Adenocarcinoma Of The Prostate Research Articles

Inflammatory Patterns in the Prostate Gland and Serum Cytokine Activities in Primary Adenocarcinoma of the Prostate in Port Harcourt, Nigeria

Introduction: Chronic inflammation and pro-inflammatory cytokines such as (1L-6 and TNF-α) have been implicated in prostate carcinogenesis and metastasis. This study aims to evaluate serum concentrations of IL-6 and TNF-α, and to determine their association with clinicopathological patterns of prostate cancer in affected patients. Materials and Methods: Ninety (90) patients with histologically diagnosed prostate cancer (PCa), treated at the Urology Division of the University of Port Harcourt Teaching Hospital (UPTH), Nigeria were involved in this study. The enzyme-linked immunosorbent assay (ELISA) technique was used to assay cytokines (IL-6 and TNF-α), and serum PSA. Gleason Scores were categorized as well differentiated (GS of ≤ 6), moderately differentiated (GS = 7), and poorly differentiated (GS 8-10). Results were analyzed with IBM SPSS version 20.0. Pearson’s correlation test was used to determine the correlation between the cytokines (IL-6 and TNF-α) and Gleason Scores. Results: The modal age group with PCa was 60-69 years. The mean age of patients was 68.788.26 years, and the mean serum PSA 93.2478pg/ml. Serum levels of IL-6 and TNF-α were 8.0pg/ml, 11.2pg/ml and (27.0±26.4pg/ml) respectively. Forty-six subjects had poorly differentiated PCa (GS 8-10); 17 moderately differentiated (GS 7); and 27 well differentiated (GS ≤ 6). Mean serum levels of IL-6, TNF-α and PSA (113.1ng/ml) were raised and found highest in those with poorly differentiated PCa. Conclusion: The observed correlation was positive but weak. The patients might have commenced undeclared anti-inflammatory drugs that depressed inflammation. However, a larger sample size would probably confirm the prognostic value of IL-6 and TNF-α in PCa subjects.

SABR-Dual: a phase II/III trial of two-fraction versus five-fraction stereotactic radiotherapy for localized low- and favorable intermediate-risk prostate cancer.

Dose-escalated radiotherapy is known to improve progression free survival in patients with localized prostate cancer, and recent advances have led to the standardization of ultrahypofractionated stereotactic ablative radiotherapy (SABR) delivered in just 5-fractions. Based on the known effectiveness of the accepted though invasive 2-fraction treatment method of high-dose-rate brachytherapy and given the ubiquity of prostate cancer, a further reduction in the number of treatments of external-beam SABR is possible. This study aims to evaluate the safety, efficacy, and non-inferiority of generalizable 2-fraction SABR compared to the current 5-fraction regimen. 502 patients will be enrolled on this phase II/III randomized control trial. Eligible patients will have previously untreated low- or favorable intermediate-risk adenocarcinoma of the prostate. Patients will be randomized between standard SABR of 40Gy in 5 fractions given every-other-day and 27Gy in 2 fractions at least two days apart but completing within seven days. MRI-based planning, radiopaque hydrogel spacer insertion, and fiducial marker placement are required, and SABR will be delivered on either a standard CT-guided linear accelerator or MR-LINAC. The primary endpoint will be freedom from disease progression, with additional secondary clinical, toxicity, and quality of life endpoints. This study will be the largest prospective randomized trial, adequately powered to demonstrate non-inferiority, comparing 2-fraction SABR to standard 5-fraction SABR for localized prostate cancer. As the protocol does not obligate use of an MRI-LINAC or other adaptive technologies, results will be broadly generalizable to the wider community. This trial is registered on Clinicaltrials.gov: ClinicalTrials.gov Identifier: NCT06027892.

Saddle Pulmonary Embolus Treated With Bilateral Emergent Aspiration Pulmonary Thrombectomy

A 77 year old man with recurrent lower extremity thrombosis presented with acute onset shortness of breath and new onset hypoxemia three days after prostatectomy for adenocarcinoma of the prostate. He had been off anticoagulation during the perioperative period. In addition to his new diagnosis of prostate cancer he also had a remote history of treated non-invasive melanoma. Based on this presentation he was at high risk of developing thromboembolic disease. Computed tomography angiogram (CTA) of his chest confirmed a large saddle pulmonary embolus, echocardiogram was positive for new right ventricular wall motion dyskinesis and lower extremity ultrasound revealed bilateral acute and chronic deep vein thrombosis. Given his high bleeding risk, hypoxia and elevated troponin I, he underwent emergent successful aspiration pulmonary thrombectomy. This case is of interest to hospitalists and intesivists as it provides an overview of the current invasive management of pulmonary embolus in the acute setting when systemic anticoagulation is contraindicated. Emergent Aspiration Pulmonary Thrombectomy can restore pulmonary artery flow and cardiopulmonary hemodynamics. A collaborative team based approach that involves the emergency department, intensive care unit, interventional teams and hospitalists is favored.

