Surgical Castration Research Articles

Abstract 4239: Alternate-day fasting enhances the activity of anti-androgen therapy in prostate cancer models

Abstract Prostate cancer (PCa) is the most common cancer diagnosed in men in the Western countries. Epidemiological studies have suggested that environmental factors such as the Western diet, characterized by the consumption of high caloric food containing large amounts of animal protein and fats, play a key role in the pathogenesis of PCa. We propose that dietary intervention, by reducing caloric or protein intake, may be beneficial for the treatment of PCa. Our previous data suggests that dietary protein restriction reduces tumor growth in a LuCaP23.1 patient-derived xenograft (PDX) model of PCa. Thus, we tested the hypothesis whether caloric restriction induced by alternate-day fasting has a similar effect. Interestingly, caloric restriction had antitumor activity in the LuCaP23.1 model but only alternate-day fasting reduced the expression of androgen receptor (AR), a major driver of PCa growth. Therapies targeting AR activity, termed androgen deprivation therapies including the AR antagonist enzalutamide (ENZ), are the current standard of care for PCa. To address the therapeutic potential of combining alternate-day fasting with anti-androgens, we utilized the syngeneic mouse PCa xenograft models MyC-CaP and PTEN−/− RB−/−, and the human LuCaP23.1 PDX model. These AR-positive xenograft models harbor the oncogenic drivers most frequently found in PCa (i.e., MYC amplification and loss of the tumor suppressor PTEN). Here, we show that alternate-day fasting enhances the activity of ENZ in these PCa xenograft models. Interestingly, the combination of alternate-day fasting with ENZ treatment reduced AR expression and signaling, and decreased proliferation and tumor growth as compared to either single treatment alone. Consistent with these findings, the reduction of AR activity by the depletion of endogenous androgens following surgical castration was enhanced with alternate-day fasting. Conversely, dietary protein restriction had no effect in combination ENZ in vivo, suggesting that modulation of AR by alternate-day fasting enhances the effect of anti-androgens. Transcriptomic analysis of tumors from fasted mice confirmed decreased AR transcriptional activity and revealed that several nutrient sensitive pathways were reduced by this dietary regimen, including PI3K/AKT signaling, mTORC1 signaling, and glycolysis. Additionally, we observed that several known factors induced by fasting were upregulated in tumors from fasted mice, including SIRT1 which has been suggested to modulate AR transcriptional activity. In conclusion, we demonstrate that alternate-day fasting reduces AR signaling and enhances the activity of ENZ in several PCa xenograft models. Overall, this study suggests that caloric restriction may improve the efficacy of anti-androgen therapy in PCa patients. Citation Format: Ricardo Cordova, May Elbanna, Angela Klunk, Christopher Rupert, Li Shen, Yanqing Wang, David Goodrich, Ron Wek, Kirk Staschke, Luigi Fontana, Roberto Pili. Alternate-day fasting enhances the activity of anti-androgen therapy in prostate cancer models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4239.

Effects of pharmacological castration on endocrinological and chemical profiles in captive red and fallow deer

In wildlife captive management, contraception is highly desirable due to inbreeding risk and needed control of intra- and inter-specific aggressions. Deer, for which surgical castration can cause abnormal growth of the antlers, are suitable candidates for pharmacological castration. The aim of this study was to evaluate the effect of pharmacological castration on the physiological patterns and volatile chemical profiles of two deer species. We placed a subcutaneous implant of deslorelin acetate (4.7 mg) on four male red deer (Cervus elaphus) and two male fallow deer (Dama dama) (N = 6) living together in a mixed-sex and -species group housed at a wildlife rescue centre in Tuscany, Italy. We combined hormone measurements and chemical investigation of metatarsal scent-gland odour secretions to test whether pharmacological castration will influence the volatile chemical profile, potentially modifying the olfactory communication during the rutting season. We used radioimmunoassay technique to determine faecal and plasma testosterone as well as faecal cortisol levels, and solid-phase microextraction coupled to gas chromatography-mass spectrometry to analyse the scent-gland odour secretions. We found that deer testosterone levels decreased after the subcutaneous deposition of the implant. However, castrated red deer exhibited more variability in testosterone concentrations throughout the study period compared to fallow deer, whose testosterone levels remained low after the implant. We detected a total of 124 (red deer) and 88 (fallow deer) volatile compounds in male scent-gland odour secretions, including naturally occurring ketones, alcohols, aldehydes, terpenes, carboxylic acids, esters, volatile fatty acids, and hydrocarbons. Odour richness, but not total abundance or ratios of compounds, changed with testosterone levels in red deer. In conclusion, our preliminary findings suggest that deslorelin acetate, causing a decrease of testosterone level and impacting the chemical profile of odour secretions, could work as a non-invasive contraception approach in human-managed populations of deer.

