Metastatic Prostate Adenocarcinoma Research Articles

9316 Modulation Of Intracellular Lipid Access By ATGL Determines Ferroptosis Sensitivity In Castration-resistant Prostate Cancer

Abstract Disclosure: P. Cao: None. D. Awad: None. J. Han: None. D.E. Frigo: Grant Recipient; Self; GTx, Inc.. Other; Self; Familial relationship with Biocity Biopharmaceuticals, Hummingbird Bioscience, Bellicum Pharmaceuticals, Maia Biotechnology, Alms Therapeutics, Hinova Pharmaceuticals and Barricade Therapeutics. Ferroptosis induction has recently been recognized as a novel therapeutic approach to alter the outcomes of drug-resistant cancer. Ferroptosis is cell death that is caused by the intracellular accumulation of toxic lipid hydroperoxides. Due to their elevated metabolism, castration-resistant prostate cancer (CRPCs) are highly prone to ferroptosis; yet, many of them manage to avert this cellular fate. We have identified a key enzyme involved in lipid metabolism, adipose triglyceride lipase (ATGL), that engenders CRPCs with the ability to resist ferroptosis. Our data has shown that ATGL deletion by CRISPR-Cas9 knockout method sensitized human CRPC cell lines such as C4-2, C4-2BLT, and PC3 cells to the ferroptosis inducer RSL3. In all cases, RSL3-mediated cell death could be blocked by the antioxidant Ferrostatin-1, confirming ferroptosis as the mechanism of cell death. Knocking out ATGL also augmented the ferroptosis inducer-mediated increase in lipid peroxides as indicated by the increased ratio of oxidized to non-oxidized C11-BODIPY 581/591. With regards to the mechanism for the sensitivity of ATGL KO to ferroptosis induction, previous research has established that the enzyme long-chain acyl-CoA synthetase 4 (ACSL4) is universally essential to facilitate ferroptosis. More specifically, ATGL(PNPLA2) was found to inversely correlate with ACSL4 in the Taylor et al., the TCGA PanCancer Atlas, and Metastatic Prostate Adenocarcinoma (SU2C/PCF Dream Team) datasets in both primary and metastatic tumors. qPCR and western blot analysis of ACSL4 levels further showed that ACSL4 expression is closely tied to the lipase activity of ATGL. Addition of arachidonic acid significantly induced ferroptosis when combined with RSL3 in a dose-dependent manner only in ATGL KO cells. This indicates that PUFAs can render ATGL KO cells even more sensitive to RSL3-induced ferroptosis while cells with functional ATGL remain highly resistant, further reinforcing that ATGL is an essential safeguard of CRPC against ferroptosis. ATGL KO cells also demonstrated sensitivity to the antiandrogen Enzalutamide. The combination of Enzalutamide and RSL3 substantially decreased cell viability in ATGL KO cells as compared to control cells, indicating a strong synergy effect particularly seen in ATGL KO cells. In summary, this work demonstrates that ATGL is an important and novel regulator of ferroptosis in CRPC and supports the use of ferroptosis inducer as a new therapeutic approach in CRPC. Presentation: 6/2/2024

6463 A Case of Tumour-Induced Osteomalacia Which Remitted After Treatment of Metastatic Prostate Cancer

Abstract Disclosure: J. Chua: None. M. Chuah: None. A case Tumour-induced osteomalacia (TIO) which remitted after treatment of metastatic prostate cancer. Dr Chua Jia Min, Dr Matthew Chuah Bingfeng Abstract Case report: A 69-year-old gentleman with a known history of bladder cancer presented to the emergency department with fatigue, lower back pain and bilateral lower limb weakness worsening over the past one month. MRI and bone scan revealed extensive osteoblastic bone metastases across the skeletal system. This gentleman was referred to the Endocrinology service for the evaluation of high PTH. His corrected calcium was normal at 2.17mmol/L (2.09-2.46mmol/L) and iPTH was raised at 8.74pmol/L (1.60-6.90pmol/L). He was noted to have severe hypophosphatemia 0.34mmol/L (0.94-1.50mmol/L). Bicarbonate levels were normal, there was no glycosuria or proteinuria. There was no history of IV ferrous carboxymaltose use. Further investigations were consistent with urinary phosphate loss - TRP was 0.398 and TMP-GFR was 0.199. ALP was elevated at 282ug/L (39-99ug/L). 25-hydroxyvitamin D was low at 12 ug/L, which accounted for the high PTH levels (secondary hyperparathyroidism). FGF-23 levels returned high at 1293 RU/ml (<180 RU/ml). BMD showed osteoporosis with T-score of -2.6 at the left femoral neck. He was subsequently diagnosed with metastatic prostate adenocarcinoma, based on histology from a bone biopsy of an affected vertebrae. PSA was markedly raised at 606ug/L. A diagnosis of TIO secondary to metastatic prostate cancer was made. The patient was started on PO sodium-phosphate solution 4ml TDS (approximately 3mmol/kg/day of elemental phosphorus), calcitriol 0.25mcg BD and vitamin D was replaced. After phosphate was replete, the patient's weakness and fatigue improved. He was subsequently started on androgen deprivation therapy with leuprorelin acetate injection once every 3 months and apalutamide daily. SC denosumab 60mg Q6monthly was also commenced in view of extensive bone metastases. Repeat imaging showed response to treatment with decrease in the size of the prostate and bone lesions. His PSA levels are now undetectable and TMP-GFR has normalised. His oral phosphate and calcitriol doses were gradually reduced and subsequently stopped. His calcium and phosphate levels remain within normal limits on no supplementation, suggesting remission of his TIO. PTH levels normalised after vitamin D repletion. Learning points TIO is a rare paraneoplastic syndrome usually associated with mesenchymal tumours, and treatment involves resection of the causative tumour. Cases of TIO secondary to prostate cancer (an epithelial cancer) are exceedingly rare. Despite metastatic disease, this patient responded exceedingly well to his cancer therapy. Suppression of the tumour cells with androgen deprivation therapy resulted in the lack of phosphotonin production and remission of his TIO. Presentation: 6/1/2024

