Integrated Bioinformatics Analysis Identified ASNS and DDIT3 as the Therapeutic Target in Castrate-Resistant Prostate Cancer.

Many studies have demonstrated the mechanisms of progression to castration-resistant prostate cancer (CRPC) and novel strategies for its treatment. Despite these advances, the molecular mechanisms underlying the progression to CRPC remain unclear, and currently, no effective treatments for CRPC are available. Here, we characterized the key genes involved in CRPC progression to gain insight into potential therapeutic targets. Bicalutamide-resistant prostate cancer cells derived from LNCaP were generated and named Bical R. RNA sequencing was used to identify differentially expressed genes (DEGs) between LNCaP and Bical R. In total, 631 DEGs (302 upregulated genes and 329 downregulated genes) were identified. The Cytohubba plug-in in Cytoscape was used to identify seven hub genes (ASNS, AGT, ATF3, ATF4, DDIT3, EFNA5, and VEGFA) associated with CRPC progression. Among these hub genes, ASNS and DDIT3 were markedly upregulated in CRPC cell lines and CRPC patient samples. The patients with high expression of ASNS and DDIT3 showed worse disease-free survival in patients with The Cancer Genome Atlas (TCGA)-prostate adenocarcinoma (PRAD) datasets. Our study revealed a potential association between ASNS and DDIT3 and the progression to CRPC. These results may contribute to the development of potential therapeutic targets and mechanisms underlying CRPC progression, aiming to improve clinical efficacy in CRPC treatment.

Novel percutaneous technique for creation of porcine model of tricuspid regurgitation via two routes.

OBJECTIVE: To develop an experimental porcine model of tricuspid regurgitation using two induction routes: the inferior vena cava and superior vena cava. METHODS: Tricuspid regurgitation was generated using the loop wire cutting method. The tricuspid regurgitation jet direction was controlled by accessing the valve through the inferior (n = 7) or superior (n = 6) vena cava. The occurrence, direction, and progression of tricuspid regurgitation were assessed postoperatively, and echocardiography was performed at 4 to 6 weeks. Right heart dilatation was assessed using computed tomography after 6 weeks. RESULTS: Moderate to severe or torrential tricuspid regurgitation occurred immediately after the procedure in 12 of 13 animals. The jet was directed toward the septum in five of seven animals in the inferior vena cava group and toward the posterolateral side in four of six animals in the superior vena cava group. The dimensions of the right heart (right atrium, ventricle, and tricuspid valve annulus) were significantly enlarged at the 4- to 6-week follow-up echocardiographic examination and confirmed to be enlarged by computed tomography, independent of the route used. CONCLUSION: The loop wire cutting method successfully induced a disease model of tricuspid regurgitation while controlling the regurgitation jet direction via two procedural routes.

The Association of Subspecialty and Sex with Industry Payments to Internal Medicine Physicians Who Recently Completed Training.

BACKGROUND: Financial relationships with drug and medical device companies may impact quality of care and academic research. However, little is known when and how these financial relationships develop among newly independent physicians who recently completed from residency or fellowship programs in internal medicine (IM). OBJECTIVE: To compare patterns of industry payments among IM graduates. DESIGN: Retrospective, observational cohort study. SUBJECTS: IM graduates from residency or fellowship programs between January 2015 and December 2019. MAIN MEASURES: We analyzed Open Payments reports made between July 2015 and June 2021 to recent graduates of U.S. Accreditation Council for Graduate Medical Education (ACGME)-accredited residency and fellowship programs in IM. The primary outcome was general payments accepted by these physicians, stratified by procedural (i.e., critical care medicine/pulmonary medicine, cardiac/cardiovascular disease, and gastroenterology) and non-procedural (i.e., infectious disease, general internal medicine, and other specialties) subspecialties. The secondary outcomes included general payments stratified by sex and age at residency or fellowship training completion. KEY RESULTS: There were 41,669 IM physicians with a median age of 33.0 years. In the first 3 years after completion, the proportion of physicians accepting any general payments was 72.6%, 91.9%, and 86.8% in Critical Care Medicine/Pulmonary Medicine, Cardiac/Cardiovascular Disease, and Gastroenterology, compared to 56.1%, 52.6%, and 52.3% in Infectious Disease, General Internal Medicine, and Other Specialties (p<0.0001). After adjusting for confounding variables, the procedural group showed an increased hazard ratio (HR) for accepting any general payments and at least $5000 of general payments compared to the non-procedural group. The HRs of accepting any general payments in the procedural subspecialty were 2.26 (95% CI, 2.11-2.42) and 2.83 (95% CI, 2.70-2.97) in female and male physicians, respectively (p-value < 0.0001). CONCLUSION: Industry financial relationships among newly independent physicians in IM exist immediately after completion of training and are influenced by subspecialty, sex, and age.