MP02-18 CARDIOVASCULAR AND QOL BENEFITS: WHY BILATERAL ORCHIECTOMY SHOULD BE OFFERED TO ALL TRANSFEMININE WOMEN (INCLUDING THOSE AWAITING VAGINOPLASTY SURGERY)

You have accessJournal of UrologyCME1 Apr 2023MP02-18 CARDIOVASCULAR AND QOL BENEFITS: WHY BILATERAL ORCHIECTOMY SHOULD BE OFFERED TO ALL TRANSFEMININE WOMEN (INCLUDING THOSE AWAITING VAGINOPLASTY SURGERY) Robert Victor, Jenna Stelmar, Nance Yuan, Shannon Smith, Grace Lee, and Maurice Garcia Robert VictorRobert Victor More articles by this author , Jenna StelmarJenna Stelmar More articles by this author , Nance YuanNance Yuan More articles by this author , Shannon SmithShannon Smith More articles by this author , Grace LeeGrace Lee More articles by this author , and Maurice GarciaMaurice Garcia More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003213.18AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Transgender women who receive gender-affirming feminizing hormone therapy (GAHT; typically estrogen and an anti-androgen) have been shown to experience significantly higher cardiovascular disease related mortality compared to cis-men. Patients also complain of anti-androgen side effects (urinary frequency). Gender-affirming vaginoplasty (GA-V) surgery includes bilateral orchiectomy, but surgery wait times at high volume centers are 1-4 years. We hypothesized that pre-vaginoplasty gender-affirming bilateral orchiectomy (GA-BO) could offer several specific medical benefits: 1. Reduced baseline estrogen dosage, 2. Cessation of anti-androgen; 3. Greater QOL related to decreased GAHT side effects. METHODS: We performed a retrospective chart review of all patients who underwent GA-BO or GA-V from 4/2017-12/2020 and compared pre- vs. post-op hormone dosages. We also administered a questionnaire to capture patient satisfaction with GAHT side effects. RESULTS: A total of 106 patients underwent GA-BO and 64 underwent GA-V. After GA-BO, all hormone dosages decreased post-op (Figure 1): oral estradiol (-29%; p*<0.001); IM estradiol valerate (-48%; p*<0.001); and oral progesterone (-49%; p*<0.001). There was a greater decrease in hormone dosages after GA-V: oral estradiol dosage, (-44%; p*<0.001); IM estradiol valerate, (-71%; p*<0.001); and progesterone, (-55%; p*<0.03). After both GA-BO and GA-V, all patients (100%) discontinued Spironolactone (p*<0.001), and over 90% reported improved QOL related to elimination of Spironolactone’s diuretic function side effects. CONCLUSIONS: GA-BO offers transfeminine patients the benefits of significantly lower daily GAHT medications and dosages, and improved QOL related to elimination of anti-androgen side effects. Based on these findings, combined with the fact that there is typically a long wait time for GA-V and no observed negative effects of GA-BO on GA-V, we conclude that GA-BO should be offered to all transfeminine patients, either as a stand-alone procedure or as a pre-vaginoplasty surgery option. Source of Funding: Richard Onofrio, MD Research Grant © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e19 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Robert Victor More articles by this author Jenna Stelmar More articles by this author Nance Yuan More articles by this author Shannon Smith More articles by this author Grace Lee More articles by this author Maurice Garcia More articles by this author Expand All Advertisement PDF downloadLoading ...

