of 24 (8-46) months. There were no differences in the LRR in Kaplan-Meier plots before (P = 0.29) and after PSM (P = 0.42). CONCLUSION: Microwave ablation provides higher TRIFECTA achievement, and shorter OT than RFA. No significant differences were found regarding the LRR.

Regulatory T cells are expanded by Teriparatide treatment in humans and mediate intermittent PTH-induced bone anabolism in mice.

Teriparatide is a bone anabolic treatment for osteoporosis, modeled in animals by intermittent PTH (iPTH) administration, but the cellular and molecular mechanisms of action of iPTH are largely unknown. Here, we show that Teriparatide and iPTH cause a ~two-threefold increase in the number of regulatory T cells (Tregs) in humans and mice. Attesting in vivo relevance, blockade of the Treg increase in mice prevents the increase in bone formation and trabecular bone volume and structure induced by iPTH Therefore, increasing the number of Tregs is a pivotal mechanism by which iPTH exerts its bone anabolic activity. Increasing Tregs pharmacologically may represent a novel bone anabolic therapy, while iPTH-induced Treg increase may find applications in inflammatory conditions and transplant medicine.

Thermal Ablation for Small Renal Masses: Identifying Anthropometric Factors for Predicting Perioperative and Oncological Outcomes.

OBJECTIVES: To test for specific anthropometric parameters to predict perioperative outcomes after thermal ablation (TA) for renal cell carcinoma (RCC). MATERIALS AND METHODS: Retrospective single center (2008-2022) analysis of 538 T1a-b RCC patients treated with TA. We tested for specific anthropometric parameters, namely skin to tumor distance (STTD), perirenal fat thickness (PFT), median psoas muscle axial area (PMAA) and median paravertebral muscle axial area (PVMAA), to predict TRIFECTA achievement: (1) absence of CLAVIEN-DINDO≥ 3 complications; (2) complete ablation; (3) absence of ≥ 30% decrease in eGFR. Univariable (ULRM) and multivariable logistic regression models (MLRM) were used for testing TRIFECTA achievement. RESULTS: Overall, 103 patients (19%) did not achieve TRIFECTA. Of all anthropometric factors, only lower PMAA was associated with no TRIFECTA achievement (10 vs. 11 cm2, P = .02). However, ULRMs and MLRMs did not confirmed the aforementioned association. We than tested for the 3 specific TRIFECTA items. In separate ULRM and MLRM predicting incomplete ablation, both continuously coded STTD (Odds Ratio [OR]: 1.02; CI: 1.01-1.03; P = .02) and STTD strata (STTD > 10 cm; OR: 2.1; CI: 1.1-4.1; P = .03) achieved independent predictor status. Conversely, in separate ULRM and MLRM predicting CLAVIEN-DINDO ≥3 complications, both continuously coded PFT (OR: 1.04; CI: 1.01-1.07; P = .01) and PFT strata (PFT ≥ 14 mm; OR: 3.3; CI: 1.6-10.2; P = .003) achieved independent predictor status. Last, none of the anthropometric parameters were associated with eGFR decrease ≥ 30%. CONCLUSION: None of the tested anthropometric parameters predicted TRIFECTA achievement. However, when the 3 specific TRIFECTA items were tested, STTD and PFT were associated with, respectively, incomplete ablation and CLAVIEN-DINDO ≥ 3 complications.

Single-Use Flexible Ureteroscopes: How Difficult Is It Today to Stay Up to Date? A Pictorial Review of Instruments Available in Europe in 2023.

The invention of the flexible ureteroscope (fURS) and its subsequent spread have revolutionized the surgical management of urolithiasis and upper tract urothelial carcinoma (UTUC). During the last few years, single-use flexible ureteroscopes (su-fURSs) have been developed to improve the limitations of reusable fURSs, namely their cost, durability and risk of device contamination. Since the introduction of the first fully disposable digital fURS, several su-fURSs have been developed by various manufacturers. In this pictorial review, we combined the different physical and technical features of su-fURSs currently available on the market with Food and Drug Administration (FDA) and European Conformity (CE) approval, in order to help surgeons choose the appropriate device according to each case requirement and personal preferences. To the best of our knowledge, 17 su-fURSs with CE and FDA approval have been developed to date.

Predicting Peri-Operative Outcomes in Patients Treated with Percutaneous Thermal Ablation for Small Renal Masses: The SuNS Nephrometry Score.

