Prostate Lobes Research Articles

High-intensity focused ultrasound (HIFU) hemiablation of the prostate: Late follow-up MRI findings in non-recurrent patients

ObjectivesFocal therapy with high-intensity focused ultrasound (HIFU) is an emerging option for the treatment of prostate cancer and often followed up by MRI. Image assessment of treatment failure, however, requires proper knowledge about typical procedure-related changes in prostate MRI, which is sparse, in particular for unilateral HIFU treatment and late follow up (beyond 6 months). The goal of this study was therefore to compile the type and frequency of such MRI findings in selected patients without recurrent cancer 12 months after prostate hemiablation. MethodsData from a prospective multicenter trial on HIFU hemiablation were reviewed retrospectively. Trial patients have had a late follow-up by MRI (at around 12 months) and either MRI/transrectal ultrasound (TRUS) fusion or standard TRUS-guided biopsy. This work deliberately included patients with non-recurrent cancer in the treated prostate lobe in per-protocol biopsy leaving 30 men with initial International Society of Urological Pathology (ISUP) Grade Group of 1 or 2. Six categories of potential HIFU-related MRI features were assessed by an expert committee and then evaluated by two readers in consensus: 1. shrinkage of the treated lobe, 2. residual prostate tissue, 3. fluid-filled cavity, 4. fibrosis, 5. hematoma residuals (in the prostate or seminal vesicles) and 6. contrast enhancement of the ablated area. ResultsShrinkage of the ablated lobe was seen in 93% of the cases with an average percent volume change of −37% (range: −70% to +108%). In the contralateral lobe, the volume remained practically the same (–2% on average, p = 0.804). In the ablated lobe, the frequency of fibrosis was 97%. Residual prostate tissue was seen in 93% of the cases. The frequency for fluid-filled cavities was 97%, with the wide majority (90%) contiguous with the urethra. Hematoma residuals in the prostate and in seminal vesicles were found in 47% and 10% of the patients, respectively. Contrast enhancement was both rim-like (50%) as well as diffuse (33%) within the ablated area. ConclusionIn our case series of HIFU hemiablation in the prostate, shrinkage, residual prostate tissue, fluid-filled cavities contiguous with the urethra and fibrosis were very common late MRI findings of the ablated lobe in non-recurrent patients. Rim-like contrast enhancement or diffuse one within the ablated area were less frequent.

PD11-04 LOSS OF OSTEOPONTIN LEADS TO THE RESOLUTION OF E. COLI-INDUCED PROSTATIC INFLAMMATION AND FIBROSIS

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Basic Research & Pathophysiology (PD11)1 Sep 2021PD11-04 LOSS OF OSTEOPONTIN LEADS TO THE RESOLUTION OF E. COLI-INDUCED PROSTATIC INFLAMMATION AND FIBROSIS Petra Popovics, Asha Jain, Francesca Van, Hannah Ruetten, Mark Cadena, Kristen S. Uchtmann, Chad M. Vezina, and William A. Ricke Petra PopovicsPetra Popovics More articles by this author , Asha JainAsha Jain More articles by this author , Francesca VanFrancesca Van More articles by this author , Hannah RuettenHannah Ruetten More articles by this author , Mark CadenaMark Cadena More articles by this author , Kristen S. UchtmannKristen S. Uchtmann More articles by this author , Chad M. VezinaChad M. Vezina More articles by this author , and William A. RickeWilliam A. Ricke More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000001986.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Fibrogenic and inflammatory processes in the prostate are linked to the development of lower urinary tract symptoms (LUTS) in men, but the molecular mechanism is unknown. We previously established that osteopontin (OPN), a pro-fibrotic cytokine, is more abundant in the prostate of men with LUTS compared to prostate tissue with normal histology. We also identified that OPN secretion is stimulated by inflammatory cytokines in prostate stromal cells and hypothesized that OPN exacerbates the prostatic inflammatory environment. The current study investigates whether the lack of OPN ameliorates inflammation-induced prostatic fibrosis and urinary dysfunction in mice following transurethral instillation of E. coli. METHODS: Uropathogenic Escherichia coli (UTI89) or saline (control) was instilled via a transurethral catheter (OD 0.8, 100 ul) two times, 3 days apart to C57BL/6J (WT) or B6.129S6(Cg)-Spp1tm1Blh/J (OPN-KO) mice. Urinary function was assessed by weekly void spot assays (VSA). Prostatic collagen was visualized with picrosirius red (PSR) staining and inflammation by immunohistochemistry of the pan-leukocyte marker CD45. RNA-Seq analysis was performed from the ventral prostate lobe. RESULTS: Urinary frequency significantly increased (2.05-fold, p=0.0097) 33 days after E. coli instillation in WT but not in OPN-KO mice. One week after infection, the ventral and dorsal prostate lobes were significantly inflamed (more CD45 cells) and collagen fibers were thicker in both WT and OPN-KO mice. In contrast, 2 months after instillation, OPN-KO mouse prostates contained significantly less total collagen and inflammation compared to WT mice. RNAseq analysis identified that E. coli-instilled WT mice expressed more inflammatory and fibrotic marker RNAs, such as Col3a1, Il1b, MMP3, Mmp7 and Cxcl12 than OPN-KO mice. CONCLUSIONS: Our results show that by preventing the inflammation-related increase in OPN levels, mice undergo accelerated recovery from fibrosis and do not develop chronic inflammation. This suggests that drugs targeting OPN signaling could be beneficial for LUTS patients whose symptoms are primarily linked to fibrosis. Source of Funding: The study was supported by an NIH NIDDK K01 (K01DK127150) and a K12 award (K12DK100022-06, both to PP) and by U54 DK104310 (to WAR and CMV) © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e198-e199 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Petra Popovics More articles by this author Asha Jain More articles by this author Francesca Van More articles by this author Hannah Ruetten More articles by this author Mark Cadena More articles by this author Kristen S. Uchtmann More articles by this author Chad M. Vezina More articles by this author William A. Ricke More articles by this author Expand All Advertisement Loading ...