Ambient particulate matter exposure and urologic cancer: a longitudinal nationwide cohort study.

Increased particulate matter (PM) exposure is positively associated with increased incidence and mortality of many human malignancies. However, evidence of urologic cancer is limited. We aimed to evaluate the association between PM10 exposure and the relative risk of urologic cancer. This nationwide longitudinal cohort study included 231,997 participants who underwent a baseline health examination in 2008 from the National Health Information Database of Korea. The primary endpoint was newly diagnosed urologic cancer according to PM10 exposure. Of the total 231,99 participants, 50,677 developed urologic cancer during a median follow-up of 6.7 years. After controlling for confounding factors, participants in the high PM10 exposure group had a higher risk of kidney cancer (hazard ratio [HR] 1.111, 95% confidence interval [CI] 1.068-1.157) and prostate cancer (HR 1.083, 95% CI 1.058-1.109) than those in the low PM10 exposure group. However, in urothelial cell carcinoma, there was no significant increase in the HRs in the high PM10 exposure group. For kidney cancer, participants with the following characteristics were more susceptible: age < 65 years, female sex, decreased regular physical activity, current smoking, no diabetes, no hypertension, normal body mass index, and desirable total cholesterol level. For prostate cancer, participants with the following characteristics were more susceptible: decreased regular physical activity, current smoking, and no hypertension. High PM10 exposure is associated with an increased risk of overall urologic cancers, especially kidney and prostate cancer.

The Development of a Permanent Implantable Spacer with the Function of Size Adjustability for Customized Treatment of Regurgitant Heart Valve Disease.

The Pivot Mandu is an innovative device featuring a leak-tight adjustable 3D balloon spacer, incorporating inner mesh support, an outer e-PTFE layer, and a compliant balloon in the middle layer with a specialized detachable system. To assess its feasibility, proof of concept was rigorously evaluated through bench testing and survival porcine animal experiments. The results demonstrated successful remote inflation of the balloon system, with the balloon spacer exhibiting sustained patent and functional integrity over an extended observation period of up to 6 months. A noteworthy feature of the newly designed 3D balloon spacer is its capability for easy size adjustment during procedures, enhancing its adaptability and practicality in clinical settings. This three-layered 3D balloon spacer, with its established long-term patency, exhibits highly encouraging outcomes that hold promise in overcoming the current limitations of spacer devices for heart valve diseases. Given the compelling results from preclinical investigations, the translation of the Pivot Mandu into human trials is strongly warranted.

Impact of Particulate Matter With an Aerodynamic Diameter <2.5 µm Concentration on Postoperative Renal Function in Living Kidney Donors.

BACKGROUND: Ambient air pollution has become 1 of the most important public health issues worldwide. In particular, particulate matter with an aerodynamic diameter <2.5 µm (PM2.5) is a fatal component of air pollution. We aimed to analyze whether perioperative exposure to PM2.5 is associated with the deterioration of renal function in living kidney donors. METHODS: This study was conducted on 232 kidney donors with postoperative 2-year glomerular filtration rate (GFR). The GFR was determined by serum creatinine-based method using the Modification of Diet in Renal Disease equation and radionuclide-based method using 99mTc-DTPA renal scintigraphy. Perioperative exposure to PM2.5 was calculated using data from the AIRKOREA System. Multiple linear and logistic regression analyses were performed to estimate the associations between mean PM2.5 concentration and postoperative 2-year GFR. RESULTS: Postoperative Modification of Diet in Renal Disease-estimated GFRs of kidney donors with low PM2.5 concentrations were significantly higher than those of those with high PM2.5 concentrations. A 1-µg/m3 increase in mean PM2.5 concentration was associated with decreased GFR by 0.20 mL/min/1.73 m2. In addition, a 1-µg/m3 increase in mean PM2.5 concentration was associated with an 11% increased risk of chronic kidney disease stage ≥3 at 2 years after donor nephrectomy. CONCLUSION: In patients who underwent donor nephrectomy, exposure to PM2.5 negatively affects renal function and is positively associated with the prevalence of chronic kidney disease.