Metastatic prostate adenocarcinoma to the brain – a clinicopathologic analysis of 21 cases

BackgroundBrain metastasis from prostate adenocarcinoma (PCa) is rare, often leading to death within a year. Its infrequent occurrence and atypical histopathologic features contribute to lower consideration in the differential diagnosis of tumor brain metastasis. This study aims to assess the clinical characteristics and distinctive histopathologic features of metastatic PCa in the brain for timely and enhanced diagnostic accuracy.DesignA retrospective search spanning 20 years (2003–2022) was conducted on our archives and identified 21 cases diagnosed as “metastatic prostate adenocarcinoma (mPCa)” in brain biopsies and resections. All existing slides were thoroughly reviewed to evaluate the histopathology of the mPCa.ResultThe mean age at presentation for brain metastasis was 70 years. Of 21 cases, 5 were dural-based lesions, 16 were true intraparenchymal metastases, including 2 sellar/suprasellar masses, 3 frontal, 3 temporal, 3 occipital, 1 cerebellum, and 4 involving multiple brain lobes. The average interval between initial diagnosis and brain metastasis was 90.75 months. Notably, brain metastasis was the initial presentation for one patient, while another patient, initially diagnosed with prognostic grade group (GG) 2 PCa in 1/12 cores, presented with isolated brain metastasis two years later. Architecturally, tumor cells were arranged in sheets or nests in most cases; however, four cases showed histologic cribriform patterns, and five displayed papillary architecture. Cytohistology varied from uniform monomorphic to highly pleomorphic cells with prominent nucleoli (8/19) and high mitotic activity. Interestingly, 1 case showed small round blue cell morphology, another had focal areas of rhabdoid and spindle cell differentiation, and 6 had cytoplasmic clearing. Almost half of the cases (47%) showed necrosis.ConclusionmPCa to the brain can present with variable histomorphology. Therefore, consideration of mPCa in the differential diagnosis of metastatic brain lesions, even with non-suggestive imaging, is imperative in male patients with or without a history of primary disease. Accurate and prompt diagnosis is crucial, given the recent advancements in treatment that have improved survival rates.

Connecting Gene Variation to Treatment Outcomes in Metastatic Castration-Resistant Prostate Adenocarcinoma: Insights into Second-Generation Androgen Receptor Axis-Targeted Therapies.

Prostate cancer (PC) is one of the most commonly diagnosed tumours among men. Second-generation androgen receptor axis-targeted (ARAT) agents, namely abiraterone acetate (AbA) and enzalutamide (ENZ), are currently used in the management of metastatic castration-resistant PC (mCRPC). However, the treatment is challenging due to the lack of prognostic biomarkers. Meanwhile, single-nucleotide polymorphisms (SNPs) have emerged as potential prognostic indicators of mCRPC. Thus, this study evaluated the impact of relevant SNPs on the treatment outcomes of 123 mCRPC patients enrolled in a hospital-based cohort study. The CYP17A1 rs2486758 C allele was associated with a 50% reduction in the risk of developing castration resistance (hazard ratio (HR) = 0.55; p = 0.003). Among patients without metastasis at tumour diagnosis and under AbA, a marginal association between YBX1 rs10493112 and progression-free survival was detected (log-rank test, p = 0.056). In the same subgroup, significant associations of HSD3B1 rs1047303 (CC/CA vs. AA; HR = 3.41; p = 0.025), YBX1 rs12030724 (AT vs. AA; HR = 3.54; p = 0.039) and YBX1 rs10493112 (log-rank test, p = 0.041; CC vs. AA/AC; HR = 3.22; p = 0.053) with overall survival were also observed, which were confirmed by multivariate Cox analyses. Although validation with larger cohorts is required, these findings suggest that SNPs could enhance the prognosis assessment of mCRPC patients, leading to a more personalised treatment.