Diffused Pulmonary Uptake of Tc-99m Methylene Diphosphonate Bone Scan in Patient with Prostate Cancer without Blood Test and Correlative/Cross-Sectional Imaging Abnormalities: A Case Report

Introduction: Bone scan using Tc-99m methylene diphosphonate (MDP) is a commonly used procedure for evaluating bone metastasis in cancer patients. Extra-osseous pulmonary uptake in bone scans is mostly an incidental finding and occurs in a multitude of disorders. Clinicians should be alert to any findings on clinical or complementary diagnostic tools. We presented a case of prostate cancer male patients who demonstrated diffuse pulmonary uptake on Tc-99m MDP bone scan without any blood test and correlative/cross-sectional imaging abnormality Case Presentation: An 80-year-old male with adenocarcinoma of the prostate with a Gleason score of 6 (3+3). The PSA level was 0.009. The patient had a history of recurrent atrial fibrillation (AF), postural dizziness, HTN, Gout, and chronic renal failure, but all of these comorbidities were under control. The patient underwent a bone scan to annually check for the presence of bone metastases. Three hours after administering 740 MBq Tc-99m MDP intravenously. The reports didn’t show any increased uptake that would indicate metastases in the bones. Instead, diffuse bilateral pulmonary uptake and a mild increase in cardiac uptake were present. On the same day, a computed tomography (CT) scan of the thorax revealed 3 micro-nodules in the right upper lung that were described as benign lesions, and a chest X-ray confirmed normal results. The patient’s laboratory results were within normal range, and there were no clinical lung symptoms or complaints. Considering the patient history of persistent AF, chronic renal failure, and a complaint of postural dizziness, the bone scan finding may indicate involvement of amyloidosis. The relationship between amyloidosis and cancer was also widely noted. Conclusions: Tc-99m MDP may play a role in evaluating amyloidosis involvement in an uncommon place such as the lungs. Future research should focus on analyzing diagnostic options in the patient’s condition in this situation. Keywords: cancer, diffused pulmonary uptake, amyloidosis, bone scan

Abstract 1049: Prevalence of KDM6A expression loss in human cancer: A tissue microarray study on 6,560 cancers from 114 different tumor types

Abstract KDM6A, also known as UTX (ubiquitously transcribed X chromosome tetratricopeptide repeat protein) is an epigenetic regulator constituting a critical part of the COMPASS-like complex. KDM6A mutations occur commonly in cancer. These are of interest because KDM6A loss results in a dependency on EZH2, a potential therapeutic target. Most data on KDM6A have been obtained by next generation sequencing (NGS). However, since most KDM6A mutations are truncating and KDM6A is located on the X chromosome, many mutations result in a complete expression loss which can be detected by immunohistochemistry (IHC). To learn more on the prevalence of KDM6A expression loss and its role in cancer, a tissue microarray containing 6,560 samples from 114 different tumor entities and 608 samples of 76 different normal tissue types was analyzed. In normal tissues, KDM6A staining was rather ubiquitously seen in nuclei. In cancer, KDM6A staining was considered weak (1+) in 581 (11.2%), moderate in 1,927 (37%), and strong in 2,362 (45.4%) of 5,206 interpretable tumors. A complete loss of KDM6A staining occurred in 336 (6.5%) of tumors. At least one case with a complete KDM6A expression loss was observed in 51 of 114 tumor categories. KDM6A staining was most commonly lost in different categories of urothelial carcinomas (19.5-39.2%), squamous cell carcinomas of the esophagus (27.1%), hepatocellular carcinoma (18.4%), gastric carcinoma (3.2-12.5%), papillary renal cell carcinoma (9.5%), adenocarcinoma of the prostate (5.9-9.4%), chromophobe renal cell carcinoma (8.9%), Ewing sarcoma (8.3%), pheochromocytoma (8.3%), and metastatic malignant melanoma (8%). A KDM6A expression loss in less than 8% of cases was observed in 32 further tumor entities. KDM6A expression loss was more than twice as frequent in tumors from male (8.4% of 2,526) than in tumors from female patients (3.9% of 2,024; p<0.0001). It is concluded that KDM6A IHC is a suitable method for the detection of truncating KDM6A mutations, especially in males. These make up for about 2/3 of all KDM6A mutations and may exert specific biological effects than differ from the various KDM6A missense mutations known to also occur. Citation Format: Florian Viehweger, Natalia Gorbokon, Maximilian Lennartz, Viktor Reiswich, Florian Lutz, Till Krech, Andreas M. Luebke, Claudia Hube-Magg, Guido Sauter, Ronald Simon, Stefan Steurer, Andreas H. Marx, Christian Bernreuther, Martina Kluth, Sarah Minner. Prevalence of KDM6A expression loss in human cancer: A tissue microarray study on 6,560 cancers from 114 different tumor types [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 1049.