MP50-12 CLINICOPATHOLOGIC ANALYSIS AND DIGITAL EVALUATION OF ORCHIECTOMY SPECIMENS IN PATIENTS WITH GENDER DYSPHORIA

You have accessJournal of UrologyCME1 Apr 2023MP50-12 CLINICOPATHOLOGIC ANALYSIS AND DIGITAL EVALUATION OF ORCHIECTOMY SPECIMENS IN PATIENTS WITH GENDER DYSPHORIA Ivan De La Riva, Ruoji Zhou, Alcino Gama, Bonnie Choy, Bogdan Isaila, Diana Bowen, Robert Brannigan, and Ximing Yang Ivan De La RivaIvan De La Riva More articles by this author , Ruoji ZhouRuoji Zhou More articles by this author , Alcino GamaAlcino Gama More articles by this author , Bonnie ChoyBonnie Choy More articles by this author , Bogdan IsailaBogdan Isaila More articles by this author , Diana BowenDiana Bowen More articles by this author , Robert BranniganRobert Brannigan More articles by this author , and Ximing YangXiming Yang More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003298.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Gender-affirmation therapy for transgender individuals is an area of increasing importance in genitourinary pathology. These patients undergo various forms of hormonal replacement therapy (HRT) followed by bilateral orchiectomy. To date, there are very limited studies on the histological and biochemical alterations in these testes. METHODS: We conducted a retrospective search of the database for gender-affirming orchiectomies performed at our institution from 2018 to 2022. Clinical features, including age, length and types of hormonal treatment, and pathologic features, were reviewed and summarized. 19 cases were subjected to whole slide imaging scanning for digital analysis using the Leica system. Immunohistochemistry for OCT4 and CD117 was performed on selected cases. RESULTS: Atrophic changes and decreased spermatogenesis were found in all the gender-affirming orchiectomy specimens examined, with decreased mean tubule diameter (102.9 μm, 202 tubules examined) compared to the tubular size of germ cell neoplasia in situ (GCNIS) and normal testis (139.3 μm and 143.7 μm, 326 and 185 tubules examined, respectively). All cases showed significant maturation arrest, with 55 testes showing aspermatogenesis and the remaining 14 testes showing hypospermatogenesis. Various degrees of basement membrane thickening were observed in all testes, and 55.1% of the testes were found to have focal tubule hyalinization/obliteration. The number of Leydig cells was reduced, with marked cytoplasmic vacuolization and degenerative changes. In a subset of specimens, scattered germ cells displayed prominent nucleomegaly. Using digital analysis, the average nuclear size of these abnormal germ cells was 14.4 μm in diameter (35 cells counted), approaching or exceeding the size of the neoplastic nucleus in GCNIS (mean diameter=12.1 μm, 33 cells counted). However, the enlarged nuclei of these germ cells demonstrated a smooth nuclear membrane, small nucleoli, and fine granular and smudged chromatin, significantly different from the nuclei in GCNIS. Furthermore, immunohistochemistry staining of the germ cells with nucleomegaly in tested cases demonstrated negative staining for both OCT4 and CD117, militating again the possibility of GCNIS. CONCLUSIONS: All the testes from gender-affirming orchiectomies in our study exhibit significantly reduced spermatogenesis, including maturation arrest and atrophic changes. In addition, the presence of scattered germ cells with nucleomegaly in these specimens can mimic GCNIS. Source of Funding: NA © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e689 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Ivan De La Riva More articles by this author Ruoji Zhou More articles by this author Alcino Gama More articles by this author Bonnie Choy More articles by this author Bogdan Isaila More articles by this author Diana Bowen More articles by this author Robert Brannigan More articles by this author Ximing Yang More articles by this author Expand All Advertisement PDF downloadLoading ...

Pain Assessment and Acute Phase Response in Donkeys Submitted to Inguinal Orchiectomy.

In most animals, pain can compromise physiological functions and delay healing so, rapid detection of pain through behavior and inflammatory reaction with biomarkers are necessary. This study aimed to evaluate pain, physiological variations and Acute Phase Proteins (APP) in donkeys undergoing orchiectomy technique by inguinal access. For this research, 15 male northeastern donkeys kept in extensive management were selected, with a mean age of 4.5±3.1 years. All animals had the same anesthetic protocol, using dissociative anesthesia and local block with lidocaine, followed by orchiectomy by inguinal access. Due to their predisposition to complications, the inguinal technique is the most indicated to minimize complications and excessive inflammation in donkeys' orchiectomy, the donkeys were evaluated regarding behavioral assessment of pain, hematological parameters, APP and the surgical wound, during 0 hour, 24 hours, 48 hours and 72 hours. As for the physiological parameters and APP, no significant differences were observed between times, due to the use of nonsteroidal antiinflammatory drugs. In the macroscopic evaluation of the surgical wound, it was observed that there were no significant differences between the times, with animals presenting mean scores of 1.8±0.414, in 48 hours 1.6 ± 0.507, and in 72 hours 1.6 ± 0.507. Most animals had mild to moderate edema in the scrotum and foreskin regions. As for pain assessment, the average scores were between 2 and 3, representing mild and moderate pain, not requiring intervention. However, further research is needed to elucidate the behavior of PFAs in the face of variables and the creation of new pain scales for animals raised in an extensive system.

Retroperitoneal germ cell tumor, primary or secondary: A diagnostic conundrum

Abstract Germ cell tumor, seminoma, is the most common cancer in young men’s testis. However, a small subset of tumors (1%–2%) originate in other locations and are referred to as primary extragonadal germ cell tumors. But such type of tumors’ origin is thought to be controversial as a significant bulk may represent metastases from primary occult/regressed testicular germ cell tumors. The entire primary extragonadal germ cell tumor is mostly non-seminomatous and present in higher ages than primary testicular germ cell tumors, most of which are seminoma. A 50-year-old male presented with a brief history of abdominal pain for 10 days. Ultrasonography of his abdomen revealed multiple enlarged retroperitoneal lymph nodes. Biopsy and immunohistochemistry of the left iliac node showed features consistent with metastatic seminoma. Ultrasound of the left testis showed a hypoechoic lesion. Positron emission tomography scan showed increased tracer uptake in both the testes without any abnormal enhancing mass lesion and increased fluorodeoxyglucose uptake in the retroperitoneal lymph nodes. A high left inguinal orchidectomy revealed no tumor but a fibrotic scar tissue showing atrophic and ghost tubules, dense lymphoplasmacytic cells, and increased vascularity, implying regressed (burnt-out) seminoma. Regression of testicular seminoma shows a distinct constellation of findings permitting its diagnosis as a primary testicular tumor, which is imminent from a prognostic and therapeutic perspective.