Our objective was to develop a new, simple, and ablation-specific nephrometry score to predict peri-operative outcomes and to compare its predictive accuracy to PADUA and RENAL scores. Overall, 418 patients were treated with percutaneous thermal ablation (microwave and radiofrequency) between 2008 and 2021. The outcome of interest was trifecta status (achieved vs. not achieved): incomplete ablation or Clavien-Dindo ≥ 3 complications or postoperative estimated glomerular filtration rate decrease ≥ 30%. First, we validated the discrimination ability of the PADUA and RENAL scoring systems. Second, we created and internally validated a novel scoring (SuNS) system, according to multivariable logistic regression models. The predictive accuracy of the model was tested in terms of discrimination and calibration. Overall, 89 (21%) patients did not achieve trifecta. PADUA and RENAL scores showed poor ability to predict trifecta status (c-indexes 0.60 [0.53-0.67] and 0.62 [0.55-0.69], respectively). We, therefore, developed the SuNS model (c-index: 0.74 [0.67-0.79]) based on: (1) contact surface area; (2) nearness to renal sinus or urinary collecting system; (3) tumour diameter. Three complexity classes were created: low (3-4 points; 11% of no trifecta) vs. moderate (5-6 points; 30% of no trifecta) vs. high (7-8 points; 65% of no trifecta) complexity. Limitations include the retrospective and single-institution nature of the study. In conclusion, we developed an immediate, simple, and reproducible ablation-specific nephrometry score (SuNS) that outperformed PADUA and RENAL nephrometry scores in predicting peri-operative outcomes. External validation is required before daily practice implementation.

Prosocial priming and bystander effect in an online context.

The present study tested the effect of priming the concept of prosociality on the bystander effect in an online environment. Participants were sent an e-mail requesting a plea for help and randomly assigned to one of four conditions in a 2 (Bystander: 0 vs. 14) × 2 (Priming: present vs. absent) design. The results demonstrated support for the study hypothesis. As expected, the virtual presence of many others significantly reduced e-mail responsiveness except when the request for help is preceded by prosocial priming. Implications of these findings for the literature on the bystander effect and priming are discussed.

Antegrade versus retrograde common iliac artery revascularization and occurrence of erectile dysfunction.

AIM: To assess the effect of antegrade and retrograde common iliac artery (CIA) revascularization on erectile dysfunction (ED) using the validated International Index of Erectile Function (IIEF) questionnaire, on patients treated for chronic occlusions of the CIA. MATERIALS AND METHODS: Clinical data of patients who were submitted either to endovascular CIA revascularization (group A) or to femoral-femoral crossover bypass (group B) due a unilateral total occlusion of the CIA between 01/2015 and 12/2019 were retrospectively analyzed. Primary outcomes included the evaluation of ED using the IIEF questionnaire, before and 30 days after the operation. A P value <0.05 was considered statistically significant. RESULTS: A total of 33 patients underwent endovascular (14 patients, group A) or surgical treatment (19, group B) Before the operation, no differences were recorded in the occurrence of ED between the two groups, neither in the results of the IIEF questionnaire. After the intervention, patients of group A performed significantly better than those of group B in terms of IIEF questionnaire (18 ± 10.1 versus 12.1 ± 14.8, P=0.01). Age and COPD were negatively correlated with the preoperative results of the IIEF questionnaire (OR 0.049, 95%CI 0.02-0.05, P<0.001 and OR 0.29, 95%CI 0.01-0.56, P=0.03, respectively) and the postoperative results of the IIEF questionnaire (OR 0.02, 95% CI 0.01-0.04, P<0.001, and OR 0.46, 95% CI 0.17-0.75, P=0.001, respectively). CONCLUSIONS: Patients who were submitted to endovascular antegrade revascularization for occlusion of the CIA performed significantly better in terms of IIEF questionnaire than those who underwent surgical femoral-femoral crossover bypass and therefore retrograde HA revascularization. KEY WORDS: Common iliac artery occlusion, Erectile dysfunction, Femoro-femoral bypass, Iliac artery angioplasty, IIEF-5.

Thermal ablation for small renal masses: Identifying the most appropriate tumor size cut-off for predicting perioperative and oncological outcomes.