Relation between Delay Time to Surgical Treatment of Prostate Cancer and Disease Recurrence Risk

Introduction: There is no consensus in the literature on a reasonable delay time from diagnosis to radical prostatectomy (RP) surgery, without worsening the prognosis. Objective: To evaluate the influence of the delay on the risk of disease recurrence in patients with acinar adenocarcinoma of the prostate treated with RP. Method: Four hundred and twelve patients undergoing RP were retrospectively evaluated. Of these, 172 were excluded due to incomplete data and another 28 due to preoperative staging as high-risk prostate cancer (PSA > 10 ng/mL or Gleason score on biopsy > 7). Pre-and postoperative stagings were compared and survival analysis was performed using the Kaplan-Meier method to investigate the influence of time on discordance between pre- and postoperative stagings. Results: For the 212 patients of the sample, the average time from diagnosis to RP was 176.1 ± 120.2 days (median 145.5 days), ranging from 29 to a maximum of 798 days. The Kaplan-Meier curve indicated that the cancer worsened the longer the delay between diagnosis and surgery. Patients undergoing surgery within 60 days had an approximately 95% probability of not increasing the initial risk of recurrence. This number fell to 80%, 70% and 50% in patients operated on up to 100, 120 and 180 days, respectively. Conclusion: Delay in performing RP represents a continuous risk of relapse. The ideal time for RP is up to 60 days from prostate biopsy, as the probability of upstaging is less than 5% in this period.

The prognostic value of ductal adenocarcinoma of the prostate in patients with advanced prostate cancer treated with abiraterone acetate.

167 Background: Previous studies have indicated that ductal adenocarcinoma of the prostate (DA) is associated with adverse prognosis in patients with localized prostate cancer (PCa). However, the clinical significance of DA in advanced PCa remains largely ambiguous. This study endeavors to investigate the relationship between the existence of DA in prostate biopsy specimens and treatment outcomes among patients with advanced PCa receiving abiraterone acetate (AA) therapy. Methods: We retrospectively analyzed data from 440 patients with advanced PCa who received AA at either the metastatic hormone-sensitive (mHSPC, N=123) or castration-resistant PCa (mCRPC, N=317) stage. The presence of DA and its proportion was evaluated based on prostate biopsy specimens. Kaplan-Meier curves and COX regression were used to evaluate the predictive significance of DA on AA efficacy, including PSA response, PSA progression-free survival (PSA-PFS), and radiographic progression-free survival (rPFS). Results: In aggregate, DA was detected in 35/440 (8.0%) patients, with 13/440 (3.0%) and 22/440 (5.0%) men harboring DA<5% and ≥5%, respectively, in the total tumors. The overall PSA response rate in the entire cohort was 302/440 (68.6%), and it was comparable for people with and without DA, with both groups having a response rate of 68.6%. Of note, compared with patients without DA, men with DA have significantly longer median PSA-PFS (mPSA-PFS, 12.1- vs. 25.0-Mo, P=0.005) and median rPFS (mrPFS, 19.8 vs. 38.2-Mo, P=0.034). Subgroup analysis based on DA proportion further revealed that in comparison with PCa without DA, DA≥5% was an indicator of favorable PSA-PFS (HR, 95%CI: 0.28, 0.14-0.56, p<0.001) and rPFS (HR, 95%CI: 0.35, 0.18-0.72, p=0.004), while DA<5% was not. In multivariate COX regression analysis, after adjusting by clinicopathological factors, including mCRPC/mHSPC stage, ISUP grading, metastatic burden, pain score and pretreatment hemoglobin, alkaline phosphatase, and lactate dehydrogenase, DA≥5% was still independently associated with better therapeutic efficacy of AA treatment (PSA-PFS: HR, 95%CI: 0.36, 0.17-0.74, p<0.001; rPFS: HR, 95%CI: 0.47, 0.23-0.96, p=0.040). Conclusions: A DA proportion ≥5% in the tumor is related to improved treatment efficacy for individuals with advanced PCa receiving AA. Thus, in the pathological diagnosis of PCa, it is necessary to routinely report the presence and proportion of DA in order to aid with treatment decision-making.

Construction and validation of a prognostic nomogram for ductal adenocarcinoma of the prostate: A population-based study.