Identification of Lineage-specific Transcriptional Factor-defined Molecular Subtypes in Small Cell Bladder Cancer.

Small cell/neuroendocrine bladder cancers (SCBCs) are rare and highly aggressive tumors that are associated with poor clinical outcomes. We discovered that lineage-specific transcription factors (ASCL1, NEUROD1, and POU2F3) defined three SCBC molecular subtypes that resemble well-characterized subtypes in small cell lung cancer. The subtypes expressed various levels of neuroendocrine (NE) markers and distinct downstream transcriptional targets. Specifically, the ASCL1 and NEUROD1 subtypes had high NE marker expression and were enriched with different downstream regulators of the NE phenotype (FOXA2 and HES6, respectively). ASCL1 was also associated with the expression of delta-like ligands that control oncogenic Notch signaling. POU2F3, a master regulator of the NE low subtype, targeted TRPM5, SOX9, and CHAT. We also observed an inverse association between NE marker expression and immune signatures associated with sensitivity to immune checkpoint blockade, and the ASCL1 subtype had distinct targets for clinically available antibody-drug conjugates. These findings provide new insight into molecular heterogeneity in SCBCs with implications for the development of new treatment regimens. PATIENT SUMMARY: We investigated the levels of different proteins in a specific type of bladder cancer (small cell/neuroendocrine; SCBC). We could identify three distinct subtypes of SCBC with similarity to small cell/neuroendocrine cancers in other tissues. The results may help in identifying new treatment approaches for this type of bladder cancer.

Impact of modified bladder neck suspension on early recovery of continence after robot-assisted radical prostatectomy (RARP).

The incontinence after RARP significantly decreases the quality of life in prostate cancer patients. A number of techniques have been introduced for the recovery of continence after RARP. Although, the mechanism of the continence recovery is still unclear. We aimed to evaluate the early recovery of continence after RARP by inducing early anterior adhesion and reducing the hypermobility of the urethra through the modified bladder neck suspension (BNS) procedure. From March 2018 to February 2020, a total of 227 consecutive patients who underwent RARP (by single surgeon) were included. Patients were divided into two groups based on operation procedure (Standard procedure vs BNS procedure). Demographics, perioperative variables, and pathologic outcome were analyzed. We assessed recovery of continence at 1, 3, 6 and 9 months after surgery. Postoperative recovery of continence defined as the use of no pad during 24 h. Multivariable logistic regression analyses were performed to evaluate independent predictors of the early recovery of continence at 1 month. We performed RARP with standard procedure (n = 106) or BNS procedure (n = 121). There was no statistical difference in perioperative variables between the two groups except anastomosis time (21.6 ± 12.9 vs 17.0 ± 7.6, p = 0.003). The pad free continence rate were 80.2% (standard group) and 91.3% (BNS group) at 9 month after RARP (p = 0.037). However, early continence rate (1mo) were significantly higher in the BNS group (12.3% vs 29.1%, p = 0.004). On multivariate logistic analyses, BNS procedure (odds ratio [OR] 2.78, 95% confidence interval [CI] 1.03-7.45, p = 0.0426), age (OR 0.92, CI 0.86-0.98, p = 0.0154) were independent factor for early recovery of continence after RARP. The modified bladder neck suspension procedure showed significantly better outcomes than the standard procedure in terms of the early recovery of urinary continence.

Comparing 12-core and 20-core biopsy for prostate cancer diagnosis with transperineal MR/US fusion biopsy: assessing the effective number of systemic cores using propensity score matching.