PD18-11 THE "BUTTERFLY", A NOVEL MINIMALLY INVASIVE TRANSURETHRAL RETRACTION DEVICE FOR BPH

You have accessJournal of UrologyBenign Prostatic Hyperplasia: Surgical Therapy & New Technology III (PD18)1 Sep 2021PD18-11 THE "BUTTERFLY", A NOVEL MINIMALLY INVASIVE TRANSURETHRAL RETRACTION DEVICE FOR BPH Ran Katz, Ali Safadi, Muhamad Abu Ahmed, Shmuel Roizman, Amnon Zisman, Maharan Kabha, Yoram Dekel, Jack Baniel, and shachar Aharoni Ran KatzRan Katz More articles by this author , Ali SafadiAli Safadi More articles by this author , Muhamad Abu AhmedMuhamad Abu Ahmed More articles by this author , Shmuel RoizmanShmuel Roizman More articles by this author , Amnon ZismanAmnon Zisman More articles by this author , Maharan KabhaMaharan Kabha More articles by this author , Yoram DekelYoram Dekel More articles by this author , Jack BanielJack Baniel More articles by this author , and shachar Aharonishachar Aharoni More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002007.11AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The Butterfly Prostatic Retraction Device is a novel minimally invasive, non-surgical implant that is delivered into the prostatic urethra in order to retract the lateral lobes of the prostate, increase the diameter of the prostatic urethra thus treating symptoms associated with BPH. The device is made of nitinol and consists of two lateral wings connected by several transverse rails and is available in five sizes. It is folded into a 5 mm introducer, inserted via rigid cystoscopy and deployed in the prostatic urethra between the verumontanum and the bladder neck. In body temperature the device expands, pushes the prostate lobes laterally, opening a wide path in the prostatic urethra while preserving the bladder neck. It is designed for day surgery or in office settings. We present our results in the management of men suffering from BPH. METHODS: A prospective, Open-Label clinical study for assessing the safety and efficacy of the Butterfly device in male patients suffering from LUTS due to BPH was performed enrolling up to date 50 men who were treated for BPH for at least one year and were candidates for prostatectomy. All patients had Qmax≤ 13 ml/sec and IPSS > 12. Patients with previous prostate procedure, prostatitis, cystolithiasis, prostate median lobe, urethral/bladder neck stricture and atonic bladder were excluded. The study was approved by the hospitals’ IRBs. Insertion of the device was performed under sedation in a day care setting. No catheter was left. Follow up visits were performed at 2 weeks, 1, 3, 6, and 12 months and included uroflowmetry, IPSS, QoL and sexual function questionnaires. Cystoscopy was performed on 3 and 12 months. RESULTS: Patient age range was 50-82 years. 23 patients completed a 1 year follow up and median follow up was 9 months. In one-year Qmax improved by 33%, IPSS score by 40% and QoL score improved by 38% compared to baseline. No patient reported deterioration of sexual function and all sexually active patients reported antegrade ejaculation. On cystoscopy, gradual coverage of the device with urethral mucosa was observed and there were no cases of encrustation. No unanticipated device related AE occurred. In one patient the device was re-positioned. Five patients elected to remove the device and returned to alpha blocker therapy. Seven patients underwent TURP. One patient developed a bulbar urethral stricture. CONCLUSIONS: The butterfly device is simple and efficient minimally invasive device for the management of LUTS due to BPH with a low complication rate, comparable to other minimally invasive devices, and good tolerability. Source of Funding: Butterfly Medical - Yokneam, Israel © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e359-e359 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ran Katz More articles by this author Ali Safadi More articles by this author Muhamad Abu Ahmed More articles by this author Shmuel Roizman More articles by this author Amnon Zisman More articles by this author Maharan Kabha More articles by this author Yoram Dekel More articles by this author Jack Baniel More articles by this author shachar Aharoni More articles by this author Expand All Advertisement PDF downloadLoading ...

MP64-01 PREDICTING RISK OF SIDE-SPECIFIC EXTRAPROSTATIC EXTENSION IN MEN WITH PROSTATE CANCER USING EXPLAINABLE ARTIFICIAL INTELLIGENCE