This study aimed to establish and validate a nomogram for ductal adenocarcinoma of the prostate (DAC) to accurately predict the prognosis of DAC patients. The data of 834 patients with confirmed DAC were obtained from the Surveillance, Epidemiology, and End Results database. The cases were randomly assigned to the training and internal validation cohorts. Data from patients attending our institution as an external validation cohort (n = 35). Nomogram and web-based dynamic nomogram were constructed based on Cox regression analysis, and their prediction accuracy was evaluated by concordance index (C-index), calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis. Multivariate analyses identified age, T-stage, N-stage, M-stage, surgery, lymph node dissection, Gleason score, and PSA as independent prognostic factors for overall survival. The C-index and calibration curves demonstrate the good discriminative performance of the prediction model. The area under the curve further confirmed the accuracy of the nomogram in predicting survival. In addition, the area under the curve and decision curve analysis were better than the 7th tumor-node-metastasis staging system. The Kaplan-Meier curves of the nomogram-based risk groups showed significant differences (P < .001). We constructed and validated the first nomogram to predict patients with DAC.

Actinium-225-PSMA radioligand therapy of metastatic castration-resistant prostate cancer (WARMTH Act): a multicentre, retrospective study

Actinium-225 (225Ac) prostate-specific membrane antigen (PSMA) radioligand therapy (RLT) is a novel therapy for metastatic castration-resistant prostate cancer (mCRPC). We aimed to report the safety and antitumour activity of 225Ac-PSMA RLT of mCRPC in a large cohort of patients treated at multiple centres across the world. This retrospective study included patients treated at seven centres in Australia, India, Germany, and South Africa. We pooled data of consecutive patients of any age and Eastern Cooperative Oncology Group performance status with histopathologically confirmed adenocarcinoma of the prostate who were treated with one or more cycles of 8 MBq 225Ac-PSMA RLT administered intravenously for mCRPC. Previous lines of mCRPC treatment included taxane-based chemotherapy, androgen-receptor-axis inhibitors, lutetium-177 (177Lu) PSMA RLT, and radium-223 dichloride. The primary outcomes were overall survival and progression-free survival. Between Jan 1, 2016, and May 31, 2023, 488 men with mCRPC received 1174 cycles of 225Ac-PSMA RLT (median two cycles, IQR 2-4). The mean age of the patients was 68·1 years (SD 8·8), and the median baseline prostate-specific antigen was 169·5 ng/mL (IQR 34·6-519·8). Previous lines of treatment were docetaxel in 324 (66%) patients, cabazitaxel in 103 (21%) patients, abiraterone in 191 (39%) patients, enzalutamide in 188 (39%) patients, 177Lu-PSMA RLT in 154 (32%) patients, and radium-223 dichloride in 18 (4%) patients. The median follow-up duration was 9·0 months (IQR 5·0-17·5). The median overall survival was 15·5 months (95% CI 13·4-18·3) and median progression-free survival was 7·9 months (6·8-8·9). In 347 (71%) of 488 patients, information regarding treatment-induced xerostomia was available, and 236 (68%) of the 347 patients reported xerostomia after the first cycle of 225Ac-PSMA RLT. All patients who received more than seven cycles of 225Ac-PSMA RLT reported xerostomia. Grade 3 or higher anaemia occurred in 64 (13%) of 488 patients, leukopenia in 19 (4%), thrombocytopenia in 32 (7%), and renal toxicity in 22 (5%). No serious adverse events or treatment-related deaths were recorded. 225Ac-PSMA RLT shows a substantial antitumour effect in mCRPC and represents a viable therapy option in patients treated with previous lines of approved agents. Xerostomia is a common side-effect. Severe bone marrow and renal toxicity are less common adverse events. None.

Carboplatin and Etoposide for the Treatment of Metastatic Prostate Cancer with or without Neuroendocrine Features: A French Single-Center Experience.

Chemotherapy using carboplatin and etoposide (CE) is frequently pragmatically proposed to treat metastatic prostate cancer (mPC), both primary small-cell neuroendocrine (PSC-NE) carcinoma and adenocarcinoma with or without neuroendocrine (NE) marker elevation. However, the real benefit of CE is poorly reported in the recent therapeutic context. We retrospectively analyzed the efficacy and tolerance of CE chemotherapy in these three different groups of mPC patients. Efficacy endpoints included radiological response, progression-free survival (PFS), and overall survival (OS), as well as PSA response and PFS2/PFS1 ratio in patients with adenocarcinoma. Sixty-nine patients were included in this single-center study (N = 18 with PSC-NE carcinoma and 51 with adenocarcinoma with (N = 18) or without (N = 33) NE marker elevation). Patients with adenocarcinoma were highly pretreated with next-generation hormonal agents (NHAs) and taxanes. In patients with adenocarcinoma, a PSA response ≥50% was observed in six patients (15.8%), four of whom had NE marker elevation. The radiological response was higher in PSC-NE and tended to be higher in adenocarcinoma when NE marker elevation was present. Comparing patients with adenocarcinoma with vs. without NE marker elevation, the median PFS was 3.7 and 2.1 months and the median OS was 7.7 and 4.7 months, respectively. Overall, 62.3% of patients experienced grade 3-4 adverse events (mainly hematological), and three treatment-related deaths were recorded. Reports of the clinical results of CE suggest that we should not mix PSC-NE and castration-resistant adenocarcinoma of the prostate. In patients with heavily pretreated adenocarcinoma, the benefit/risk ratio of CE chemotherapy seems unfavorable due to poor response and high toxicity.