PD20-04 TRENDS IN PROSTATE CANCER DIAGNOSIS IN TRANSGENDER WOMEN: A NATIONAL STUDY

You have accessJournal of UrologyCME1 Apr 2023PD20-04 TRENDS IN PROSTATE CANCER DIAGNOSIS IN TRANSGENDER WOMEN: A NATIONAL STUDY Farnoosh Nik-Ahd, Amanda De Hoedt, Christi Butler, Jennifer T. Anger, Peter R. Carroll, Matthew R. Cooperberg, and Stephen J. Freedland Farnoosh Nik-AhdFarnoosh Nik-Ahd More articles by this author , Amanda De HoedtAmanda De Hoedt More articles by this author , Christi ButlerChristi Butler More articles by this author , Jennifer T. AngerJennifer T. Anger More articles by this author , Peter R. CarrollPeter R. Carroll More articles by this author , Matthew R. CooperbergMatthew R. Cooperberg More articles by this author , and Stephen J. FreedlandStephen J. Freedland More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003286.04AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Little is known about prostate cancer (CaP) screening and diagnosis in transgender women (TW). To date, only 10 case reports have been published on CaP in this population. In this study, we sought to understand the clinical characteristics and CaP screening history at prostate cancer diagnosis among TW. METHODS: This is a retrospective study of all patients ages 18 and older across the entire Veterans Affairs Health System (VAHS) in the United States from January 2000-February 2022 with both an ICD code for CaP and at least one ICD code related to transgender identity. Detailed chart review was performed to stratify patients by gender-affirming hormone usage. Data abstracted included PSA at diagnosis, consistency of PSA screening, clinical stage, bilateral orchiectomy status, biopsy grade group, and primary treatment modality. Consistent PSA screening was defined as screening at least every 2 years between ages 55-69, as per American Urological Association screening guidelines. RESULTS: After detailed chart review, 133 TW with CaP were identified. After stratification by use of estrogen for gender-affirming hormone therapy, 99 had no prior estrogen use, 15 were formerly on estrogen but had stopped prior to diagnosis, and 19 were actively on estrogen at diagnosis. Only 25-33% of TW were undergoing consistent guideline-based PSA screening regardless of estrogen usage. Median duration of estrogen use was 44 months and 11 months, respectively, for those formerly on estrogen and those actively on estrogen at diagnosis. Among all patients, PSA, PSA density, and grade group were highest among those on estrogen at diagnosis followed by those formerly on estrogen. CONCLUSIONS: This is the largest study of CaP in TW to date. Nonetheless, our study population of 133 CaP patients was much lower than expected given the estimated TW population within the VAHS. The degree to which this represents the effects of estrogen therapy on CaP diagnosis and/or dramatic underdiagnosis due to limited guideline-based PSA screening even among those with CaP requires further study. Future work should aim to understand the incidence and long-term outcomes of CaP in this population and establish guidelines for CaP screening for those on gender-affirming hormone therapy. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e584 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Farnoosh Nik-Ahd More articles by this author Amanda De Hoedt More articles by this author Christi Butler More articles by this author Jennifer T. Anger More articles by this author Peter R. Carroll More articles by this author Matthew R. Cooperberg More articles by this author Stephen J. Freedland More articles by this author Expand All Advertisement PDF downloadLoading ...

Apalutamide in the treatment of a patient with non-metastatic castration-resistant prostate cancer

The treatment of patients with prostate cancer, who do not qualify for the radical therapy is based on the use of surgical or pharmacological castration methods. The effectiveness of the so-called androgen deprivation tends to decrease over time. Even in the absence of distant metastases on imaging studies, the resistance for the hormonal castration may be developed. At this moment, the use of new generation androgen receptor inhibitors may reduce the risk of metastases or death. The paper presents a case report of a patient with prostate cancer without distant metastases who started therapy with apalutamide at the moment of developing re-sistance to the pharmacological castration.