Metastatic prostate adenocarcinoma presenting with ptosis due to sphenoid sinus metastasis: a rare case report

Metastatic prostate adenocarcinoma presenting with ptosis due to sphenoid sinus metastasis: a rare case report

Peritoneal Carcinosis, An Atypical Metastatic Site in Prostate Adenocarcinoma: A Case Report

Adenocarcinoma of the prostate is the second most common malignant tumour. It can spread in three ways: locally, via the lymphatic system or through the bloodstream. Diffuse peritoneal carcinosis is a rare entity during the evolution of prostate adenocarcinoma and only a few cases have been reported in the literature. This case report presents a patient with synchronous metastatic prostatic adenocarcinoma with peritoneal carcinosis. This case highlights the rarity of this type of prostate adenocarcinoma metastasis.

Abstract 5899: Evaluation of Up284 as a selective proteasome inhibitor for prostate cancer therapy

Abstract Recent research into prostate cancer treatment has unveiled a promising contender known as Up284. In laboratory experiments, this compound has exhibited a remarkable preference for targeting prostate cancer cells as opposed to normal cells. Specifically, in vitro cell viability assays using MTT have shown that prostate cancer cells display high sensitivity to Up284 at low nanomolar IC50 values, while primary human prostate epithelial cells and mouse keratinocytes exhibit minimal sensitivity. This establishes a notable therapeutic window between cancerous and non-cancerous cells, with Up284 significantly inhibiting colony formation in PC3 cells. Additional functional assays have confirmed Up284's potential, including the 4UbFL Reporter Gene assay, which has revealed robust, dose-dependent proteasome inhibition. This effect is supported by the accumulation of polyubiquitinated proteins in various prostate cancer cell lines following Up284 treatment, suggesting a distinct mechanism of toxicity compared to bortezomib. Furthermore, Up284 has been found to induce apoptosis in PC3 cells, surpassing the efficacy of bortezomib. Competitive binding assays have shown that Up284 exhibits a stronger binding affinity to the proteasomal receptor RPN13 than the prototype inhibitor RA190B. This is further supported by a Cellular Thermo Stabilization Assay (CETSA), which indicates that Up284 stabilizes RPN13 in cells. A preliminary in vivo study utilizing the bone metastatic prostate cancer genetically engineered mouse model(BMPC GEMM) model for metastatic prostate adenocarcinoma has demonstrated that Up284 leads to significant tumor regression and increased levels of poly-ubiquitinated proteins in residual tumor tissues. Moreover, when Up284 is conjugated with an E3 ligase ligand, it successfully degrades RPN13, resulting in the death of PC3 cells. Up284 has also shown favorable pharmacokinetics/pharmacodynamics (PK/PD) profiles and safety in animal models. It is well-tolerated in mice and holds promise for oral administration, demonstrating a proteasome-dependent reporter protein stabilization effect superior to ixazomib. Importantly, Up284 has induced tumor regression and improved survival rates in various cancer models, including ovarian and breast cancers. In conclusion, Up284 emerges as a lead candidate for targeted prostate cancer therapy due to its high specificity, substantial therapeutic index, and potent anti-cancer activity both in vitro and in vivo. Further development and clinical investigation of Up284 are warranted to fully explore its therapeutic potential. Citation Format: Balasubramanyam Karanam, Ravi Anchoori, Yung Chang. Evaluation of Up284 as a selective proteasome inhibitor for prostate cancer therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5899.