Abstract C090: High GLUT1 membrane expression and low PSMA membrane expression in ductal adenocarcinoma and intraductal carcinoma of the prostate

Abstract Background: Both Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma (IDC) of the prostate are generally associated with aggressive clinical behavior and poor prognosis and can be lethal. Furthermore, previous studies linked aggressive clinical behavior and poor prognosis with discordant FDG positivity and low Prostate-specific membrane antigen (PSMA) expression. A recent study only cited a DAC patient with low 68Ga-PSMA-11 PET/CT uptake but high 18F-FDG PET/CT uptake, however, there is lack of directly compared articles nor large data sets. IDC-P has similar cribriform pattern in the pathological structure as a mean differential diagnosis for DAC. Hence, the objective of this study was to investigate the expression of PSMA and GLUT1 in DAC and IDC-P patients. Methods: The study was conducted on 87 DAC or IDCP patients without any treatment and 97 PAC patients with a Gleason score ≥ 8 of prostate biopsies and prostatectomy samples between August 2017 and August 2022. We performed immunohistochemical staining and scoring of various cancer component samples from the patients to reflect the protein expression levels of PSMA and GLUT1. Results: PSMA expression in PAC tissues was significantly higher than in DAC/IDC-P tissues (141.2 vs 78.6, p &amp;lt; 0.001). There was no significant difference in PSMA membrane expression between DAC/IDC-P and adjacent acinar adenocarcinoma (78.6 vs 93.4, p = 0.166). GLUT1 expression was higher in DAC/IDC-P tissue than in acinar adenocarcinoma tissue adjacent to DAC/IDC-P (68.6 vs 51.3, p = 0.007), but was still lower than that in PAC tissue (68.6 vs 93.1, p = 0.0014). It is worth noting that GLUT1 membrane expression in DAC/IDC-P was significantly increased than in PAC (13.0 vs 6.6, p = 0.025), and in acinar adenocarcinoma adjacent to DAC/IDC-P (13.0 vs 2.0, p &amp;lt; 0.001). Conclusions: In DAC and IDC-P tissues, PSMA membrane expression is low, while GLUT1 expression, especially GLUT1 membrane expression is high. These findings imply that DAC and IDC-P cells may have higher glucose metabolic and raise interest in targeting membrane GLUT1 as a novel anticancer strategy for DAC/IDC-P and other prostate cancer with high glucose metabolism. Citation Format: Xingming Wang, Xiaomei Gao, Lin Qi, Ye Zhang, Hongling Yin, Yu Gan, Yi Cai. High GLUT1 membrane expression and low PSMA membrane expression in ductal adenocarcinoma and intraductal carcinoma of the prostate [abstract]. In: Proceedings of the 16th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2023 Sep 29-Oct 2;Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2023;32(12 Suppl):Abstract nr C090.

UTILITY OF P63 IMMUNO-EXPRESSION IN DISTINGUISHING BENIGN MIMICKER LESIONS FROM ADENOCARCINOMA PROSTATE-AN OBSERVATIONAL ANALYTICAL STUDY

In men, prostate cancer (PCA) is the second most common malignancy and is the sixth leading cause of death amongst them. Differentiation of benign mimicker lesions (BML) of the prostate from PCA can be challenging sometimes, especially when limited amount of tissue is available. Several immuno-histochemical (IHC) markers are recommended for distinguishing such lesions; which becomes expensive for the patient. The present study was planned to study the utility of P63 IHC marker for diagnosis of benign, BML and adenocarcinoma of the prostate (ACP). The present - observational and analytical study - was conducted on 50 biopsy specimens of the prostate in the Department of Pathology at IIMSR, Lucknow during the period January 2017 to September 2022. The lesions included were: 20 specimens of benign prostatic hyperplasia (BPH), 17 of BML, 3 of prostatic intraepithelial neoplasia (PIN) and 10 of PCA. In the BML group, 5 specimens of basal cell hyperplasia (BCH), 4 specimens of simple atrophy (SA), 3 specimens of post atrophic hyperplasia (PAH) and 5 specimens of adenosis were studied. In the present study, all specimens of BPH and BML are positive for P63 expression on IHC staining. In the PIN group, 2 out of 3 specimens were positive for P63. All 10 specimens of adenocarcinoma prostate were negative for P63 expression. We conclude that use of P63 IHC staining is adequate for distinguishing benign and BMLof prostate fromACPin majority of the specimens.