You have accessJournal of UrologyProstate Cancer: Localized: Surgical Therapy VI (MP64)1 Sep 2021MP64-01 PREDICTING RISK OF SIDE-SPECIFIC EXTRAPROSTATIC EXTENSION IN MEN WITH PROSTATE CANCER USING EXPLAINABLE ARTIFICIAL INTELLIGENCE Jethro Kwong, Adree Khondker, Christopher Tran, Emily Evans, Amna Ali, Munir Jamal, Thomas Short, Frank Papanikolaou, John Srigley, and Andrew Feifer Jethro KwongJethro Kwong More articles by this author , Adree KhondkerAdree Khondker More articles by this author , Christopher TranChristopher Tran More articles by this author , Emily EvansEmily Evans More articles by this author , Amna AliAmna Ali More articles by this author , Munir JamalMunir Jamal More articles by this author , Thomas ShortThomas Short More articles by this author , Frank PapanikolaouFrank Papanikolaou More articles by this author , John SrigleyJohn Srigley More articles by this author , and Andrew FeiferAndrew Feifer More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002104.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Current machine learning (ML) models are limited by poor interpretability, precluding their routine use in planning nerve-sparing at radical prostatectomy (RP). We aimed to leverage explainable artificial intelligence techniques to provide accurate, interpretable, and personalized predictions for side-specific extraprostatic extension (ssEPE). METHODS: A retrospective sample of 900 prostatic lobes (450 patients) from RP specimens at our institution between 2010 and 2020, was used as the training cohort. Features (ie: variables) included patient demographics, clinical, sonographic, and site-specific data from transrectal ultrasound-guided prostate biopsy. The label (ie: outcome) of interest was the presence of ssEPE in the prostatectomy specimen. A ten-fold stratified cross-validation method was performed to train a gradient-boosted model, optimize hyperparameters, and for internal validation. Our model was further externally validated using a testing cohort of 122 lobes (61 patients) from RP specimens at a separate institution between 2016 and 2020. An existing model from the literature which has the highest performance for predicting ssEPE was selected as the baseline model for comparison. Discriminative capability was quantified by area under receiver-operating-characteristic (AUROC) and precision-recall curve (AUPRC). Clinical utility was determined by decision curve analysis. Shapley Additive exPlanations were used to interpret the ML model’s predictions. RESULTS: The incidence of ssEPE in the training and testing cohorts were 30.7 and 41.8%, respectively. Our model outperformed the baseline model with a mean AUROC of 0.81 vs 0.75 (p<0.01) and mean AUPRC of 0.69 vs 0.60, respectively, on cross-validation of the training cohort. Similarly, our model performed favourably on the testing cohort with an AUROC of 0.81 vs 0.76 (p=0.03) and AUPRC of 0.78 vs 0.72. On decision curve analysis, our model achieved a higher net benefit for threshold probabilities between 0.15 to 0.65. A web application incorporating our model was developed in which de-identified patient data can be inputted to generate an individualized ssEPE prostate map with annotated explanations to highlight which features had the greatest impact on model predictions (www.ssepe.ml). CONCLUSIONS: We have developed a user-friendly application that enables physicians without prior ML experience to assess ssEPE risk and understand the factors driving these predictions to aid surgical planning and patient counselling. Source of Funding: None © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1110-e1110 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Jethro Kwong More articles by this author Adree Khondker More articles by this author Christopher Tran More articles by this author Emily Evans More articles by this author Amna Ali More articles by this author Munir Jamal More articles by this author Thomas Short More articles by this author Frank Papanikolaou More articles by this author John Srigley More articles by this author Andrew Feifer More articles by this author Expand All Advertisement Loading ...

Translational Development of a Zr-89-Labeled Inhibitor of Prostate-specific Membrane Antigen for PET Imaging in Prostate Cancer

PurposeWe present here a Zr-89-labeled inhibitor of prostate-specific membrane antigen (PSMA) as a complement to the already established F-18- or Ga-68-ligands.ProceduresThe precursor PSMA-DFO (ABX) was used for Zr-89-labeling. This is not an antibody, but a peptide analogue of the precursor for the production of [177Lu]Lu-PSMA-617. The ligand [89Zr]Zr-PSMA-DFO was compared with [68Ga]Ga-PSMA-11 and [18F]F-JK-PSMA-7 in vitro by determination of the Kd value, cellular uptake, internalization in LNCaP cells, biodistribution studies with LNCaP prostate tumor xenografts in mice, and in vivo by small-animal PET imaging in LNCaP tumor mouse models. A first-in-human PET was performed with [89Zr]Zr-PSMA-DFO on a patient presenting with a biochemical recurrence after brachytherapy and an ambiguous intraprostatic finding with [18F]F-JK-PSMA-7 but histologically benign cells in a prostate biopsy 7 months previously.Results[89Zr]Zr-PSMA-DFO was prepared with a radiochemical purity ≥ 99.9% and a very high in vitro stability for up to 7 days at 37 °C. All radiotracers showed similar specific cellular binding and internalization, in vitro and comparable tumor uptake in biodistribution experiments during the first 5 h. The [89Zr]Zr-PSMA-DFO achieved significantly higher tumor/background ratios in LNCaP tumor xenografts (tumor/blood: 309 ± 89, tumor/muscle: 450 ± 38) after 24 h than [68Ga]Ga-PSMA-11 (tumor/blood: 112 ± 57, tumor/muscle: 58 ± 36) or [18F]F-JK-PSMA-7 (tumor/blood: 175 ± 30, tumor/muscle: 114 ± 14) after 4 h (p < 0.01). Small-animal PET imaging demonstrated in vivo that tumor visualization with [89Zr]Zr-PSMA-DFO is comparable to [68Ga]Ga-PSMA-11 or [18F]F-JK-PSMA-7 at early time points (1 h p.i.) and that PET scans up to 48 h p.i. clearly visualized the tumor at late time points. A late [89Zr]Zr-PSMA-DFO PET scan on a patient with biochemical recurrence (BCR) had demonstrated intensive tracer accumulation in the right (SUVmax 13.25, 48 h p.i.) and in the left prostate lobe (SUV max 9.47), a repeat biopsy revealed cancer cells on both sides.Conclusion[89Zr]Zr-PSMA-DFO is a promising PSMA PET tracer for detection of tumor areas with lower PSMA expression and thus warrants further clinical evaluation.

Urodynamic Effects of Prostatic Urethral Lift Procedure for Male Voiding Lower Urinary Tract Symptoms.