OBJECTIVES: To test TRIFECTA achievement [1) absence of CLAVIEN-DINDO ≥3 complications; 2) complete ablation; 3) absence of ≥30% decrease in eGFR] and local recurrence rates, according to tumor size, in patients treated with thermal ablation (TA: radiofrequency [RFA] and microwave ablation [MWA]) for small renal masses. METHODS: Retrospective analysis (2008-2020) of 432 patients treated with TA (RFA: 162 vs. MWA: 270). Tumor size was evaluated as: 1) continuously coded variable (cm); 2) tumor size strata (0.1-2 vs. 2.1-3 vs. 3.1-4 vs. >4 cm). Multivariable logistic regression models and a minimum P-value approach were used for testing TRIFECTA achievement. Kaplan-Meier plots depicted local recurrence rates over time. RESULTS: Overall, 162 (37.5%) vs. 140 (32.4%) vs. 82 (19.0%) vs. 48 (11.1%) patients harboured, respectively, 0.1 to 2 vs. 2.1 to 3 vs. 3.1 to 4 vs. >4 cm tumors. In multivariable logistic regression models, increasing tumor size was associated with higher rates of no TRIFECTA achievement (OR:1.11; P< 0.001). Using a minimum P-value approach, an optimal tumor size cut-off of 3.2 cm was identified (P< 0.001). In multivariable logistic regression models, 3.1 to 4 cm tumors (OR:1.27; P< 0.001) and >4 cm tumors (OR:1.49; P< 0.001), but not 2.1 to 3 cm tumors (OR:1.05; P= 0.3) were associated with higher rates of no TRIFECTA achievement, relative to 0.1 to 2 cm tumors. The same results were observed in separate analyses of RFA vs. MWA patients. After a median (IQR) follow-up time of 22 (12-44) months, 8 (4.9%), 8 (5.7%), 11 (13.4%), and 5 (10.4%) local recurrences were observed in tumors sized 0.1 to 2 vs. 2.1 to 3 vs. 3.1 to 4 vs. >4 cm, respectively (P= 0.01). CONCLUSION: A tumor size cut-off value of ≤3 cm is associated with higher rates of TRIFECTA achievement and lower rates of local recurrence over time in patients treated with TA for small renal masses.

Correlation Between Long-Term Acetylsalicylic Acid Use and Prostate Cancer Screening with PSA. Should We Reduce the PSA Cut-off for Patients in Chronic Therapy? A Multicenter Study.

Purpose: To evaluate the prostate cancer (PCa) detection rate in men with chronic use of Aspirin and to compare it with the detection rate of non-users. Patients and Methods: Prospectively maintained database regarding patients undergoing prostate biopsy over the last 10 years in five institutions. Patients were divided into two groups according to their exposure to Aspirin. We relied on multivariable linear and logistic regression models to test whether Aspirin administration was associated with lower PSA values at prostate biopsy, higher PCa diagnosis, and higher Gleason Grade Grouping (GGG) at biopsy. Results: Were identified 1059 patients, of whom 803 (76%) did not take Aspirin vs 256 (24%) were taking it. In multivariable log-linear regression analysis, Aspirin administration was associated with lower PSA levels (OR 0.83, 95% CI 0.71-0.97, p = 0.01), after controlling for age, prostate volume, smoking history, associated inflammation at prostate biopsy, presence of PCa at biopsy, and GGG. In multivariable logistic regression analysis, Aspirin administration was not found to be a predictor of PCa at prostate biopsy (OR 1.40, 95% CI 0.82-2.40, p = 0.21) after controlling for age, PSA, smoking history, prostate volume, findings at digital rectal examination and the number of biopsy cores. In patients with PCa at prostate biopsy (n = 516), Aspirin administration was found to predict higher GGG (OR 2.24, 95% CI 1.01-4.87, p = 0.04). Conclusion: Aspirin administration was found to be a predictor of more aggressive GGG. These findings suggest that a lower PSA threshold should be considered in patients taking Aspirin, as, despite low PSA levels, they might harbour aggressive PCa.

The role of MRI/TRUS fusion biopsy in the diagnosis of clinically significant prostate cancer.