Stable Therapeutic Transgenic FIX Levels for More Than 10 Years in Subjects with Severe Hemophilia B Who Received scAAV2/8-LP1-Hfixco Adeno-Associated Virus Gene Therapy

Background: Previously, we reported data from a first-in-human, dose-escalation, Phase 1 gene therapy trial demonstrating a dose-dependent increase in transgenic factor IX (FIX) expression in 10 adults with severe hemophilia B (FIX activity ≤1%). This was achieved following a single intravenous infusion of a self-complementary adeno-associated virus (scAAV) vector containing the wild-type FIX gene (codon-optimized), under the control of a synthetic liver-specific promoter and pseudotyped AAV8 capsid (scAAV2/8-LP1-hFIXco; ClinicalTrials.gov:NCT00979238). We now report durable efficacy and long-term safety over at least 10 years of follow-up in these participants. Methods: FIX activity, annualized bleeding rate (ABR), use of FIX concentrates, safety (specifically transaminitis and oncogenesis), and FIX expression kinetics were evaluated in the 10 participants following a bolus infusion of scAAV2/8-LP1-hFIXco at a dose of 2x10 11vg/kg (N=2), 6x10 11vg/kg (N=2), or 2x10 12vg/kg (N=6), between 2010 and 2012. Results: As of December 31, 2022, the median follow-up was 10.7 years (range 4-12 years). A total of 11 treatment-related adverse events occurred in 10 participants, including transient elevation of liver transaminases within 3 months of vector infusion in 4 of 6 patients treated with the high vector dose, without any recurrence. Two new serious adverse events were reported: (1) non-mucinous lung adenocarcinoma in situ, identified incidentally following a bullectomy for spontaneous pneumothorax 5 years after gene therapy in a 48-year-old participant considered not related to gene therapy following molecular studies, and (2) adenocarcinoma of the prostate in a 72-year-old participant 12 years after gene therapy. Tissue evaluation of the latter case is ongoing. No FIX inhibitors, thrombosis, persistent transaminitis or deaths were observed. Transgenic FIX expression has remained stable, with mean (±SD) FIX activity (one-stage) for the three dose cohorts of 1.7±0.9, 2.3±0.9 and 4.9±2.2 IU/dL, respectively (Figure 1). The mean and median ABR over the 10-year period following gene therapy of all 10 participants were 1.95 and 1.6 compared to 16.5 and 14, respectively, before gene therapy. This represents an 8.5-fold reduction in bleeding events (Wilcoxon signed rank test p=0.002). In the 6 high-dose participants, the ABR was 21-fold lower (mean=1.16, median 1, paired t-test, p&amp;lt;0.008). Mean and median FIX concentrate usage before gene therapy in the 10 participants were 2869 and 2526 IU/kg dropping to 945 and 274 IU/kg, respectively, over a 10-year period after gene therapy (p=0.0003). All participants developed a persistent, high-titer polyclonal anti-AAV8 capsid-specific antibody response after administration of scAAV2/8-LP1-hFIXco. Conclusion: Expression of transgenic FIX has remained stable over a period of 10 years following systemic administration of scAAV2/8-LP1-hFIXco resulting in sustained clinical benefit, with substantial reduction in ABR and FIX concentrate use.

High GLUT1 membrane expression and low PSMA membrane expression in Ductal Adenocarcinoma and Intraductal Carcinoma of the prostate.