Aims: Primary objective is to investigate whether prostatic urethral lift (PUL) results in an improvement of urodynamic parameters that define bladder outlet obstruction (urethral resistance algorithm [urethral resistance factor (URA)], Schäfer grade, detrusor pressure at maximum flow [PdetQmax], and detrusor pressure at bladder opening [PdetOpen]). Materials and Methods: Twenty patients (main inclusion criteria: ≥50 years of age, benign prostatic obstruction (BPO), international prostate symptom score (IPSS) ≥13, prostate volume ≤60 mL, and no middle prostate lobe) were enrolled in the study and a PUL was performed. Patients underwent urodynamic investigation and filled out the IPSS and quality of life (QoL) before and after PUL. A paired t-test was used to analyze the results. Results: The mean age was 68 years (range 55-79), mean prostate volume (TRUS) was 45 mL (range 20-59), and mean prostate-specific antigen was 2.0 μg/L (0.2-4.4). IPSS of the 16 patients reduced significantly (from 22.20 to 14.47, p = 0.000). Qmax during pressure flow study improved significantly (from 4.5 to 7.2 mL/s, p = 0.001), no significant difference was found in Qmax during free uroflowmetry. There was no significant difference found in postvoiding residual. URA decreased significantly post-treatment (from 52 to 37 cmH2O, p = 0.000). The Schäfer obstruction plot decreased significantly (from 3.5 to 2.6, p = 0.022). Seven patients underwent Greenlight Laser Vaporization of the prostate after the PUL attributable to unsatisfactory results. Conclusions: PUL has desobstructive effects, but they seem clinically modest. The procedure improves urodynamic parameters as well as QoL in males with lower urinary tract symptoms based on BPO. However, the mechanism how PUL leads to a remarkable symptom relief remains unclear and cannot be explained by the desobstructive mechanisms we observed.

Suppressive Effect and Molecular Mechanism of Houttuynia cordata Thunb. Extract against Prostate Carcinogenesis and Castration-Resistant Prostate Cancer.

Simple SummaryThis study explored the chemopreventive effects of Houttuynia cordata Thunb. (HCT) extracts against prostate carcinogenesis in both androgen-sensitive prostate cancer and castration-resistant prostate cancer (CRPC) using the Transgenic Rat for Adenocarcinoma of Prostate (TRAP) model, CRPC xenograft mice, and prostate cancer cell lines. HCT suppressed cell proliferation and stimulated apoptosis via inactivation of AKT/ERK/MAPK in both androgen-sensitive prostate cancer and CRPC cell lines. HCT also inhibited cell migration and EMT phenotypes through the STAT3/Snail/Twist pathway. One of the active compounds of HCT was identified as rutin. Consistent with in vitro study, the incidence of adenocarcinoma in the TRAP model and CRPC tumor growth in the xenograft model were suppressed by induction of apoptosis and inactivation of AKT/ERK/MAPK by HCT intake. Our data demonstrated that HCT attenuated androgen-sensitive prostate cancer and CRPC by mechanisms that may involve inhibition of cell growth and caspase-dependent apoptosis pathways.Houttuynia cordata Thunb. (HCT) is a well-known Asian medicinal plant with biological activities used in the treatment of many diseases including cancer. This study investigated the effects of HCT extract and its ethyl acetate fraction (EA) on prostate carcinogenesis and castration-resistant prostate cancer (CRPC). HCT and EA induced apoptosis in androgen-sensitive prostate cancer cells (LNCaP) and CRPC cells (PCai1) through activation of caspases, down-regulation of androgen receptor, and inactivation of AKT/ERK/MAPK signaling. Rutin was found to be a major component in HCT (44.00 ± 5.61 mg/g) and EA (81.34 ± 5.21 mg/g) in a previous study. Rutin had similar effects to HCT/EA on LNCaP cells and was considered to be one of the active compounds. Moreover, HCT/EA inhibited cell migration and epithelial-mesenchymal transition phenotypes via STAT3/Snail/Twist pathways in LNCaP cells. The consumption of 1% HCT-mixed diet significantly decreased the incidence of adenocarcinoma in the lateral prostate lobe of the Transgenic rat for adenocarcinoma of prostate model. Similarly, tumor growth of PCai1 xenografts was significantly suppressed by 1% HCT treatment. HCT also induced caspase-dependent apoptosis via AKT inactivation in both in vivo models. Together, the results of in vitro and in vivo studies indicate that HCT has inhibitory effects against prostate carcinogenesis and CRPC. This plant therefore should receive more attention as a source for the future development of non-toxic chemopreventive agents against various cancers.

Abstract 1760: Role of Batf-dependant Th17 immune response in PTEN-null mouse model

Abstract Basic leucine zipper transcription factor ATF-like (BATF) belongs to the activator protein 1 (AP-1) family of transcription factors and has been shown to be predominantly expressed in cells of hematopoietic origin, especially in T cells. Mice deficient for BATF were first described to lack T helper cell type 17 (Th17). Th17 cells are a distinct lineage of CD4+ T helper cells that provide protective immunity to infections but are also involved in chronic inflammation and autoimmunity. However, the role of Th17 response in prostate cancer remains controversial. In this study, we took a genetic approach to explore the role of BATF-dependent Th17 cells in prostate cancers by interbreeding BATF-deficient (Batf-/-) mice with mice that are conditionally mutant for PTEN, an established preclinical model for prostate cancer. Batf+/+;Pten-/- and Batf+/-;Pten-/- mice presented similar prostate phenotypes thus were put into one group (named Batf+), which were compared to the Batf-/-;Pten-/- group (named Batf-). We found that Batf- prostates were clearly smaller than Batf+ prostates at 30 weeks. The genitourinary bloc weight was significantly heavier in Batf+ mice than in Batf- mice at 12 and 30 weeks. Batf+ mice developed significantly higher percent of invasive adenocarcinomas in different prostate lobes at 9, 12, and 30 weeks, respectively compared to Batf- mice. Tumors in Batf- mice exhibited lower rates of cellular proliferation and higher apoptosis, as well as reduced inflammatory cell infiltration and angiogenesis in the prostatic stroma. Moreover, Batf- mice exhibited significantly reduced mRNA and protein levels of Th17 cytokines, AP-1 family members and IL-23R, and reduced NF-kB pathway activity in both spleen and prostate tissues. CD4+ T cells from Batf- mice cultured under Th17 conditions for 4 days, expressed reduced AP-1 family-regulated genes compared to Batf+ mice. Prostate cancer cells (LNCaP) with overexpression of BATF in vitro exhibited increased IL-23R expression. Prostate tissues from Batf- mice cultured under IL-6 or Th17 conditions for 4 days had reduced IL-23R expression compared to that from Batf+ mice. Taken together, our results suggest that Batf promotes the initiation and progression of prostate adenocarcinoma via Th17-mediated inflammatory immune responses and that the Batf-IL-23-IL-17 axis is a critical pathway that is needed for prostate adenocarcinoma development and progression. This work was supported by the NIH-National Institute of General Medical Sciences COBRE on Aging and Regenerative Medicine (P20GM103629, PD: S. Michal Jazwinski; PI: Q.Z.) and the Carol Lavin Bernick Faculty Grant from Tulane University (PI: Q.Z.). Citation Format: Qiuyang Zhang, Sen Liu, Bing Zhang. Role of Batf-dependant Th17 immune response in PTEN-null mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1760.