BACKGROUND: The aim of this work is to evaluate the detection rate of magnetic resonance imaging/transrectal ultrasound (MRI/TRUS) fusion-guided biopsy for clinically significant prostate cancers (Cs PCas), with particular interest in biopsy-naive patients and patients in active surveillance. MRI-targeted biopsy improves cancer detection rate (DR) in patients with prior negative biopsies; the current literature focuses on biopsy naive patients. We also evaluated the pathologic concordance between biopsies and surgical specimens. METHODS: MRI/TRUS fusion-guided biopsies were performed between February 2016 and February 2019. Patients with previous negative biopsies, biopsy-naive or in active surveillance (AS) were included. Cs PCas were defined through Epstein's criteria. RESULTS: A total of 416 men were enrolled. The overall DRs and Cs PCa DRs were 49% and 34.3%, respectively. Cs PCas were 17.2%, 44.9% and 73.4%, respectively for PI-RADS 3, 4 or 5. Among biopsy-naive patients, 34.8% were found to have a Cs PCa, while a 43.6% tumour upgrading was achieved in men with a low risk of PCa. In patients who underwent radical prostatectomy (RP), the concordance between biopsy Gleason score (GS) (bGS) and pathological GS (pGS) was 90.8%. CONCLUSION: Our study highlights the role of MRI/TRUS fusion prostate biopsy in the detection of PCa in patients with previous negative biopsies focusing on Cs PCa diagnosis. The MRI/TRUS fusion biopsy is also emerging as a diagnostic tool in biopsy-naïve patients and deserves a fundamental role in AS protocols. A greater concordance between bGS and pGS can be achieved with targeted biopsies.

Keratinizing squamous metaplasia of the bladder: Our experience and current approaches.

INTRODUCTION: Bladder mucosa is anatomically covered by urothelial epithelium. The replacement of the urothelium with stratified squamous cells is defined as squamous metaplasia which can be keratinizing or non-keratinizing. Clinically, it is also known as leukoplakia or keratinizing cystitis of the bladder. Although several etiologic factors have been proposed such as chronic inflammation, irritative stimuli and infection, its pathogenesis is not clearly understood. The natural history of squamous metaplasia and clinical treatment are controversial. Many authors consider squamous metaplasia as a premalignant lesion, so it is fundamental to find an effective treatment to reduce the risk of developing bladder squamous carcinoma. CASE DESCRIPTION: We report our management of a 58-year-old man with histological evidence of keratinizing squamous metaplasia and severe lower urinary tract symptoms. After repeated transurethral resections, the patient was treated with intravesical instillation of hyaluronic acid showing the regression of the lesion with an improvement of macroscopic appearance followed by the resolution of clinical symptoms. CONCLUSION: The therapeutic management of keratinizing squamous metaplasia is controversial, and currently no effective medical therapy is available for its treatment. Actually, patients undergo transurethral resections and a multidisciplinary approach is required to avoid cystectomy. Annual cystoscopy with multiple biopsies should be performed to determine the presence of dysplasia. Moreover, the therapeutic treatment with hyaluronic acid instillations could be the starting point and the gold standard in the follow-up of our patient. However, at present, further studies are required to formulate an adequate policy for therapeutic management of this unusual lesion of the bladder mucosa.

IL-17 Receptor Signaling in Osteoblasts/Osteocytes Mediates PTH-Induced Bone Loss and Enhances Osteocytic RANKL Production.

Primary hyperparathyroidism (PHPT) is a condition where elevated PTH levels lead to bone loss, in part through increased production of the osteoclastogenic factor IL-17A, by bone marrow (BM) T-helper 17 (Th17) cells, a subset of helper CD4+ T cells. In animals, PHPT is modeled by continuous PTH treatment (cPTH). In mice, an additional critical action of cPTH is the capacity to increase the production of RANKL by osteocytes. However, a definitive link between IL-17A and osteocytic expression of RANKL has not been made. Here we show that cPTH fails to induce cortical and trabecular bone loss and causes less intense bone resorption in conditional knock-out (IL-17RAΔOCY ) male and female mice lacking the expression of IL-17A receptor (IL-17RA) in dentin matrix protein 1 (DMP1)-8kb-Cre-expressing cells, which include osteocytes and some osteoblasts. Therefore, direct IL-17RA signaling in osteoblasts/osteocytes is required for cPTH to exert its bone catabolic effects. In addition, in vivo, silencing of IL-17RA signaling in in DMP1-8kb-expressing cells blunts the capacity of cPTH to stimulate osteocytic RANKL production, indicating that cPTH augments osteocytic RANKL expression indirectly, via an IL-17A/IL-17RA-mediated mechanism. Thus, osteocytic production of RANKL and T cell production of IL-17A are both critical for the bone catabolic activity of cPTH. © 2018 American Society for Bone and Mineral Research.