Both Ductal Adenocarcinoma (DAC) and Intraductal Carcinoma (IDC) of the prostate are generally associated with aggressive clinical behavior and poor prognosis, which were linked with discordant FDG positivity and low Prostate-Specific Membrane Antigen (PSMA) expression. A recent study only cited a DAC patient with low 68Ga-PSMA-11 PET/CT uptake but high 18F-FDG PET/CT uptake, however, there is lack of directly compared articles nor large data sets. Hence, the objective of this study was to investigate the expression of PSMA and GLUT1 in DAC and IDC-P patients. The study was conducted on 87 DAC or/and IDC-P patients without any treatment and 97 PAC patients with a Gleason score ≥8 of prostate biopsies and prostatectomy samples between August 2017 and August 2022. We performed immunohistochemical staining and scoring of various cancer component samples from the patients to reflect the protein expression levels of PSMA and GLUT1. PSMA expression in PAC was significantly higher than in DAC/IDC-P (141.2 vs 78.6, p < 0.001). There was no significant difference in PSMA expression between DAC/IDC-P and adjacent PAC (78.6 vs 93.4, p = 0.166). GLUT1 expression was higher in DAC/IDC-P than in adjacent PAC (68.6 vs 51.3, p = 0.007), but was still lower than that in pure PAC (68.6 vs 93.1, p = 0.0014). It is worth noting that GLUT1 membrane expression in DAC/IDC-P was significantly increased than in pure PAC (13.0 vs 6.6, p = 0.025), and in PAC adjacent to DAC/IDC-P (13.0 vs 2.0, p < 0.001). In DAC/IDC-P tissues, PSMA expression is low, while GLUT1 expression, especially GLUT1 membrane expression is high. These findings imply that DAC/IDC-P may have higher glucose metabolic and raise interest in targeting membrane GLUT1 as a novel anticancer strategy for DAC/IDC-P and other prostate cancer with high glucose metabolism.

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.

Genomic and Evolutionary Characterization of Concurrent Intraductal Carcinoma and Adenocarcinoma of the Prostate.

The genomic, transcriptomic, and epigenomic characterization of concurrent intraductal carcinoma and adenocarcinoma of the prostate deepens the biological understanding of this lethal disease and provides a genetic basis for developing targeted therapies.

Phase III Study of Hypofractionated, Dose Escalation Radiotherapy vs. Conventional Pelvic Radiation Therapy followed by High Dose Rate Brachytherapy Boost for High Risk Adenocarcinoma of the Prostate (PCS VI): Acute Toxicity Results

The low α\β ratio of 1.2-2 for prostate cancer (PCa) suggests high radiation-fraction sensitivity and predicts a therapeutic advantage of lager fraction size. We have recently shown (PCS5) that high risk prostate cancer patients can safely and effectively be treated with moderate hypofractionated radiation therapy (HF-RT). To date there has been no phase-III randomized clinical-trial comparing moderately HF-RT with EBRT and HDR boost (HDRB). We are reporting the acute safety of EBRT+HDRB compared to moderate HF-RT in this phase III Canadian trial. From January 2015-June 2022, 308 high-risk localized PCa patients were randomized to receive either HF-RT or EBRT+HDRB. All patients received neo-adjuvant, concurrent, and long-term adjuvant androgen deprivation therapy (ADT). EBRT+HDRB consisted of 46 Gy in 2 Gy per fraction to the pelvis and a 15 Gy in one fraction HDR boost within 3 weeks of EBRT. HF-RT include concomitant dose escalation of 68 Gy in 2.72 Gy per fraction to the prostate, and 45 Gy in 1.8 Gy per fraction to the pelvic lymph-nodes. Of the 308 patients, 148 received HF-RT and 144 EBRT+ HDRB. The remainder either withdrew from the study or were treated with standard (2 Gy per fraction) fractionation for technical reasons. In both intention to treat and as treated analysis, using log-Rank, there were more grade 1 or worse (G1+) acute GI and GU events and more G2+ acute GI events in the HF-RT than EBRT+HDRB. As treated analysis the acute G1+ and G2+ GI events were 92 vs 77 (60.1% vs. 53.5%; p < 0.017) and 21 vs 10 (13.7% vs. 6.9%; p = 0.052), respectively for HF-RT and EBRT + HDRB. Similarly, the G1+ acute GU events were 123 vs. 101 (80.4% vs.70.1%; p < 0.001) respectively for HF-RT and EBRT+HDRB. There were only four G3 GI and one G3 GU acute toxicities in both arms. No grade 4 toxicities were reported. This is the first study of EBRT+HDRB compared to moderate HF dose escalated RT in high-risk prostate cancer patients treated with long-term ADT and pelvic RT. Our results demonstrate that both treatment approaches are well-tolerated and that EBRT+HDRB carries less G2+ GI and G1+ GU acute toxicities.

Biochemical Recurrence Surrogacy for Clinical Outcomes After Radiotherapy for Adenocarcinoma of the Prostate.