Abstract 2497: Inositol Polyphosphate 4-Phosphatase Type-II B protects mice from benign prostatic hyperplasia

Abstract BPH is the most common tumor-like condition that afflicts more than 50% of men between the ages of 51-60 and over 90% in men older than 80. While connection between obesity and BPH is well established, the driving signaling pathways are not clear. BPH is a nonmalignant enlargement of prostate epithelium that requires androgen receptor (AR) signaling. INPP4B and EZH2 are highly expressed in prostate epithelium where they regulate AR signaling and play an important role in prostate cancer etiology. EZH2 is an epigenetic silencer that methylates histone H3 on K9 and K27 residues and INPP4B is a dual specificity phosphatase that dephosphorylates PI(3,4)P2 and PI(4,5)P2, membrane lipids that activate Akt and PKC signaling pathways respectively. We discovered that Inpp4b-/- male mice develop BPH at 3 months old of age and subsequently prostate intraepithelial neoplasia (PIN) when fed high fat diet. While expression of AR in the prostates of these mice is similar, AR activity is reduced. The loss of INPP4B caused reduction in EZH2 protein levels in prostate cancer cell lines and in mouse prostate. Inhibition of Akt and PKC signaling reduced EZH2 levels in ventral and dorsolateral prostate lobes of Inpp4b-/- males, suggesting that INPP4B upregulates EZH2 levels by suppressing Akt and PKC signaling pathways. Consistent with decline in EZH2 levels, Inpp4b-/- males have reduced levels of H3K27me3 and H3K9me2 in the ventral prostate, and high fat diet exacerbated this phenotype. Our data suggests that INPP4B modulates epigenetic profile of prostate epithelium by stabilizing EZH2 levels. Both loss of INPP4B and high fat diet treatment lead to decline in EZH2 levels and activity and contribute to development of BPH in mouse model. Citation Format: Yasemin Ceyhan, Manqi Zhang, Irina U. Agoulnik. Inositol Polyphosphate 4-Phosphatase Type-II B protects mice from benign prostatic hyperplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2497.

Pesticide Dichlorvos Promotes Morphological Alternations in the Rat Prostate

The complex process of carcinogenesis can be modulated by the action of environmental endocrine disruptors, such as the organophosphate pesticide Dichlorvos (DDVP), capable of interfering in homeostasis of different organs and leading to the development of neoplastic lesions. Considering that prostate cancer is the second most common neoplasm in men, worldwide, it is emphasized the importance of studying morphological alterations using animal models. In rodents, tumor initiation can be induced by the carcinogen N-methyl-N-nitrosourea (MNU) and tumor promotion can be stimulated by the administration of testosterone, combinated or not with the use of pesticides. The present study aimed to evaluate the influence of DDVP on the development of morphological alterations in the ventral prostate of rats, after chemical induction by MNU. Thereunto, 32 Fischer 344 rats, aged 90 days, were randomly separated into four experimental groups: Control, DDVP, MNU, MNU+DDVP. For chemical induction, the MNU and MNU+DDVP groups were inoculated with MNU (15 mg/kg), followed by daily subcutaneous injections of testosterone cypionate (2.5 mg/kg), for 20 days. Animals of the DDVP and MNU+DDVP groups, from 120 to 240 days old, received the basal diet supplemented with 10 mg/kg of DDVP. Subsequent to the experimental period, the prostatic ventral lobe of each animal was collected and subjected to morphometric-stereological and histopathological analysis, for the classification of the lesions found. The incidence of alterations in epithelium and stroma of all experimental groups was evaluated, such as epithelial hyperplasia (increased cell population with stratification, without atypia) (Figure A and B); atrophy (retraction of the epithelium with reduction of the secretory cytoplasm) (Figure C and D); periacinary inflammatory foci (presence of inflammatory cell infiltrate) (Figure E and F); cell atypia with presence of cytoplasmic inclusions (Figure G and H) and metaplasia with stromal hyperplasia (change in the pattern of the original epithelium without proliferative change, with an increase in the adjacent stroma) (Figure I to L). The results showed a significant increase of epithelial hyperplasia areas in MNU and MNU+DDVP groups, with 100% of the animals showing this lesion (Table 1), which demonstrates a relation between chemical induction and the proliferative process. The morphometric-stereological analysis confirmed this finding, revealing a relatively greater volume of the epithelial compartment in MNU+DDVP, compared to the Control group (Table 2). Thus, it can be concluded that DDVP, even in low concentration, associated with chemical induction by MNU, was able to disturb the morphology of the ventral prostate, promoting proliferative epithelial lesions, strongly associated with the process of carcinogenesis.

