Importance of reassessment to identify trajectories of chronic transition of clinical indicators in post-myocardial infarction management.

Despite advances in multidisciplinary acute care for myocardial infarction (MI), the clinical need to manage heart failure and elevated mortality risks in the remote phase of MI remains unmet. Various prognostic models have been established using clinical indicators obtained during the acute phase of MI; however, most of these indicators also show chronic changes in the post-MI phase. Although relevant guidelines recommend follow-up assessments of some clinical indicators in the chronic phase, systematic reassessment has not yet been fully established and implemented in a real-world clinical setting. Therefore, clinical evidence of the impact of such chronic transitions on the post-MI prognosis is lacking. We speculate that post-MI reassessment of key clinical indicators and the impact of their chronic transition patterns on long-term prognoses can improve the quality of post-MI risk stratification and help identify residual risk factors. Several recent studies have investigated the impact of the chronic transition of some clinical indicators, such as serum albumin level, mitral regurgitation, and left-ventricular dysfunction, on post-MI prognosis. Interestingly, even in MI survivors with these indicators within their respective normal ranges in the acute phase of MI, chronic transition to an abnormal range was associated with worsening cardiovascular outcomes. On the basis of these recent insights, we discuss the clinical significance of post-MI reassessment to identify the trajectories of several clinical indicators and elucidate the potential residual risk factors affecting adverse outcomes in MI survivors.

G-protein signaling of oxytocin receptor as a potential target for cabazitaxel-resistant prostate cancer.

Although the treatment armamentarium for patients with metastatic prostate cancer has improved recently, treatment options after progression on cabazitaxel (CBZ) are limited. To identify the mechanisms underlying CBZ resistance and therapeutic targets, we performed single-cell RNA sequencing of circulating tumor cells (CTCs) from patients with CBZ-resistant prostate cancer. Cells were clustered based on gene expression profiles. In silico screening was used to nominate candidate drugs for overcoming CBZ resistance in castration-resistant prostate cancer. CTCs were divided into three to four clusters, reflecting intrapatient tumor heterogeneity in refractory prostate cancer. Pathway analysis revealed that clusters in two cases showed up-regulation of the oxytocin (OXT) receptor-signaling pathway. Spatial gene expression analysis of CBZ-resistant prostate cancer tissues confirmed the heterogeneous expression of OXT-signaling molecules. Cloperastine (CLO) had significant antitumor activity against CBZ-resistant prostate cancer cells. Mass spectrometric phosphoproteome analysis revealed the suppression of OXT signaling specific to CBZ-resistant models. These results support the potential of CLO as a candidate drug for overcoming CBZ-resistant prostate cancer via the inhibition of OXT signaling.

Clinical effects of a selective urate reabsorption inhibitor dotinurad in patients with hyperuricemia and treated hypertension: a multicenter, prospective, exploratory study (DIANA).

INTRODUCTION: Dotinurad is a newer urate-lowering agent that selectively inhibits urate transporter 1 in the renal proximal tubule and increases urinary urate excretion. Currently, little is known about the clinical efficacies of dotinurad in patients with hyperuricemia and hypertension. The aim of this study was to assess the clinical effects of a selective urate reabsorption inhibitor dotinurad on serum uric acid (SUA) levels and relevant vascular markers in patients with hyperuricemia and treated hypertension. METHODS: This investigator-initiated, multicenter, prospective, single-arm, open-label, exploratory clinical trial in Japan enrolled patients with hyperuricemia and treated hypertension who received a 24-week dotinurad therapy (a starting dose at 0.5 mg once daily and up-titrated to 2 mg once daily). The primary endpoint was a percentage change in the SUA level from baseline to week 24. The secondary endpoints were cardiovascular and metabolic measurements, including changes in the cardio-ankle vascular index (CAVI) and derivatives of reactive oxygen metabolites (d-ROMs) concentration at week 24. RESULTS: Fifty patients (mean age 70.5 ± 11.0 years, with 76.0% being men, and mean SUA level 8.5 ± 1.2 mg/dL) were included in the analysis. The percentage change from baseline in the SUA level at week 24 was - 35.8% (95% confidence interval [CI] - 39.7% to - 32.0%, P < 0.001), with approximately three quarters of patients achieving an SUA level of ≤ 6.0 mg/dL at week 24. The proportional changes from baseline in the geometric mean of CAVI and d-ROMs at week 24 were 0.96 (95% CI 0.92 to 1.00, P = 0.044) and 0.96 (95% CI 0.92 to 1.00, P = 0.044), respectively. CONCLUSION: In addition to meaningful SUA-lowering effects, 24 weeks of dotinurad therapy may favorably affect arterial stiffness and oxidative stress markers, suggesting off-target vascular protection of dotinurad. Further research is expected to verify our findings and elucidate the entire off-target effects of dotinurad. Trial registration jRCTs021210013, registration date June 24, 2021.