Abstract 3043: MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer

Abstract Prostate cancer kills 30,000 men per year in the U.S. Yet, of all primary prostate cancers, only a relatively small percentage are aggressive and have the potential to become life threatening. In terms of genomic copy number alterations, concurrent amplification of MYC and loss of tumor suppressor PTEN is the strongest predictor of prostate cancer specific mortality. We have previously shown, in a novel mouse model, that combined MYC overexpression and Pten loss results in the development of precursor lesions (PIN) that lead to aggressive metastatic prostatic adenocarcinoma, yet overexpression of MYC alone or Pten loss alone result only in precursor lesion development. Here, we performed genome wide transcriptome analysis using bulk RNA seq to obtain clues regarding the synergy between MYC overexpression and Pten loss. Prostates harboring PIN lesion were dissected from mice engineered to have MYC activation alone, Pten loss alone, and the combination thereof (BMPC mice), as well as invasive primary adenocarcinomas and metastatic lesions from BMPC mice. Principal Components Analysis (PCA) analysis separated the lesions into highly distinct groups. Genes contributing the most to the first principal component were related to inflammation and cell proliferation/cell cycle progression by functional annotation. The proliferation-related genes were increased somewhat by MYC overexpression alone, were not increased Pten loss, and were more consistently increased by combined MYC overexpression and Pten loss in BMPC. Strikingly, mice with combined MYC overexpression and Pten loss showed approximately 2-4 fold higher Ki67 proliferation index than mice with MYC activation alone. PIN lesions driven by MYC overexpression or PTEN loss alone were characterized by Gene Set Enrichment Analysis (GSEA). Among the pathways with the highest negative enrichment scores in PIN samples with PTEN loss were those that generally describe ribosome biogenesis and translation. PIN lesions with Pten loss showed lower hybridization signals for the 45S rRNA, which was increased by MYC alone and somewhat more in BMPC PIN lesions. Our results demonstrate that combined activation of MYC and Pten loss drive increased cell proliferation beyond that seen with either gene alteration alone. These findings suggest that a key part of the molecular mechanisms by which MYC and PTEN alterations may synergize to drive aggressive prostate cancer is related to increased tumor cell proliferation. Surprisingly, we uncovered the novel finding that Pten loss, in the absence of MYC overexpression, is associated with decreased expression of genes coding for proteins that mediate translation, as well as decreased 45S pre-rRNA. Since ribosome biogenesis is a key driver of cell proliferation, it is likely that loss of both copies of PTEN alone, in the absence of MYC overexpression, would be selected against in early lesions in prostate cancer. Citation Format: Michael Rubenstein, Tracy Jones, Jessica Hicks, Apurv Rege, Qizhi Zheng, Carolina Gomes-Alexandre, Gretchen Hubbard, Srinivasan Yegnasubramanian, Charles Bieberich, Angelo DeMarzo. MYC activation and PTEN loss synergistically activate proliferation in a mouse model of lethal prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3043.

Abstract 2583: [68Ga]Ga-RYZ-GPC3: A glypican-3 targeted diagnostic radiopharmaceutical for hepatocellular carcinoma molecular imaging

Abstract Introduction & Purpose: Hepatocellular carcinoma (HCC) is the most common type of liver cancer. To date, the imaging of HCC is difficult, insufficient for disease staging and barely improved over the past decades. Glypican-3 (GPC3) is a cell-surface receptor highly expressed by HCC and of diagnostic and prognostic value. GPC3 has been reported as potential target for diagnosis and treatment of HCC for nuclear theranostics. RYZ-GPC3 is a DOTA modified macrocyclic peptide with high affinity for GPC3, which may allow PET imaging or nuclear therapy. Here we report the first clinical results of [68Ga]Ga-RYZ-GPC3 PET-imaging in patients with known or suspected HCC. Methods: [68Ga]Ga-RYZ-GPC3 was obtained upon labeling the peptide precursor with 68Ga from a 68Ge/68Ga-generator and heating till 90⁰C for 10 min followed by sterile filtration. After administration of 2 MBq/kg [68Ga]Ga-RYZ-GPC3, a 60 min dynamic PET scan was acquired or multiple static PET/CT were acquired at 20 min, 1, 2 and 4 hours. Besides qualitative interpretation, standardized uptake values (SUVmax, SUVmean) were measured in various compartments; HCC lesions, healthy liver (HL), kidneys, blood pool activity in the left ventricle (BP) and gastric fundus. Additionally, tumor-to-healthy liver ratios (TLR) were calculated: SUVmean,HCC divided by SUVmean,HL. Results: Radiolabeling to obtain [68Ga]Ga-RYZ-GPC3 was near quantitative, making the production highly reliable. Eleven patients (4 patients dynamic; 7 patients static protocol) were scanned. One patient did not have an HCC. Another patient had a concurrent metastatic prostate adenocarcinoma, which did not show uptake, both qualitatively and quantitatively. All HCC lesions showed uptake in qualitative assessment, even in immunohistochemistry confirmed GPC3-negative HCC lesions (3 lesions). In 23 HCC lesions, including the aforementioned GPC3-negative lesions, mean SUVmax was 17.9 (range 2.7-95.3) and mean SUVmean was 10.2 (range 1.0-49.2) at 60 minutes. Uptake in HL and BP decrease over time and become negligible 45 minutes after administration (SUVmean <1.5). The opposite occurs for HCC and TLR, which continuously increase up to 4 hours after administration (TLR 4.4 to 19.2, at 18 minutes and 4 hours respectively). In individual lesion analysis, TLR was the highest at 60 or 120 minutes post-injection scans. Uptake in the gastric fundus, gradually increases in the first hour, and decreases gradually afterwards (SUVmean from 4.0 to 12.7, back to 10.1). Conclusions: [68Ga]Ga-RYZ-GPC3 is the first peptide based PET tracer that allows the high quality molecular imaging of HCC. Thereby [68Ga]Ga-RYZ-GPC3 is suitable for the selective diagnosis of HCC. In addition, based on the biodistribution and in vivo dynamics on these diagnostic images, RYZ-GPC3 is very likely to hold therapeutic potential upon labeling with a therapeutic isotope (e.g 177Lu or 225Ac). Citation Format: Arthur J.A.T. Braat, Alex J. Poot, Constantin Lapa, Marnix G.E.H. Lam, Wolfgang A. Weber, Anna Karmann, Ye Yuan, Jessica Rearden, Ken Song, Ralph A. Bundschuh. [68Ga]Ga-RYZ-GPC3: A glypican-3 targeted diagnostic radiopharmaceutical for hepatocellular carcinoma molecular imaging [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 2583.