Effect of Moderate and High Intensity Exercise on Hypoxia and Radiosensitivity in Tumor‐Bearing Rats

Background Prostate tumors typically have hypoxic regions that are resistant to traditional radiation therapy. Prior evidence from our laboratory has demonstrated improved perfusion and reduced hypoxia of prostate tumors with moderate intensity exercise training; such changes have potential to enhance radiation therapy. However, there is a dearth of evidence for the magnitude of alterations of intra-tumor hypoxia markers with exercise, as well as the ideal intensity of exercise for combating hypoxia in solid tumors. Using a pre-clinical orthotopic model of prostate cancer, we tested the hypothesis that exercise training at both moderate and high intensities would result in a decrease in hypoxia assessed via immunohistochemical analysis of hypoxic markers. Further, that enhanced radiotherapy responses would occur in exercise trained tumor bearing animals compared to sedentary counterparts. Methods Immunocompetent male Copenhagen rats aged 6 months (n=48) were injected orthotopically (ventral lobe of prostate) with 1x105 Dunning R-3327 AT-1 prostate adenocarcinoma cells. All animals were first acclimated to treadmill exercise and randomized into three groups: tumor bearing sedentary (TBS, n=20), moderate intensity training, (TBMIT, n=12), or high intensity training (TBHIT, n=16). After 7 days of recovery from surgery, both exercise groups began progressive exercise training on a motorized treadmill at either 20/min with a 5% incline, or 30m/min 15% incline for 10 minutes a day progressing to 60 min/day for TBMIT and TBHIT, respectively, for approximately 5 weeks. Immunohistochemical analysis and whole-body ionizing radiation (2 Gy) were performed at the end of the 5-week period of training followed by clonogenic cell survival assay to assess survival fraction. Results There were no significant differences (p>0.05) in tumor mass between groups (TBS 7.8±1.1; TBMIT 7.2±1.3; TBHIT 6.4±0.9 g). Overall expression levels of hypoxia inducible factor 1-alpha (HIF-1a, n=40) were significantly greater in the TBS group vs both the TBMIT and TBHIT (TBS 37.9±7.4; TBMIT 25.5±6.1; TBHIT 14.4±5.7%, p<0.05), with a trend for increased expression in TBMIT vs TBHIT (p=0.059). The survival fraction (n=8) was also significantly higher in TBS when compared to both TBMIT and TBHIT (TBS 39.9±5.3; TBMIT 23.2±3.2; TBHIT 20.7±4.9%, p<0.05). Conclusion This study suggests that compared to sedentary counterparts, both chronic moderate and high intensity exercise training modify the tumor microenvironment (decreased levels of HIF-1a) favorably. Given exercise therapy is becoming increasingly recommended to mitigate fatigue and increase quality of life in patients, a potential therapeutic component could add to the efficacy of exercise prescription in a clinical setting.

Feasibility, safety, and efficacy of ultrasound-guided transperineal laser ablation for the treatment of benign prostatic hyperplasia: a single institutional experience.

To evaluate the feasibility, safety, and efficacy of ultrasound-guided transperineal laser ablation (TPLA) as a new minimally invasive surgical therapy (MIST) for the treatment of lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH). Under local anesthesia and conscious sedation up to two laser fibers for each prostatic lobe were inserted under US-guidance by a percutaneous approach. TPLA was performed using a continuous wave diode laser (SoracteLite-EchoLaserX4) able to generate a light-induced thermal heating and subsequent coagulative necrosis of the prostatic tissue. Patients were evaluated at 3, 6, and 12months after TPLA. Twenty-two consecutive patients were prospectively enrolled (median age 61.9years). All procedures were well tolerated and no procedural complications were recorded. Median catheterization time was 7days, while the median hospitalization time was 1day. Three out of twenty-two patients (13.6%) experienced acute urinary retention and two (9.1%) of them urinary tract infection requiring major antibiotic treatment. At 3, 6, and 12months, median prostate volume significantly decreased by a -21.3%, -29%, and -41%, respectively. At the same time point, median IPSS was 8 (-63.6%), 5 (-74%), and 6 (-75%), while median QoL score was 1 in all the scheduled timepoints of follow-up. The median postoperative Qmax at 3, 6, and 12months improved by + 57.8%, + 98%, and + 115.8%, respectively. Ejaculatory function was preserved in 21 out of 22 patients (95.5%). TPLA of the prostate appears to be a promising MIST for BPH. Long-term results and comparative studies against standard treatments are warranted before implementations of this technique in the urologist's armamentarium.

Rare presentation of metastatic adenocarcinoma of prostate as inguinal lymphadenopathy and its management

Prostate cancer is among the top ten cancers in India. Approximately half of patients with prostate cancer have metastasis on presentation, bones and regional lymph nodes being most common. A case of metastasised cancer of prostate presenting only with an inguinal mass without any other symptom is rare. A 72-year-old presented with a right inguinal mass for six months without any other complaints. Biopsy of the inguinal mass was done, and histopathology showed metastatic adenocarcinoma. His serum PSA (prostate specific antigen) was 117.325 ng/ml. PET CT (positron emission tomography-computed tomography) showed PSMA (prostate specific membrane antigen) expressing lesion in left lobe of prostate involving left seminal with metastatic pelvic, right inguinal, retroperitoneal and mediastinal adenopathy with increased tracer uptake in sclerotic skeletal lesions in right iliac bone, acetabulum and right femoral shaft. TRUS (trans rectal ultra-sonography) guided biopsy of prostate (12 CORE) was performed and showed conventional prostatic adenocarcinoma with maximum Gleason score 4+4=8, grade group IV. The patient's clinical stage was T3b N1 Mb. Patient is currently on abiraterone with degarelix with normal repeat serum PSA (0.067 ng/ml) on follow up at 5 months. Metastatic prostatic carcinoma usually presents with iliac nodes or bony metastasis, but rarely they present with inguinal lymphadenopathy and should be dealt with high clinical suspicion as they are already in advanced stage of the disease process.

High-grade tumours promote growth of other less-malignant tumours in the same prostate.