The sialyl-Tn antigen synthase genes regulates migration-proliferation dichotomy in prostate cancer cells under hypoxia.

A low-oxygen (hypoxia) tumor microenvironment can facilitate chemotherapy and radiation therapy resistance in tumors and is associated with a poor prognosis. Hypoxia also affects PCa (prostate cancer) phenotype transformation and causes therapeutic resistance. Although O-glycans are known to be involved in the malignancy of various cancers under hypoxia, the expression and function of O-glycans in PCa are not well understood. In this study, the saccharide primer method was employed to analyze O-glycan expression in PCa cells. Results showed that the expression of sTn antigens was increased in PCa cells under hypoxia. Furthermore, it was found that ST6GalNAc1, the sTn antigen synthase gene, was involved in the migration-proliferation dichotomy and drug resistance in PCa cells under hypoxia. The results of this study will contribute to the development of novel diagnostic markers and drug targets for PCa under hypoxia.

Spontaneous ureterocele wall rupture by a ureteral stone: A case report.

Ureterocele, a type of ectopic ureter characterized by cystic dilation of the distal ureter, can sometimes contain stones. Here, we present the case of a 67-year-old woman who was under observation for ureteral stone and experienced spontaneous ureterocele wall ruptured due to the stone. As illustrated in the present case, conservative observation, which is recommended as initial management of stones in ureterocele to reduce the risk of vesicoureteral reflux following transurethral ureterocele incision, may be associated with increased risk of ureterocele wall rupture and subsequent vesicoureteral reflux.

Discovery of a new candidate drug to overcome cabazitaxel-resistant gene signature in castration-resistant prostate cancer by in silico screening.

BACKGROUND: The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC. METHODS: We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models. RESULTS: We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression. CONCLUSIONS: Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting AURKB and KIF20A.

Characterizing cyclin-dependent kinase 12(CDK12)-altered aggressive prostate cancer: a twelve-case series.

BACKGROUND: Prostate cancer harboring cyclin-dependent kinase 12 (CDK12) abnormalities is a hot topic due to its distinctive clinical features, such as sensitivity to immune checkpoint inhibitors. In the last few years, precision medicine using comprehensive genome sequencing has become familiar, and the era of precision oncology has arrived in the field of prostate cancer. This study aimed to present the demographic characteristics of patients with CDK12 alterations. METHODS: In 12 patients with detected CDK12 alterations in our hospital between 2015 and 2021, we evaluated their genomic features and clinical course. CDK12 allelic status was classified into three groups: monoallelic loss, potentially biallelic loss, and biallelic loss based on the genome analyses. RESULTS: Seven patients already had metastatic cancer at the time of diagnosis, and all 12 patients had Gleason grade ≥ 4. Most cases of biallelic loss or potentially biallelic loss were metastatic cancers at the initial staging, and all these cases were categorized into Gleason grade 5. Two of the 12 patients had BRCA2/RB1 co-loss, and the other two had whole genome duplication. Five patients had a long-term survival of > 6 years, but two patients died within 4 years of diagnosis. CONCLUSION: This is the first Japanese prostate cancer case series with CDK12 alterations. CDK12-altered prostate cancer is a heterogeneous disease, and accumulating cases with detailed information leads to precision oncology.

Different types of Kounis syndrome caused by different episodes of bee sting anaphylaxis: Misfortunes never come singly.

We report our experience with a 69-year-old man who had different types of Kounis syndrome over a short time frame, caused by two episodes of bee sting anaphylaxis. After his first allergic reaction to a bee sting, he experienced a non-ST-segment elevation myocardial infarction; he was treated with percutaneous coronary intervention for near-occlusion of his right coronary artery. This episode was deemed type 2 Kounis syndrome. Four weeks later, we electively treated the nonculprit residual stenosis in his left anterior descending artery. Unfortunately, 2 weeks after this elective procedure, he experienced anaphylactic shock due to a second bee sting. Electrocardiography showed ST elevation in the anterior leads, and emergent coronary angiography showed thrombotic occlusion of the newly implanted stent in the left anterior descending artery. This second episode was deemed type 3 Kounis syndrome. Learning objectives: This is a rare example of different types of Kounis syndrome resulting from repeated exposures to an allergic source, an example that deepens our understanding of Kounis syndrome. This patient's experience illustrates the need for careful evaluation of the indications for revascularization of nonculprit lesions in patients with a history of Kounis syndrome.