Sex steroid deficiency-associated bone loss is microbiota dependent and prevented by probiotics.

A eubiotic microbiota influences many physiological processes in the metazoan host, including development and intestinal homeostasis. Here, we have shown that the intestinal microbiota modulates inflammatory responses caused by sex steroid deficiency, leading to trabecular bone loss. In murine models, sex steroid deficiency increased gut permeability, expanded Th17 cells, and upregulated the osteoclastogenic cytokines TNFα (TNF), RANKL, and IL-17 in the small intestine and the BM. In germ-free (GF) mice, sex steroid deficiency failed to increase osteoclastogenic cytokine production, stimulate bone resorption, and cause trabecular bone loss, demonstrating that the gut microbiota is central in sex steroid deficiency-induced trabecular bone loss. Furthermore, we demonstrated that twice-weekly treatment of sex steroid-deficient mice with the probiotics Lactobacillus rhamnosus GG (LGG) or the commercially available probiotic supplement VSL#3 reduces gut permeability, dampens intestinal and BM inflammation, and completely protects against bone loss. In contrast, supplementation with a nonprobiotic strain of E. coli or a mutant LGG was not protective. Together, these data highlight the role that the gut luminal microbiota and increased gut permeability play in triggering inflammatory pathways that are critical for inducing bone loss in sex steroid-deficient mice. Our data further suggest that probiotics that decrease gut permeability have potential as a therapeutic strategy for postmenopausal osteoporosis.

Hydrogen Sulfide Is a Novel Regulator of Bone Formation Implicated in the Bone Loss Induced by Estrogen Deficiency.

Hydrogen sulfide (H2 S) is a gasotransmitter known to regulate bone formation and bone mass in unperturbed mice. However, it is presently unknown whether H2 S plays a role in pathologic bone loss. Here we show that ovariectomy (ovx), a model of postmenopausal bone loss, decreases serum H2 S levels and the bone marrow (BM) levels of two key H2 S-generating enzymes, cystathione ß-synthase (CBS) and cystathione γ-lyase (CSE). Treatment with the H2 S-donor GYY4137 (GYY) normalizes serum H2 S in ovx mice, increases bone formation, and completely prevents the loss of trabecular bone induced by ovx. Mechanistic studies revealed that GYY increases murine osteoblastogenesis by activating Wnt signaling through increased production of the Wnt ligands Wnt16, Wnt2b, Wnt6, and Wnt10b in the BM. Moreover, in vitro treatment with 17ß-estradiol upregulates the expression of CBS and CSE in human BM stromal cells (hSCs), whereas an H2 S-releasing drug induces osteogenic differentiation of hSCs. In summary, regulation of H2 S levels is a novel mechanism by which estrogen stimulates osteoblastogenesis and bone formation in mice and human cells. Blunted production of H2 S contributes to ovx-induced bone loss in mice by limiting the compensatory increase in bone formation elicited by ovx. Restoration of H2 S levels is a potential novel therapeutic approach for postmenopausal osteoporosis. © 2015 American Society for Bone and Mineral Research.

IL-17A Is Increased in Humans with Primary Hyperparathyroidism and Mediates PTH-Induced Bone Loss in Mice.

Primary hyperparathyroidism (PHPT) is a common cause of bone loss that is modeled by continuous PTH (cPTH) infusion. Here we show that the inflammatory cytokine IL-17A is upregulated by PHPT in humans and cPTH in mice. In humans, IL-17A is normalized by parathyroidectomy. In mice, treatment with anti-IL-17A antibody and silencing of IL-17A receptor IL-17RA prevent cPTH-induced osteocytic and osteoblastic RANKL production and bone loss. Mechanistically, cPTH stimulates conventional T cell production of TNFα (TNF), which increases the differentiation of IL-17A-producing Th17 cells via TNF receptor 1 (TNFR1) signaling in CD4(+) cells. Moreover, cPTH enhances the sensitivity of naive CD4(+) cells to TNF via GαS/cAMP/Ca(2+) signaling. Accordingly, conditional deletion of GαS in CD4(+) cells and treatment with the calcium channel blocker diltiazem prevents Th17 cell expansion and blocks cPTH-induced bone loss. Neutralization of IL-17A and calcium channel blockers may thus represent novel therapeutic strategies for hyperparathyroidism.