Retrograde Intrarenal Surgery for Partial Staghorn Calculus in Thoracic Kidney: Case Report

BackgroundThoracic kidney (TK) presenting with symptomatic urolithiasis is a rare case scenario. Retrograde intrarenal surgery (RIRS) for calculus in TK is not reported in the literature. We report a case of partial staghorn calculus in TK managed by RIRS.Case presentationA young adult male presented with back pain and was found to have right TK and bilateral partial staghorn calculus. He also had right cryptorchidism with intraabdominally located testis. He underwent staged bilateral RIRS and laparoscopic right orchiectomy. Follow-up ultrasound imaging showed complete stone clearance in both kidneys.ConclusionsRIRS is safe and effective treatment option, in the management of urolithiasis in TK. The anatomical abnormalities in TK did not play any hindrance role in the ureteral access, renal maneuverability of the flexible ureterorenoscope and subsequent drainage of the stone dust after RIRS.

Management of testicular tumours in patients with undescended testes- a challenging but rewarding task: experience from a tertiary care cancer centre in India.

Primary objective: To study patients' clinical profile and outcomes with germ cell tumours developing in undescended testes. Case records of patients enlisted in the prospectively maintained 'testicular cancer database' at our tertiary cancer care hospital from 2014 to 2019 were retrospectively reviewed. Any patient who presented with testicular germ cell tumour with a documented history/diagnosis of undescended testes, whether surgically corrected or not, was considered for this study. The patients were managed along the standard lines of treatment for testicular cancer. We evaluated clinical features, difficulties and delays in diagnosis and complexities in management. We evaluated event-free survival (EFS) and overall survival (OS) using the Kaplan-Meier Method. Fifty-four patients were identified from our database. The mean age was 32.4 years (median age 32, range: 15-56 years). Seventeen (31.4%) had developed cancer in orchidopexy testes, and 37 (68.6%) presented with testicular cancer in uncorrected cryptorchid testes. The median age at orchidopexy was 13.5 years (range: 2-32 years). The median time from symptom onset to diagnosis was 2 months (1-36 months). There was a delay in the initiation of treatment of more than 1 month in 13 patients, with the longest delay being 4 months. Two patients were initially misdiagnosed as gastrointestinal tumours. Thirty-two (59.25%) patients had seminoma, and 22 (40.7%) patients had non-seminomatous germ cell tumours (NSGCT). Nineteen patients had metastatic disease at presentation. Thirty (55.5%) patients underwent orchidectomy upfront while in 22 (40.7%) patients, orchidectomy was done after chemotherapy. The surgical approach included high inguinal orchidectomy, exploratory laparotomy or laparoscopic surgery per the clinical situation. Post-operative chemotherapy was offered as clinically indicated. At a median follow-up of 66 months (95% CI: 51-76), there were four relapses (all NSGCT) and one death. The 5-year EFS was 90.7% (95% CI: 82.9-98.7). The 5-year OS was 96.3% (95% CI: 91.2-100). The tumours in undescended testes, particularly those without prior orchiopexy, often presented late and with bulky masses, requiring complex multidisciplinary management. Despite the complexity and challenges, our patient's OS and EFS matched that of patients with tumours in normally descended testes. Orchiopexy may help in earlier detection. In the first such series from India, we show that testicular tumours in the cryptorchid are also as curable as the germ cell tumours developing in the descended testis.A multidisciplinary disease management group with expertise in managing complex cases is crucial for a favourable outcome in these groups of patients. We also found that orchiopexy done even later in life confers an advantage in terms of early detection in a subsequently developing testicular tumour.

Blue finger syndrome as a paraneoplasic manifestation: case report [Version 2; Peer Review - Approved

We currently know that cancer is a prothrombotic condition altered by certain coagulation factors. Due to this malignity, pro-coagulation factors contribute to a metastasis-favoring hypercoagulability condition are secreted. Besides, there is evidence of a higher excretion of thrombin, favoring the formation of coagula. Here the clinical case of a 65-year-old man with multiple diseases is presented. He went to the doctor because of neurological manifestations consisting in left facial paralysis, and deviation of the commissure of the lips towards the left. In addition, the patient had horizontal nystagmus and disorders when walking. The physical examination showed a bluish coloration at the level of his fingers on his lower right limb, with suspicion of first instance vasculitis. After several tests, the patient was diagnosed as suffering from prostate cancer, bilateral orchiectomy was performed on him, and the following treatments were recommended: oncologic, antihypertensive, antidiabetic and oral anticoagulation

Nadir Prostate-specific Antigen as an Independent Predictor of Survival Outcomes: A Post Hoc Analysis of the PROSPER Randomized Clinical Trial.