Prostate cancer is a multifocal disease, but if and how individual prostate tumours influence each other is largely unknown. We therefore explored signs of direct or indirect tumour–tumour interactions in experimental models and patient samples. Low‐metastatic AT1 and high‐metastatic MatLyLu (MLL) Dunning rat prostate cancer cells were injected into separate lobes of the ventral prostate of immunocompetent rats. AT1 tumours growing in the same prostate as MLL tumours had increased tumour size and proliferation compared to AT1 tumours growing alone. In addition, the vasculature and macrophage density surrounding the AT1 tumours were increased by MLL tumour closeness. In patient prostatectomy samples, selected to contain an index tumour [tumour with the highest grade, International Society of Urological Pathology (ISUP) grade 1, 2, 3 or 4] and a low‐grade satellite tumour (ISUP grade 1), cell proliferation in low‐grade satellite tumours gradually increased with increasing histological grade of the index tumour. The density of blood vessels and CD68+ macrophages also increased around the low‐grade satellite tumour if a high‐grade index tumour was present. This suggests that high‐grade tumours, by changing the prostate microenvironment, may increase the aggressiveness of low‐grade lesions in the organ. Future studies are needed to explore the mechanisms behind tumour–tumour interactions and their clinical importance. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.

A Prospective Study on [68Ga]-PSMA PET/CT Imaging in Newly Diagnosed Intermediate- and High-Risk Prostate Cancer.

Prostate-specific membrane antigen (PSMA) ligand positron emission tomography/computed tomography (PET/CT) is an emerging modality to detect metastatic disease in patients with prostate cancer (PCa). This prospective study aimed to evaluate the role of [68Ga]-PSMA PET/CT in the initial workup of intermediate and high-risk PCa. Twenty-five patients with newly transrectal ultrasound biopsy-proven, untreated intermediate- and high-risk PCa (mean age, 68.5±6.2 years; range 55-83 years) were enrolled in this prospective study between September 2018 and June 2020 and underwent a [68Ga]-PSMA PET/CT examination. All images were analyzed both visually and semiquantitatively by measuring the maximum standardized uptake value (SUVmax) of the primary prostatic tumor and metastatic lesions. The diagnostic sensitivity of [68Ga]-PSMA PET/CT for the diagnosis of PCa was established by histopathology as the reference standard. The associations between SUVmax of the primary tumors and prostate-specific antigen (PSA) levels, Gleason scores (GSs), and metastatic extent of the disease were studied. All patients had a positive [68Ga]-PSMA PET/CT exam. Seventeen patients (58%) showed [68Ga]-PSMA avidity in both prostate lobes and 8 (32%) had unilateral uptake. SUVmax in the primary tumor significantly correlated with serum PSA values (r=0.57, P=0.003). PSMA PET/CT depicted regional lymph node metastases in 32% of patients, distant lymph node metastases in 20%, osseous metastases in 16% and pulmonary metastases in 8% of patients. Sixty percent of PSMA-positive bone metastases and 21.4% of intraprostatic tumoral lesions were missed on the contemporaneous bone scintigraphy and magnetic resonance imaging, respectively. [68Ga]-PSMA PET/CT shows promise as a valuable imaging modality with high diagnostic sensitivity in the setting of intermediate and high-risk PCa. Moreover, the SUVmax of the primary tumor has a positive correlation with PSA levels at the time of the scan.

Preserving ejaculatory function in young patients with lower urinary tract symptoms: medium- to long-term follow-up of prostatic urethral lift at a single center.

Background and aims:Prostatic urethral lift (Urolift™) is a minimally invasive technique to treat male lower urinary tract symptoms (LUTSs) due to benign prostatic hyperplasia (BPH). The aim of the present study was to assess safety and medium- to long-term outcomes in the relief of urinary symptoms.Methods:We included 35 men, affected by severe symptomatic BPH evaluated by International Prostate Symptom Score (IPSS), with normal erectile function (EF) and ejaculatory function (EjF) evaluated by the International Index of Erectile Dysfunction (IIEF-5) and Male Sexual Health Questionnaire for Ejaculatory Dysfunction (MSHQ-EjD-SF). Exclusion criteria were prostate larger than 70 cm3, bladder neck sclerosis, concomitant third prostatic lobe, and/or other cervical urethral obstruction or cancer. All patients, preoperatively, performed uroflowmetry (UFM) with peak flow (Q-max) and post void residual volume (PVR), digital rectal exam, transrectal prostate ultrasound to measure prostate volume, PSA, and cystoscopy. Follow-up was scheduled at 1–3–6 months, then yearly, evaluating UFM, IPSS, IIEF-5, and MSHQ-EjD-SF.Results:All procedures were performed by a single senior surgeon and follow-up was 33.8 ± 12 months. Preoperative PSA was 0.82 ± 0.4 ng/ml and mean operative time was 19.6 ± 10 min and 3 (2–4) implants per patient were used. Parameters reported at last follow-up schedule were: Q-max increase of 68% (p = 0.001), PVR reduction 68% (p = 0.005), and IPSS reduction 55% (p < 0.0001). EF and EjF were similarly preserved, and no patients presented retrograde ejaculation. A total of 88.6% of patients were satisfied with LUTSs improvement and 100% satisfied with EjF.Conclusion:Urolift can improve urinary disorders secondary to BPH, preserving EjF and EF. It is a safe and easy method, reproducible, and with low incidence of complications. Careful selection of patients is mandatory. The main reason for dissatisfaction is the higher expectation of better BPH symptoms relief although patients with high bladder neck and/or prostate volume >45 cm3 were aware of the possible failure.