Disseminated Intravascular Coagulation With Excessive Fibrinolysis (DIC-XFL) A Rare Association of Metastatic Prostate Adenocarcinoma: A Case Report

We present disseminated intravascular coagulation (DIC) with excessive fibrinolysis (XFL) as an unusual presenting manifestation of metastatic prostate cancer (PC), which was successfully treated with chemotherapy with Docetaxel which not only controlled the disease but also reversed the patient’s coagulopathy within seven days effectively. Thus highlighting rare and life-threatening haemorrhagic complications of prostate cancer along with its satisfactory management option.

Mainstream Model of Genetic Testing for Prostate Cancer at a Large Tertiary Cancer Centre

BackgroundAn estimated 20% to 30% of men with advanced prostate cancer carry a mutation in DNA damage repair genes, of which half are estimated to be germline. Eligibility criteria for germline genetic testing expanded significantly for Ontario patients in May 2021 and many centers adopted a “mainstream” model, defined as oncologist-initiated genetic testing. MethodsWe conducted a retrospective chart review to report on the first-year mainstream experience of a large tertiary oncologic center, the Sunnybrook Odette Cancer Centre. All patients who underwent mainstream at the discretion of their treating physician were included. A subset underwent somatic profiling as part of clinical trial screening. Descriptive statistics were used to report baseline clinicopathologic characteristics and treatments received. ResultsBetween May 1, 2021, and May 30, 2022, 174 patients with prostate cancer underwent mainstream germline genetic testing with a 19-gene panel. Median age was 75 (IQR 68-80), and 82% of patients were diagnosed with either de novo metastatic or high-risk localized prostate adenocarcinoma. Fourteen patients (8%; 95% CI 4%-12%) were found to have a deleterious germline mutation, including pathogenic or likely pathogenic variants in BRCA1/2, ATM, CHEK2, PMS2, RAD51C, HOXB13, and BRIP1. Forty-nine patients (28%; 95% CI 21%-35%) were found to have a variant of uncertain significance. Thirty-four patients also had next-generation sequencing (NGS) of their somatic tissue. Among this subset, 8 of 34 (23%) had an alteration in homologous recombination repair (HRR) genes. Of the 14 patients with a germline mutation, none had a prior personal history of malignancy and 6 (43%) did not have any first- or second-degree relatives with history of prostate, pancreatic, breast, or ovarian cancer. ConclusionWe report on the real-world characteristics of prostate cancer patients who underwent mainstream germline genetic testing. Personal history and family history of cancer cannot reliably stratify patients for the presence of pathogenic germline variants.

A multicentric, single arm, open-label, phase I/II study evaluating PSMA targeted radionuclide therapy in adult patients with metastatic clear cell renal cancer (PRadR)