This post hoc analysis of PROSPER evaluated the relationship between depth of PSA decline and clinical outcomes in enzalutamide-treated men with nonmetastatic castration-resistant prostate cancer. PROSPER was an international, randomized, double-blind, placebo-controlled, phase 3 trial that demonstrated significantly improved metastasis-free survival and overall survival with androgen deprivation therapy plus enzalutamide vs placebo. A total of 905 enzalutamide-treated men were included in this post hoc analysis. Metastasis-free survival (primary endpoint) and overall survival (secondary endpoint) were evaluated for 4 mutually exclusive subgroups defined by PSA decline: <50% (reference); ≥50% to <90%; ≥90%, nadir ≥0.2 ng/mL; and ≥90%, nadir <0.2 ng/mL. Medians and 95% confidence intervals were determined using a 12-month landmark analysis; hazard ratios and P values were based on an unstratified Cox proportional analysis model. In enzalutamide-treated men, PSA declines of <50%, ≥50% to <90%, ≥90% with nadir ≥0.2 ng/mL, and ≥90% with nadir <0.2 ng/mL were associated with median metastasis-free survival in months (95% confidence intervals) of 22.1 (14.8-not reached), 34.2 (29.4-not reached), 36.6 (33.4-not reached), and not reached, respectively, and overall survival in months (95% confidence intervals) of 40.8 (31.7-44.9), 54.4 (49.0-67.0), 64.3 (63.4-not reached), and not reached, respectively. There was a statistically significant correlation between greater depth of PSA decline and improved clinical outcomes, suggesting a previously underappreciated relationship between changes in PSA levels and clinical outcomes in nonmetastatic castration-resistant prostate cancer.

Effects of a novel recombinant Gonadotropin-Releasing Hormone-1 vaccine on the reproductive function of mixed-breed dogs (Canis familiaris) in Taiwan.

Immunocastration is an effective alternative to surgical castration for controlling the population of animals. As gonadotropin-releasing hormone (GnRH) regulates the reproductive endocrine system in mammals, it is a target antigen for vaccine formulation. Through this study, we evaluated the effectiveness of a recombinant subunit GnRH-1 vaccine for the immunocastration of the reproductive function of 16 mixed-breed dogs (Canis familiaris) provided voluntarily by different households. All the dogs were deemed clinically healthy prior to and during the experiment. A specific anti-GnRH immune response was detected at Week 4, which was maintained for at least 24weeks after vaccination. Moreover, decreased levels of sexual hormones (testosterone as well as progesterone and estrogen, respectively) were observed in both male and female dogs. Estrous suppression was apparent in female dogs, and testicular atrophy and poor semen quality (concentration, abnormality, and viability) were observed in male dogs. In conclusion, the recombinant subunit GnRH-1 vaccine could successfully suppress fertility and delay the estrous cycle in canines. These results support the efficacy of the recombinant subunit GnRH-1 vaccine; thus, it is a suitable candidate for fertility control in dogs.

Bilateral Adrenal and testicular Tumours; When a Simple Diagnosis Becomes Complicated

A 78-year-old man with a BMI 28.7, a moon face and a medical history of diabetes mellitus, hypothyroidism, undefined adrenal insufficiency and history of cardiac ablation, had been in urological follow up for both prostate and bladder cancer. PSA remained low after radiation and adjuvant ADT. Cystoscopy revealed no recurrence after transurethral resection of bladder tumour and instillation of BCG. A routine CT scan as indicated by EAU guideline, showed bilateral enlargement of the adrenal glands as the only abnormality de novo. Patient had no other symptoms than already long-existing fatigue. Considering patient's medical history, subsequently a FDG PET scan was performed which showed intense FDG uptake not only bilaterally in the adrenal glands, but also in both testes. An ultrasound of the testes demonstrated hypodense lesions with increased flow. US imaging raised the suspicion of testicular adrenal rest tumours. Differential diagnoses were primary testis tumour, metastatic disease, BCG-itis, lymphoma or rare endocrine disorders. The combination of bilateral adrenal gland hyperplasia and testicular masses reminded us of seeking the rare diagnosis of ectopic adrenal remnant in both testis and a Cushing-like feature. Endocrinological evaluation could not establish an all-encompassing diagnosis to explain all of the clinical findings. Bilateral orchidectomy was performed. Histological examination showed localization of diffuse large B cell lymphoma (DLBCL) in both testes. Patient was referred to the haematologist and started with chemotherapy, R-CHOP. The diagnostic process in this case was challenging and misleading.

Stage I seminoma: outcome of different treatment modalities & changes in patterns of care: A single institution experience.

The mainstay for management of stage I seminoma is high inguinal orchiectomy with post-orchiectomy therapeutic options including active surveillance, chemotherapy or radiation therapy. To analyze different post-orchiectomy treatment modalities outcomes of stage I seminoma patients presented to NCI, Cairo University in the period from 2005-2019. A retrospective review of all patients' records with clinical stage I seminoma who presented to our institute in the period from 2005-2019 was done. Adjuvant treatment details were extracted and we compared overall survival (OS) and disease free survival (DFS) for different modalities and changes in patterns of care over this period. Thirty five patients were identified with thirty three patients eligible for analysis. Median age was 35 years (range, 19-52). Fourteen patients were kept under active surveillance, eleven patients received adjuvant carboplatin and eight patients received adjuvant radiation to para-aortic chain. Five-year OS was 100% for all patients regardless post-operative approach. Five-year DFS was 100% for patients who received adjuvant chemotherapy or radiotherapy versus 93% for patients who were kept under active surveillance (p=0.03). Clinical stage I seminoma is a favorable disease entity with favorable disease related outcomes regardless post-operative approach. Active surveillance is reasonable and safe given equal survival to active treatment.