Can cavernous nerves be spared after radical prostatectomy? Evidence from animal studies

Purpose: The current study aims at evaluating penile erectile function after nerve-sparing radical prostatectomy (RP) based on evidence from a reliable animal model. The previous model in which the cavernous nerve (CN) is temporarily crushed is reviewed and compared to the present method of prostate lobes removal near the CN to determine which is more relevant to the clinical situation. Materials and Methods: Twenty-four rats were divided into three groups. One group was subjected to temporary CN crushing, one group was subject to prostate lobes removal near the CN, and the last group was preserved (sham group). All rats were re-examined at 4 weeks after the first surgical procedure. The pathological changes of the CNs were evaluated by their gross appearance and immunohistochemistry. Intracavernosal pressure (ICP) was measured as a parameter of male erectile function. Results: The results of the current study demonstrate that the removal of the prostate lobes near the CN led to the degeneration of CN, even with careful sparing techniques. Four weeks after the first surgical procedure, the rats' abdomens were reopened, and CNs were identified in only 60% of the rats with prostate lobes removal near the CN. Furthermore, the remaining CNs in this group were found to be histologically degenerated, with poorer erectile function presented by ICP. In contrast, the CNs after temporary crush were only mildly injured and demyelinated, with evidence of regeneration. The changes in the rats with prostate lobes removal near the CN are much more similar to those in rats with clinical RP with CN sparing. Conclusion: The current study concluded that, in the rat model, CNs will be injured, degenerated, and eventually disappear after prostate lobes removal near the CN; this is very similar to what is observed in clinical RP. Protection of the CNs for erectile function preservation should be investigated further using this animal model.

External validation of a magnetic resonance imaging-based algorithm for prediction of side-specific extracapsular extension in prostate cancer.

IntroductionRecently developed algorithm for prediction of side-specific extracapsular extension (ECE) of prostate cancer required validation before being recommended to use. The algorithm assumed that ECE on a particular side was not likely with same side maximum tumor diameter (MTD) <15 mm AND cancerous tissue in ipsilateral biopsy <15% AND PSA <20 ng/mL (both sides condition). The aim of the study was to validate this predictive tool in patients from another department.Material and methodsData of 154 consecutive patients (308 prostatic lateral lobes) were used for validation. Predictive factors chosen in the development set of patients were assessed together with other preoperative parameters using logistic regression to check for their significance. Sensitivity, specificity, negative and positive predictive values were calculated for bootstrapped risk-stratified validation dataset.ResultsValidation cohort did not differ significantly from development cohort regarding PSA, PSA density, Gleason score (GS), MTD, age, ECE and seminal vesicle invasion rate. In bootstrapped data set (n = 200 random sampling) algorithm revealed 70.2% sensitivity (95% confidence interval (CI) 58.8–83.0%), 49.9% specificity (95%CI: 42.0–57.7%), 83.9% negative predictive value (NPV; 95%CI: 76.1–91.4%) and 31.1% positive predictive value (PPV; 95%CI: 19.6–39.7%). When limiting analysis to high-risk patients (Gleason score >7) the algorithm improved its performance: sensitivity 91%, specificity 47%, PPV 53%, NPV 89%.ConclusionsAnalyzed algorithm is useful for identifying prostate lobes without ECE and deciding on ipsilateral nerve-sparing technique during radical prostatectomy, especially in patients with GS >7. Due to significant number of false positives in case of: MTD ≥15 mm OR cancer in biopsy ≥15% OR PSA ≥20 ng/mL additional evaluation is necessary to aid decision-making.

Mitochondrial Dysfunction and Cellular Senescence Due to Aging Contributes to Prostatic Fibrosis

Aging is the single largest risk factor for many common diseases that burden public health. This is especially true in the prostate; as men age, the prostate undergoes a prototypical aging change, fibrosis. The aged fibrotic prostate causes urinary symptoms which will afflict nearly every man if they live long enough. However, the molecular mechanisms responsible for the aging-dependent promotion of fibrosis are largely unknown and understudied. In this study, we sought to reveal the contribution of mitochondrial dysfunction to fibrosis in the aging prostate, ultimately leading to prostate dysfunction, urinary symptoms, and overall poor health. The demise of mitochondrial function is well established in other aging-associated diseases but has not been investigated in the prostate. Our analysis revealed an increase in cellular senescence and mitochondrial dysfunction in BPH patient tissue compared to normal prostates. Furthermore, selective inhibition of mitochondrial complex I by rotenone in cultured human prostate fibroblasts led to myofibroblast phenoconversion as characterized by increased expression of Col1a1, Col3a1, and ACTA2. To determine the contribution of mitochondrial dysfunction on fibrosis and lower urinary tract dysfunction (LUTD), we examined the prostate lobes in both aging and steroid-induced LUTD in mice. These models have been extensively characterized and exhibit an age-mediated increase in LUTD and fibrosis. We observed a decrease in mitochondrial function and an increase in cellular senescence corresponding to an increase in fibrosis and LUTD. This suggests that normal aging-dependent reductions in mitochondrial complex I function in the prostate may promote fibrosis and contribute to urinary dysfunction.

Genetic ablation of FASN attenuates the invasive potential of prostate cancer driven by Pten loss.

Loss of the tumor suppressor gene Pten in murine prostate recapitulates human carcinogenesis and causes stromal proliferation surrounding murine prostate intraepithelial neoplasia (mPIN), which is reactive to microinvasion. In turn, invasion has been shown to be regulated in part by de novo fatty acid synthesis in prostate cancer. We therefore investigated the effects of genetic ablation of Fasn on invasive potential in prostate‐specific Pten knockout mice. Combined genetic ablation of Fasn and Pten reduced the weight and volume of all the prostate lobes when compared to single knockouts. The stromal reaction to microinvasion and the cell proliferation that typically occurs in Pten knockout were largely abolished by Fasn knockout. To verify that Fasn knockout indeed results in decreased invasive potential, we show that genetic ablation and pharmacologic inhibition of FASN in prostate cancer cells significantly inhibit cellular motility and invasion. Finally, combined loss of PTEN with FASN overexpression was associated with lethality as assessed in 660 prostate cancer patients with 14.2 years of median follow‐up. Taken together, these findings show that de novo lipogenesis contributes to the aggressive phenotype induced by Pten loss in murine prostate and targeting Fasn may reduce the invasive potential of prostate cancer driven by Pten loss. © 2020 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd. on behalf of The Pathological Society of Great Britain and Ireland.