The surrogacy of biochemical recurrence (BCR) for overall survival (OS) in localized prostate cancer remains controversial. Herein, we evaluate the surrogacy of BCR using different surrogacy analytic methods. Individual patient data from 11 trials evaluating radiotherapy dose escalation, androgen deprivation therapy (ADT) use, and ADT prolongation were obtained. Surrogate candidacy was assessed using the Prentice criteria (including landmark analyses) and the two-stage meta-analytic approach (estimating Kendall's tau and the R2). Biochemical recurrence-free survival (BCRFS, time from random assignment to BCR or any death) and time to BCR (TTBCR, time from random assignment to BCR or cancer-specific deaths censoring for noncancer-related deaths) were assessed. Overall, 10,741 patients were included. Dose escalation, addition of short-term ADT, and prolongation of ADT duration significantly improved BCR (hazard ratio [HR], 0.71 [95% CI, 0.63 to 0.79]; HR, 0.53 [95% CI, 0.48 to 0.59]; and HR, 0.54 [95% CI, 0.48 to 0.61], respectively). Adding short-term ADT (HR, 0.91 [95% CI, 0.84 to 0.99]) and prolonging ADT (HR, 0.86 [95% CI, 0.78 to 0.94]) significantly improved OS, whereas dose escalation did not (HR, 0.98 [95% CI, 0.87 to 1.11]). BCR at 48 months was associated with inferior OS in all three groups (HR, 2.46 [95% CI, 2.08 to 2.92]; HR, 1.51 [95% CI, 1.35 to 1.70]; and HR, 2.31 [95% CI, 2.04 to 2.61], respectively). However, after adjusting for BCR at 48 months, there was no significant treatment effect on OS (HR, 1.10 [95% CI, 0.96 to 1.27]; HR, 0.96 [95% CI, 0.87 to 1.06] and 1.00 [95% CI, 0.90 to 1.12], respectively). The patient-level correlation (Kendall's tau) for BCRFS and OS ranged between 0.59 and 0.69, and that for TTBCR and OS ranged between 0.23 and 0.41. The R2 values for trial-level correlation of the treatment effect on BCRFS and TTBCR with that on OS were 0.563 and 0.160, respectively. BCRFS and TTBCR are prognostic but failed to satisfy all surrogacy criteria. Strength of correlation was greater when noncancer-related deaths were considered events.

Heart transplantation and human immunodeficiency virus–navigating drug-drug interactions: a case report

BackgroundAntiretroviral therapy (ART) has led to a decline in human immunodeficiency virus (HIV)-related mortality, but comorbidities, including organ dysfunction, are increasingly the focus of care. Heart transplant (HT) is a very effective therapeutic strategy for end-stage heart failure (HF); however, clinicians may be hesitant due to concerns of complex drug-drug interactions (DDIs) between ART and HT immunosuppressive regimens and the potential impact of ART on long-term HT outcomes. In this report, we describe long-term (76-month) follow-up of a patient with HIV-positive status who underwent orthotopic HT with special emphasis on complex drug interactions.Case presentationA 58-year-old man with HIV-1 developed ischemic cardiomyopathy, progressed to end-stage HF and underwent orthotopic HT. To avoid DDIs with planned immunosuppressive therapies, the ART regimen was modified to consist of lamivudine, tenofovir disoproxil fumarate, rilpivirine, and raltegravir. Following HT, the patient’s immunosuppression consisted of tacrolimus and mycophenolate mofetil. He has had normal cardiac function and no opportunistic infections and was subsequently switched to tenofovir alafenamide, emtricitabine, and bictegravir in combination for convenience. Serial HIV-1 RNA blood levels were constantly below the limit of quantification, and his CD4 count remained above 200 cells/mm3 (30–35%). Several DDIs were identified and addressed; however, his long-term post-HT complications included one episode of asymptomatic acute cellular rejection, adenocarcinoma of the prostate, basal cell carcinoma, cardiac allograft vasculopathy, and peripheral neuropathy.ConclusionThe clinical outcome of this case supports the conclusion of previously published reports, summarized here within, demonstrating that HIV-1 positive status should not preclude HT in carefully selected individuals. Both addressing potential DDIs prior to HT and long-term monitoring for routine post-transplant complications and secondary and incidental malignancies are imperative.

Prostatic Metastasis Mimicking a Ligamentum Flavum Cyst in Thoracic Spine: A Case Report

A rare finding of a prostatic carcinoma metastasized in a ligamentum flavum at thoracic spine causing posterior column spinal cord compression. We reported a man with prostatic carcinoma presented with ataxic gait. Magnetic resonance imaging revealed an extradural cystic mass adjacent to the T4 intralaminar region indenting on the spinal cord. T4 posterior decompression via en bloc excision of the ligamentum flavum cyst and laminectomy was performed. Histopathology confirmed glandular tissue within the cyst wall which corresponds to prostatic adenocarcinoma cells. Two months post-operative, patient showed improvement in his muscle strength on left L2 myotome. The preoperative diagnosis is a challenge because of the ligamentum flavum cysts rarity in the thoracic spine and non-specific clinical signs and symptoms. To our best knowledge, this is the first report of metastatic adenocarcinoma of the prostate found as ligamentum flavum cysts.