Seeing the unseen: how can we best identify transgender women within the Veterans Affairs healthcare system's electronic medical record?

One challenge in transgender research is reliably identifying patients through electronic medical records data, as there is no universal transgender International Classification of Diseases (ICD) code, but rather multiple ICD codes that can be used. To explore the sensitivity and specificity of 5 commonly used ICD codes to identify transgender patients overall and transgender women specifically (assigned male sex at birth) by using data from the Veterans Affairs (VA), the largest integrated health system in the United States. Patients aged ≥18 years were identified via ICD-9 codes 302.5 and 302.6 (Ninth Revision) and ICD-10 codes F64.0, F64.8, and F64.9 (Tenth Revision) using VA health records from 2000 to 2021 and stratified by bilateral orchiectomy status. Detailed chart review was performed on 32 randomly selected patients for each code (half with and half without orchiectomy) to confirm transgender status and to perform descriptive analyses. For each ICD code, rates of confirmed transgender status ranged from 88% to 100% for those with and without an orchiectomy, with the majority being transgender women (consistent with most veterans being assigned male sex at birth). Most transgender women (66%-100%) were undergoing estrogen gender-affirming therapy. The majority of provider-driven entries of transgender status took place from 2011 to 2020, with 75% of entries made from 2011 to 2020, consistent with increased recognition and societal acceptance of this population. False negatives were detected at a rate of 15%. Based upon these 5 ICD codes alone, we estimate that the VA has records for 9,449 to 10,738 transgender individuals. All 5 codes are very sensitive in identifying transgender patients, and the combination of these codes with orchiectomy is extremely sensitive in identifying transgender women, specifically. Major strengths of the study are the use of universal ICD codes and a large patient sample size that spans health records nationally and across multiple decades, potentially making our data more generalizable. The main limitation of this study is that subanalyses were performed on a limited number of patients, which prevented us from capturing all false positives and thus from calculating specificity for each code. Similarly, our true negatives were derived from a small, random subset of the population; as such, our calculation for specificity is an estimate. This study highlights a novel method to identify transgender women and paves the way for further research.

Paraneoplastic Hypercalcaemia as a Cause of Unexplained Renal Impairment in a Patient With Seminoma: A Case Report

A 44-year-old otherwise healthy male who had undergone left high inguinal orchidectomy, with histopathology suggestive of classical seminoma, was referred to the authors’ oncology centre for evaluation of persistently deranged renal function tests and initiation of chemotherapy. They had a large retroperitoneal mass encasing their left kidney and their creatinine was 4.2 mg/dL. Even 1 week after double J stenting, they had persistently elevated creatinine of 3.1 mg/dL, which was precluding their curative chemotherapy with bleomycin/cisplatin/etoposide regimen. In a desperate situation, to prevent further progression of disease, pre-phase chemotherapy with carboplatin and etoposide was considered. In anticipation of tumour lysis syndrome, considering the large mass and compromised renal function, a tumour lysis profile was requested, which revealed elevated serum calcium levels (15.4 mg/dL, which goes against the tumour lysis syndrome). Considering the large retroperitoneal lymph nodal mass, suppressed parathyroid hormone levels (4.1 pg/mL) and vitamin D3 being within normal range, a paraneoplastic cause of hypercalcaemia was considered. Correction of hypercalcaemia with medical measures as well as treatment of seminoma was instituted, which led to normalisation of renal function tests within the next 10 days. Here, the authors report a rare case of testicular seminoma with persistently deranged renal function, likely due to paraneoplastic hypercalcaemia, which improved after successful chemotherapy along with anti-hypercalcaemic measures, including aggressive hydration, diuretics, calcitonin, dexamethasone, and denosumab. This report shows that it is important to treat the cause along with medical management in this oncologic metabolic emergency. It also highlights the value of pre-phase chemotherapy with carboplatin and etoposide in the setting of acute renal impairment.

Simultaneous integrated boost (SIB) stereotactic body radiotherapy (SBRT) for prostate and pelvic nodes in high risk, node positive and oligometastatic prostate cancers: Safety, efficacy and quality of life outcome measures.