BackgroundDespite advancements in managing metastatic clear cell renal carcinoma (mccRCC) through antiangiogenic tyrosine kinase inhibitors and immunotherapy, there remains a demand for novel treatments for patients experiencing progression despite the use of these medications. There is currently no established standard treatment for patients receiving third therapy line. Prostate Specific Membrane Antigen (PSMA) whose high expression has been demonstrated in metastatic aggressive prostate adenocarcinoma is also highly expressed in neovessels of various solid tumors including renal cell carcinoma (RCC): 86% of clear cell RCC, 61% of chromophobe RCC, and 28% of papillary RCC. Therefore, PSMA may be a target expressed in metastatic ccRCC for radionuclide therapy using PSMA ligands radiolabeled with Lutetium-177 (PRLT). 177Lu-PSMA delivers ß-particle radiation to PSMA-expressing cells and the surrounding microenvironment with demonstrated efficacy in metastatic prostate cancer.MethodsThis is a multicenter phase I/II study designed to assess the tolerability and effectiveness of 177Lu-PSMA-1 in individuals with PSMA-positive metastatic clear cell renal cell carcinoma (ccRCC), identified through 68Ga-PSMA PET, conducted in France (PRadR). 48 patients will be treated with 4 cycles of 7.4 GBq of 177Lu-PSMA-1 every 6 weeks. The primary objective is to evaluate the safety of 177Lu-PSMA-1 (phase I) and the efficacy of 177Lu-PSMA-1 in mccRCC patients (phase II). Primary endpoints are incidence of Severe Toxicities (ST) occurring during the first cycle (i.e. 6 first weeks) and disease Control Rate after 24 weeks of treatment (DCR24w) as per RECIST V1.1. Secondary objective is to further document the clinical activity of 177Lu-PSMA-1 in mccRCC patients (duration of response (DoR), best overall response rate (BORR), progression fee survival (PFS) and overall survival (OS).DiscussionOur prospective study may lead to new potential indications for the use of 177Lu-PSMA-1 in mccRCC patients and should confirm the efficacy and safety of this radionuclide therapy with limited adverse events. The use of 177Lu-PSMA-1may lead to increase disease control, objective response rate and the quality of life in mccRCC patients.Trial registrationClinicalTrials.gov: NCT06059014.

Survival outcomes of metastatic prostate adenocarcinoma by primary metastatic site: A Surveillance, Epidemiology, and End Results (SEER) database study.

Survival outcomes of metastatic prostate adenocarcinoma by primary metastatic site: A Surveillance, Epidemiology, and End Results (SEER) database study.

The Challenge of Single-Photon Emission Computed Tomography Image Segmentation in the Internal Dosimetry of 177Lu Molecular Therapies.

The aim of this article is to review the single photon emission computed tomography (SPECT) segmentation methods used in patient-specific dosimetry of 177Lu molecular therapy. Notably, 177Lu-labelled radiopharmaceuticals are currently used in molecular therapy of metastatic neuroendocrine tumours (ligands for somatostatin receptors) and metastatic prostate adenocarcinomas (PSMA ligands). The proper segmentation of the organs at risk and tumours in targeted radionuclide therapy is an important part of the optimisation process of internal patient dosimetry in this kind of therapy. Because this is the first step in dosimetry assessments, on which further dose calculations are based, it is important to know the level of uncertainty that is associated with this part of the analysis. However, the robust quantification of SPECT images, which would ensure accurate dosimetry assessments, is very hard to achieve due to the intrinsic features of this device. In this article, papers on this topic were collected and reviewed to weigh up the advantages and disadvantages of the segmentation methods used in clinical practice. Degrading factors of SPECT images were also studied to assess their impact on the quantification of 177Lu therapy images. Our review of the recent literature gives an insight into this important topic. However, based on the PubMed and IEEE databases, only a few papers investigating segmentation methods in 177Lumolecular therapy were found. Although segmentation is an important step in internal dose calculations, this subject has been relatively lightly investigated for SPECT systems. This is mostly due to the inner features of SPECT. What is more, even when studies are conducted, they usually utilise the diagnostic radionuclide 99mTc and not a therapeutic one like 177Lu, which could be of concern regarding SPECT camera performance and its overall outcome on dosimetry.

Clinical outcomes in metastatic prostate adenocarcinoma treated with abiraterone and enzalutamide.

The management of metastatic prostate cancer has progressed immensely in the last decade. This study aims to investigate the real-world clinical outcomes of metastatic prostate adenocarcinoma treated with abiraterone and enzalutamide. The findings will assist healthcare providers in making more informed decisions when choosing between these two drugs for treating these patients. A retrospective analysis of 80 patients at our tertiary care hospital was conducted from January 2015 to July 2022. Data were analysed using SPSS version 20.0. An independent sample T-test was used for continuous data and the chi-square test for categorical data. Medians and means were calculated for continuous or ordinal variables. Kaplan-Meier survival curves presented progression-free and overall survival (OS), with comparisons made using the log-rank test. Survival rates with 95% CIs were reported, with p < 0.05 considered significant. In our final analysis of 80 patients, the median age was 65 years, with 88% having an eastern cooperative oncology group performance status between 0 and 2. Histopathology showed adenocarcinoma in 91% of cases. Grade Group III-IV disease was present in 51.3%, and 67.5% had a Gleason Score of >8. Bilateral orchidectomy was performed in 41 patients (51.25%), with a median Gonadotropin-releasing hormone analogue use of 32 months. Most patients (72.5%) were castration-sensitive. Among the 80 patients, 60 (75%) were treated with abiraterone and 20 (25%) with enzalutamide. The prostate-specific antigen (PSA) doubling time was >6 months in 80% of the abiraterone group and 75% of the enzalutamide group. PSA response rates were similar for both drugs, with comparable rates of progressive disease, partial response, stable disease and complete response (p = 0.036). There was no significant difference in median time to progression (19 months for abiraterone versus 18 months for enzalutamide) (95% CI 9.7-27.9; p = 0.004). The median OS for the entire cohort was 67 months (95% CI 39-94; p = 0.003). The findings suggest that both abiraterone and enzalutamide are effective in prolonging progression-free and overall survival in this patient population, providing comparable safety. Further studies are recommended to validate these findings and inform clinical decision-making.