PURPOSE: For transperineal (TP) prostate biopsy, target biopsy for visible lesions on MRI is important, but there is no consensus of the number of systemic biopsy cores. Our study aimed to confirm the diagnostic efficiency of 20-core systemic biopsy by comparison with 12-core using propensity score matching (PSM). METHODS: The 494 patients conducted the naive TP biopsy were retrospectively analyzed. There were 293 patients with 12-core biopsy and 201 patients with 20-core biopsy. PSM was performed for minimizing confounding variables, and the established effects' value was analyzed for 'index-positive or negative' clinically significant prostate cancer (csPCa) (Index means PIRADS Score ≥ 3 on multiparametric prostate MRI). RESULTS: At 12-core biopsy, there were 126 cases of prostate cancer (43.0%), and 97 cases of csPCa (33.1%). At 20-core biopsy, there were 91 cases (45.3%) and 63 cases (31.3%). After propensity score matching, for index-negative csPCa, the estimated odds ratio was 4.03 (95% CI 1.35-12.09, p value 0.0128), and for index-positive csPCa, the estimated odds ratio was 0.98 (95% CI 0.63-1.52, p value 0.9308). CONCLUSIONS: The 20-core biopsy did not show a higher detection rate for csPCa in comparison with the 12-core biopsy. However, when MRI did not show a suspicious lesion, 20-core biopsy showed higher odd ratio in comparison with 12-core biopsy. Therefore, if there is a suspicious lesion in MRI, 20-core biopsy is excessive and 12-core biopsy is sufficient. Whereas if there is no suspicious lesion in MRI, it is better to proceed with 20-core biopsy.

The Clinical Outcomes of Marginal Donor Hearts: A Single Center Experience.

BACKGROUND AND OBJECTIVES: Although the shortage of donor is a common problem worldwide, a significant portion of unutilized hearts are classified as marginal donor (MD) hearts. However, research on the correlation between the MD and the prognosis of heart transplantation (HTx) is lacking. This study was conducted to investigate the clinical impact of MD in HTx. METHODS: Consecutive 73 HTxs during 2014 and 2021 in a tertiary hospital were analyzed. MD was defined as follows; a donor age >55 years, left ventricular ejection fraction <50%, cold ischemic time >240 minutes, or significant cardiac structural problems. Preoperative characteristics and postoperative hemodynamic data, primary graft dysfunction (PGD), and the survival rate were analyzed. Risk stratification by Index for Mortality Prediction after Cardiac Transplantation (IMPACT) score was performed to examine the outcomes according to the recipient state. Each group was sub-divided into 2 risk groups according to the IMPACT score (low <10 vs. high ≥10). RESULTS: A total of 32 (43.8%) patients received an organ from MDs. Extracorporeal membrane oxygenation was more frequent in the non-MD group (34.4% vs. 70.7, p=0.007) There was no significant difference in PGD, 30-day mortality and long-term survival between groups. In the subgroup analysis, early outcomes did not differ between low- and high-risk groups. However, the long-term survival was better in the low-risk group (p=0.01). CONCLUSIONS: The outcomes of MD group were not significantly different from non-MD group. Particularly, in low-risk recipient, the MD group showed excellent early and long-term outcomes. These results suggest the usability of selected MD hearts without increasing adverse events.

Direct Extracorporeal Membrane Oxygenation Bridged Heart Transplantation: The Importance of Multi-Organ Failure.

Background and Objectives: Recently, approximately 40% of all heart transplantation (HTx) in South Korea are performed using the direct extracorporeal membrane oxygenation (ECMO) bridging method. We conducted a study to examine the clinical outcome of direct ECMO-bridged HTx and to investigate the impact of multi-organ failure (MOF). Methods: From June 2014 to September 2022, a total of 96 adult patients who underwent isolated HTx at a single tertiary hospital were included in the study. The patients were sub-grouped into ECMO (n=48) and non-ECMO group (n=48), and the ECMO group was subdivided into awake (n=22) and non-awake (n=26) groups based on mechanical ventilator (MV) dependency. Baseline characteristics, 30-day, and 1-year mortality were analyzed retrospectively. Results: The 1-year survival rate was significantly lower in the ECMO group (72.9% vs. 95.8%, p=0.002). There was a significant difference in the 30-day survival rate between the awake and non-awake ECMO groups (81.8% vs. 65.4%, p=0.032). In the univariate analysis of logistic regression for 1-year mortality, the odds ratio was 8.5 for ECMO bridged HTx compared to the non-ECMO group, 12.3 in patients who required MV (p=0.003), and 23 with additional hemodialysis (p<0.001). Conclusions: Patients who required MV in ECMO bridged HTx showed higher preoperative MOF rates and early mortality than those extubated. When considering ECMO bridged HTx, the severity of MOF should be thoroughly investigated, and careful patient selection is necessary.