121 Background: SBRT in high risk (HR), node positive (N+) and oligometastatic (OM) prostate cancers is limited by pelvic nodal coverage, larger treatment volumes and use of hormone therapy. We report the safety, efficacy and patient reported quality of life measures (QOL) for SIB-SBRT for prostate and pelvic nodal treatment in HR, N+ and OM (non-regional node or skeletal deposits) cohorts. Methods: 22 patients of NCCN category HR, N+, OM adenocarcinoma prostate and all staged by MRI prostate and PSMA PETCT scan received SIB-SBRT from April 2019 to October 2021. All received long term androgen (ADT) deprivation therapy (80%) or surgical castration (20%). ADT was neo-adjuvant, concomitant and adjuvant for at least 2 years and for OM 2nd generation hormone treatment. SIB-SBRT to prostate and pelvic nodal regions (until common iliac level) was 35-36.25 Gy and 25 Gy in 5 fractions respectively. Post ADT gross PSMA avid nodes and skeletal deposits received 30 Gy in 5 fractions. SIB-SBRT was by volumetric modulated arc therapy (VMAT) with intrafraction imaging and hexapod robotic couch corrections on alternate days. Baseline IPSS and Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP) QOL recorded and then post SIB-SBRT at 6 weeks and then 3 monthly till 2 years. Dosimetry followed standard published literature. Results: 22 patients were treated over 3 years with median age of 70 years. The median PSA at baseline was 45ng/ml with 90% Gleason score 8+. The OM disease included nonregional nodes or 1-2 skeletal deposits. After median follow up of 20 months acute grade 2 genitourinary (GU) and gastrointestinal (GI) toxicities were 10% and 12%, respectively. Late grade 2 GU and GI toxicities were 4% and 9%, respectively. Late grade 3 GU and GI toxicity was seen in 2 patients each requiring medical management. 2- year overall survival and biochemical failure-free survival was 95% and 90% respectively. Baseline median IPSS score was 9 and median EPIC CP score was 12/60. Mean urinary incontinence domain scores worsened significantly from baseline to 6 months and obstructive scores improved from baseline to 6 months with more than 95% patients not using any pads at 6 months. Bowel frequency scores were maximum at 6 weeks post SBRT and it persisted till 6 months. Sexual function scores declined gradually and recovered only in a few at last follow up. Vitality/hormonal scores were unchanged from baseline till 6 months. Conclusions: SIB-SBRT for HR, N+ and OM prostate cancers is safe and effective, with good QOL. The encouraging PSA control and minimal grade 3 toxicity and favorable therapeutic ratio achieved reflect the feasibility of LINAC based SIB-SBRT. This warrants long term follow-up with effective bladder/rectal protocol measures and optimal use of ADT in a prospective setting.

Defective excitation-contraction coupling and mitochondrial respiration precede mitochondrial Ca2+ accumulation in spinobulbar muscular atrophy skeletal muscle

Polyglutamine expansion in the androgen receptor (AR) causes spinobulbar muscular atrophy (SBMA). Skeletal muscle is a primary site of toxicity; however, the current understanding of the early pathological processes that occur and how they unfold during disease progression remains limited. Using transgenic and knock-in mice and patient-derived muscle biopsies, we show that SBMA mice in the presymptomatic stage develop a respiratory defect matching defective expression of genes involved in excitation-contraction coupling (ECC), altered contraction dynamics, and increased fatigue. These processes are followed by stimulus-dependent accumulation of calcium into mitochondria and structural disorganization of the muscle triads. Deregulation of expression of ECC genes is concomitant with sexual maturity and androgen raise in the serum. Consistent with the androgen-dependent nature of these alterations, surgical castration and AR silencing alleviate the early and late pathological processes. These observations show that ECC deregulation and defective mitochondrial respiration are early but reversible events followed by altered muscle force, calcium dyshomeostasis, and dismantling of triad structure.

PI5P4Kα supports prostate cancer metabolism and exposes a survival vulnerability during androgen receptor inhibition.

Phosphatidylinositol (PI)regulating enzymes are frequently altered in cancer and have become a focus for drug development. Here, we explore the phosphatidylinositol-5-phosphate 4-kinases (PI5P4K), a family of lipid kinases that regulate pools of intracellular PI, and demonstrate that the PI5P4Kα isoform influences androgen receptor (AR) signaling, which supports prostate cancer (PCa) cell survival. The regulation of PI becomes increasingly important in the setting of metabolic stress adaptation of PCa during androgen deprivation (AD), as we show that AD influences PI abundance and enhances intracellular pools of PI-4,5-P2. We suggest that this PI5P4Kα-AR relationship is mitigated through mTORC1 dysregulation and show that PI5P4Kα colocalizes to the lysosome, the intracellular site of mTORC1 complex activation. Notably, this relationship becomes prominent in mouse prostate tissue following surgical castration. Finally, multiple PCa cell models demonstrate marked survival vulnerability following stable PI5P4Kα inhibition. These results nominate PI5P4Kα as a target to disrupt PCa metabolic adaptation to castrate resistance.