TRPS1 expression in primary and metastatic prostatic adenocarcinoma, muscle invasive bladder urothelial carcinoma, and breast carcinoma: Is TRPS1 truly specific and sensitive for a breast primary?

Trichorhinophalangeal syndrome type 1 (TRPS1) has been reported to be a sensitive and specific immunohistochemical (IHC) marker for breast carcinomas, especially when determining primary site of origin. However, there is limited data on TRPS1 expression in prostate and bladder cancers.A two-phase study was performed with 1) an exploratory cohort analyzing TRPS1 gene alterations in prostate, bladder, and breast carcinoma and TPRS1 mRNA expression data in prostate and bladder carcinoma; and 2) TRPS1 and GATA3 IHC in a confirmatory cohort in prostate, bladder, and breast carcinoma samples.Gene alterations were identified in a subset of breast, bladder, and prostate carcinomas and mRNA was consistently detected. In the IHC cohort, 183/210 (87.1 %) of breast, 22/69 (31.9 %) of prostate, and 20/73 (27.4 %) of urothelial carcinomas showed staining with TRPS1. Intermediate to high expression of TRPS1 was observed in 173/210 (82.8 %) of breast, 17/69 (24.6 %) of prostate, and 15/73 (20.5 %) of urothelial carcinomas. Furthermore, in prostate cancer, 26.9 % of pelvic lymph node metastases and 50 % in sites of distant metastases showed expression. Increased TRPS1 mRNA expression (p = 0.032) and IHC expression (p = 0.040) correlated with worse overall survival in bladder cancer. By comparison, GATA3 IHC stained 136/210 (64.8 %) of breast, 0/69 (0 %) of prostate, and 63/73 (93 %) of bladder carcinomas. Intermediate to high expression of GATA3 was seen in 131/210 (62.4 %) of breast and 63/73 (93 %) of bladder carcinomas.This study shows there is significant staining of TRPS1 in bladder and prostate cancers. As a result, comprehensive studies are needed to establish the true specificity of TRPS1 IHC stain across various tumor types before its widespread clinical adoption.

Ethnic Incidence of Metastatic Prostate Carcinoma in a Veteran Affairs Medical Center’s (VAMC) And Early Surveillance Guided by Sites of Metastases

Abstract Introduction/Objective Ethnic difference in incidence, mortality, and prognosis for prostate adenocarcinoma is well known with disparities between African American (AA), Caucasian and Asian origin population reported by tumor heterogeneity and increased number of gene mutations in genomic profiling. Early metastasis of prostate cancer with younger age at the presentation in AA ethnicity has been noted. Earlier screening, biopsy and tumor molecular profiling may lead to a decrease in morbidity and mortality related to metastatic prostate cancer. While there are known differences in the incidence of prostate cancer between different ethnic groups and differences in ethnic access to care and diagnosis varies widely between distinct medical practices, the ethnic incidence of diagnoses of metastatic prostatic adenocarcinoma and distribution of sites particularly in a Veteran population has not been well studied. Methods/Case Report A retrospective search was performed from December 2019 to October 2022 for metastatic prostatic carcinoma specimens at regional Veteran Affairs Medical Center (VAMC). Both H &amp; E and immunohistochemical antibodies for prostate were reviewed and used in the diagnosis of metastatic carcinoma of prostate origin. Results (if a Case Study enter NA) A total of 21 cases with metastatic prostatic adenocarcinoma were found from which 9 were metastases to bone, 5 were metastases to lymph node and 7 were metastatic to other organ sites. Majority of the cases were of ethnic African American veterans (12/21, 57%), followed by Caucasian Americans (7/21, 33%), and 2 of unknown ethnicity (2/21, 10%). On examination, most frequent site of metastases by ethnic African Americans was lymph node in 4 out of the 5 (80%) total cases metastatic to lymph node, and 5 out of 6 total cases (83%) with metastases to different organ sites together. On the other hand, ethnic Caucasian Americans the most common metastatic site was bone with 6 out of 10 total cases (60%) metastatic to bone. Conclusion African American Veteran patients have a higher incidence of metastatic prostate carcinoma and a higher incidence of earlier metastases. A similar trend was seen in the study population with African Americans making up most of the study population and also suggestively having more cases of lymph node and other organ metastases. The increased proportion of African Americans in the study population with lymph node metastases suggests targeting lymph nodes for biopsy for early detection of the metastatic prostatic carcinoma.