Oral anticoagulants and concurrent rifampin administration in tuberculosis patients with non-valvular atrial fibrillation.

BACKGROUND: Evidence and guidelines for Non-vitamin K antagonist oral anticoagulants (NOACs) use when prescribing concurrent rifampin for tuberculosis treatment in patients with non-valvular atrial fibrillation (NVAF) are limited. METHODS: Using the Korean National Health Insurance Service database from January 2009 to December 2018, we performed a population-based retrospective cohort study to assess the net adverse clinical events (NACE), a composite of ischemic stroke or systemic embolism and major bleeding, of NOACs compared with warfarin among NVAF patients taking concurrent rifampin administration for tuberculosis treatment. After a propensity matching score (PSM) analysis, Cox proportional hazards regression was performed in matched cohorts to investigate the clinical outcomes. RESULTS: Of the 735 consecutive patients selected, 465 (63.3%) received warfarin and 270 (36.7%) received NOACs. Among 254 pairs of patients after PSM, the crude incidence rate of NACE was 25.6 in NOAC group and 32.8 per 100 person-years in warfarin group. There was no significant difference between NOAC and warfarin use in NACE (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.48-1.14; P = 0.172). Major bleeding was the main driver of NACE, and NOAC use was associated with a statistically significantly lower risk of major bleeding than that with warfarin use (HR, 0.63; 95% CI, 0.40-1.00; P = 0.0499). CONCLUSIONS: In our population-based study, there was no statically significant difference in the occurrence of NACE between NOAC and warfarin use. NOAC use may be associated with a lower risk of major bleeding than that with warfarin use.

Irreversible electroporation for prostate cancer using PSMA PET-CT.

Background: To demonstrate the clinical usefulness of prostate-specific membrane antigen (PSMA) positron emission tomography (PET) computerized tomography (CT) for irreversible electroporation (IRE) in prostate cancer patients. Methods: From January to May 2021, 17 men were diagnosed with localized prostate cancer through preoperative mpMRI and [18F] florastamin PSMA PET-CT imaging, followed by transperineal MRI-ultrasound fusion-guided biopsy. The patients underwent IRE focal therapy at the target lesions under general anesthesia. To evaluate the treatment outcome, serum prostate-specific antigen (PSA) levels were followed up in the 1st, 3rd, 6th, 9th, 12th months, and mpMRI was taken in the 1st and 12th months, followed by MR fusion biopsy in the 12th month post-IRE. Results: The mean age of the patients was 66.1 ± 9.3 with a median PSA of 7.5 ng/ml. After the treatment, PSA nadir was 4.06 ± 3.4, and 11 (64.7%) achieved decline of PSA more than 50% from the baseline. Rate of negative biopsy for prostate cancer is 88% (15/17) at 12 months MR fusion biopsy after the IRE treatment. Among the relapsed cases, 1 (6.9%) patient recurred at margin of treated area, and 1 (6.9%) patient was from outfield recurrence. When excluding initial four patients, none of the patients had cancer recur. Conclusions: When treating with IRE focal therapy, PSMA-PET CT is a potentially valuable diagnostic approach for localizing prostate cancer; it supports the detection of lesions with conventional mpMRI, enabling to perform the procedure more completely.

Cancer Research Line (CAREL): Development of Expanded Distributed Research Networks for Prostate Cancer and Lung Cancer.

Objectives: Big data-based multicenter medical research is expected to bring significant advances to cancer treatment worldwide. However, there are concerns related to data sharing among multicenter networks. Clinical data can be shielded by firewalls using distributed research networks (DRNs). We attempted to develop DRNs for multicenter research that can be easily installed and used by any institution. Patients and Methods: We propose a DRN for multicenter cancer research called the cancer research line (CAREL) and present a data catalog based on a common data model (CDM). CAREL was validated using 1723 patients with prostate cancer and 14 990 patients with lung cancer in a retrospective study. We used the attribute-value pairs and array data type JavaScript object notation (JSON) format to interface third-party security solutions such as blockchain. Results: We developed visualized data catalogs of prostate and lung cancer based on the observational medical outcomes partnership (OMOP) CDM, from which researchers can easily browse and select relevant data. We made the CAREL source code readily available for download and application for relevant purposes. In addition, it is possible to realize a multicenter research network using CAREL development sources. Conclusion: CAREL source can enable medical institutions to participate in multicenter cancer research. Our technology is open source, so small institutions that cannot afford to spend high costs can use it to develop a platform for multicenter research.

Combined MRI and PSA Strategy Improves Biopsy Decisions Compared with PSA Only: Longitudinal Observations of a Cohort of Patients with a PSA Level Less Than 20 ng/mL.

RATIONALE AND OBJECTIVES: To assess the diagnostic performances of prostate specific antigen (PSA) and PSA with prostate magnetic resonance imaging (MRI) to predict prostate cancer in patients with PSA ≤ 20 ng/mL. MATERIALS AND METHODS: Patients suspected of prostate cancer with a PSA test and prebiopsy MRI were included (n = 881). Prostate biopsy results or follow-up clinical data for 2 years were used to determine the presence of prostate cancer. The diagnostic performance of PSA, MRI, and PSA with MRI (referred to as the protocol) was evaluated. The positive predictive value (PPV) and negative predictive value (NPV) of the MRI were calculated in subgroups of patients with specific ranges of PSA level. RESULTS: Prostate cancer and CSC were diagnosed in 220 and 162 patients, respectively. Adding MRI to PSA could greatly improve specificity and PPV (0.833 and 0.567) for detecting CSC, compared to PSA ≥ 4 ng/mL alone (0.248 and 0.0219). Even though the sensitivity of the protocol (0.679) was lower than PSA (0.938), the NPV of the protocol was comparable to PSA (0.929 vs. 0.924). The protocol consistently showed the superior PPV and NVP to PSA only in not only patients within the gray zone of PSA, but also in patients with higher PSA. CONCLUSION: In conclusion, this longitudinal observational study confirmed that adding prebiopsy MRI to PSA was consistently beneficial in patients with PSA ≤ 20 ng/mL for avoiding unnecessary biopsy despite decrease in the sensitivity.

A Single Dose of Novel PSMA-Targeting Radiopharmaceutical Agent [177Lu]Ludotadipep for Patients with Metastatic Castration-Resistant Prostate Cancer: Phase I Clinical Trial.

[177Lu]Ludotadipep, which enables targeted delivery of beta-particle radiation to prostate tumor cells, had been suggested as a promising therapeutic option for mCRPC. From November 2020 to March 2022, a total of 30 patients were enrolled for single dose of [177Lu]Ludotadipep RPT, 6 subjects in each of the 5 different activity groups of 1.9 GBq, 2.8 GBq, 3.7 GBq, 4.6 GBq, and 5.6 GBq. [177Lu]Ludotadipep was administered via venous injection, and patients were hospitalized for three days to monitor for any adverse effects. Serum PSA levels were followed up at weeks 1, 2, 3, 4, 6, 8, and 12, and PSMA PET/CT with [18F]Florastamin was obtained at baseline and again at weeks 4 and 8. The subjects required positive PSMA PET/CT prior to [177Lu]Ludotadipep administration. Among the 29 subjects who received [177Lu]Ludotadipep, 36 treatment emergent adverse events (TEAEs) occurred in 17 subjects (58.6%) and 4 adverse drug reactions (ADRs) in 3 subjects (10.3%). Of the total 24 subjects who had full 12-week follow-up data, 16 (66.7%) showed decrease in PSA of any magnitude, and 9 (37.5%) showed a decrease in PSA by 50% or greater. A total of 5 of the 24 patients (20.8%) showed disease progression (PSA increase of 25% or higher from the baseline) at the 12th week following single dose of [177Lu]Ludotadipep. These data thus far suggest that [177Lu]Ludotadipep could be a promising RPT agent with low toxicity in mCRPC patients who have not been responsive to conventional treatments.