Aberrant expression of GATA3 in metastatic adenocarcinoma of the prostate: an important pitfall.

The distinction of high-grade prostate cancer (PCa) from poorly differentiated urothelial carcinoma (UC) can be somewhat challenging on clinical and morphological grounds alone, yet it is of great importance for prognostication and choice of treatment. GATA3 is a useful immunohistochemical marker to confirm urothelial origin. However, recent works report strong GATA3 immunoexpression in primary high-grade PCa. The aim of this study was to explore GATA3 expression specifically in metastatic PCa. The pathology databases of four tertiary institutions were queried for cases of metastatic PCa. Available slides and clinical records were reviewed by experienced genitourinary pathologists. Prostatic markers (PSA, PSAP, NKX3.1) and GATA3 immunohistochemistry were performed. A total of 163 metastatic PCa cases were included. At least one prostate marker was positive in each case of non-regional distant metastasis, confirming prostatic origin. GATA3 strong staining was found in four (2.5%) cases: two liver, one bone and one non-regional lymph-node metastases. All four patients had Grade Group 5 PCa at the initial diagnosis. The metastatic prostatic adenocarcinomas were solid, either with no gland formation (n = 3) or with only focal cribriforming (n = 1). To our knowledge, this is the first study exploring GATA3 expression specifically in metastatic PCa. Despite being infrequent, GATA3 positivity in high-grade PCa may lead to misdiagnosis, with clinical implications. We recommend a panel of immunohistochemical markers, both prostatic and urothelial, for ruling out UC, either in primary tumour samples or in the event of metastases of unknown primary, when a genitourinary origin is suspected.

Toothache as the Leading Clinical Symptom of Metastatic Prostate Adenocarcinoma

Abstract Metastatic tumours in the oral region are rare and account for approximately 1% of all malignant oral tumours. Metastatic spread to the oral cavity has mostly been found in the jaws compared to the soft tissues but mandibular metastasis as the first manifestation of undiscovered prostate adenocarcinoma is very rare. We present the case of a 56-year-old man that had teeth extraction in a peripheral hospital following a complaint of toothache. Five months after the teeth extraction, he presented at University of Nigeria Teaching Hospital Ituku-Ozalla, Enugu, with complaints of lower urinary tract symptoms, left jaw pain, left jaw mass, difficulty in opening the mouth, low back pain, lower limb edema, and abdominal distension. After review by the gastroenterology, urology, and maxillofacial teams, the working diagnoses were metastatic prostate cancer, primary jaw tumor, and primary liver cell carcinoma. Abdominal computed tomography (CT) scan was suggestive of metastatic liver disease from an occult site. It also showed metastatic deposits on the right lung and an enlarged prostate with a suspicious focus. Craniofacial CT scan done was suggestive of an aggressive tumour of the left mandible while prostate-specific antigen was 116.5 ng/mL. He had a digitally guided prostate biopsy and an incisional biopsy of the left jaw mass. Histopathologic examination of both specimens was consistent with adenocarcinoma, hence establishing a diagnosis of prostate adenocarcinoma with metastasis to the left jaw, the liver, and the right lung.

68Ga-PSMA-11 PET/CT in a Case of Isolated Parietal Peritoneal Metastasis From Prostate Adenocarcinoma.

Isolated peritoneal metastasis of prostate cancer is extremely rare. We present 68Ga-PSMA-11 PET/CT findings in a case of isolated parietal peritoneal metastasis from prostate adenocarcinoma 35 months after radical prostatectomy. The peritoneal metastases showed multifocal intense PSMA uptake, but subtle structural abnormalities on 68Ga-PSMA-11 PET/CT. The patient was subsequently treated with androgen deprivation therapy. The peritoneal metastases progressed 25 months after the initiation of androgen deprivation therapy and were removed surgically. Histologic and immunohistochemical evaluation revealed metastatic prostate adenocarcinoma with treatment-related neuroendocrine differentiation. This case demonstrates the usefulness of 68Ga-PSMA-11 PET/CT in identifying atypical metastasis from prostate adenocarcinoma.