Salvage focal brachytherapy in castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy.

Introduction: Treatment strategy for castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy has not been established. Case presentation: We described a case of castration-resistant prostate cancer with neuroendocrine differentiation after initial external beam radiotherapy followed by salvage androgen deprivation therapy. Magnetic resonance imaging detected recurrence of a suspicious lesion in the left lobe of the prostate, although the prostate-specific antigen level was <0.2 ng/mL. Transperineal prostate saturation needle biopsy detected adenocarcinoma with neuroendocrine differentiation. The patient underwent salvage focal brachytherapy and had a prostate-specific antigen progression-free survival of 20 months with no obvious adverse events. No recurrence has been detected on magnetic resonance imaging for 18 months. Conclusion: Salvage focal brachytherapy for prostate cancer after external beam radiotherapy can be one of the treatment strategies for local recurrence of castration-resistant prostate cancer with neuroendocrine differentiation.

Influence of response to prior docetaxel on sensitivity to cabazitaxel in prostate cancer patients with PTEN alterations.

The purpose of this study was to investigate factors predicting the sensitivity to cabazitaxel therapy in metastatic castration-resistant prostate cancer (mCRPC) patients with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) alterations. This single-institution, retrospective study included 12 mCRPC patients with PTEN alterations who had received cabazitaxel therapy. Five patients (41%) responded to cabazitaxel therapy with a prostate-specific antigen (PSA) level decline of ≥30% from baseline, and all of them had responded to prior docetaxel therapy with a PSA decline of ≥30%. None of the patients with a poor response to prior docetaxel therapy responded well to cabazitaxel therapy. Of the seven patients who did not respond to cabazitaxel and whose PSA declined from baseline was <30%, five (71%) were also refractory to prior docetaxel therapy. The PSA responses to docetaxel and cabazitaxel were significantly correlated (p = 0.027). Kaplan-Meier analysis revealed that progression-free survival (PFS) for cabazitaxel was significantly shorter for prior docetaxel nonresponders (3.3 versus 9.1 months, p = 0.028). Multivariate analysis revealed that a poor response to prior docetaxel (PSA decline < 30%) (hazard ratio [HR] = 6.382, 95% confidence interval [CI] 1.172-34.750, p = 0.032) and baseline PSA of ≥20 ng/ml (HR = 33.584, 95% CI 2.332-483.671, p = 0.010) were independent prognostic factors for PFS with cabazitaxel therapy. These results demonstrate cross-resistance between docetaxel and cabazitaxel. The response to prior docetaxel therapy can influence the sensitivity to cabazitaxel therapy in mCRPC patients with PTEN alterations.

A Japanese case of castration-resistant prostate cancer with BRCA2 and RB1 co-loss and TP53 mutation: a case report.

BACKGROUND: Abnormalities in homologous recombination contribute to the aggressive nature of castration-resistant prostate cancer. Retinoblastoma transcriptional corepressor 1 (RB1) and breast cancer 2 (BRCA2) exist close to each other in the same chromosome, and the significance of their concurrent loss has become a hot topic in the field of cancer research. CASE PRESENTATION: A 61-year-old man presented with a chief complaint of a mass on his head and was diagnosed as multiple bone metastases from prostate cancer. He was treated with standard medication, but he died 2 years 6 months after being diagnosed with prostate cancer. Simultaneous biallelic loss of RB1 and BRCA2 as well as a truncating mutation of tumor protein p53 (TP53) were revealed by genomic analysis. CONCLUSION: To our knowledge, this is the first report of castration-resistant prostate cancer (CRPC) with BRCA2 and RB1 co-loss and TP53 mutation. To establish a treatment strategy for highly malignant cases with such multiple genetic features is important.

Multiple metastases of androgen indifferent prostate cancer in the urinary tract: two case reports and a literature review.

BACKGROUND: Prostate cancer (PC) is mainly known to metastasize to bone, lung and liver, but isolated metastases of prostate cancer, including ductal carcinoma, in the urinary tract are very rare. We describe two patients with nodular masses in the urinary tract (the anterior urethra or the urinary bladder) that were found on cystoscopy during treatment of castration-resistant prostate cancer. CASE PRESENTATION: In both cases, the pathological diagnosis from transurethral tumor resection showed that they were androgen indifferent prostate cancer (AIPC), including aggressive variant prostate cancer (AVPC) in Case 1 and treatment-induced neuroendocrine differentiation prostate cancer (NEPC) in Case 2. In Case 1, Loss of genetic heterozygosity (LOH) of BRCA2 and gene amplification of KRAS was identified from the urethra polyps. In Case 2, homozygous deletion was observed in PTEN, and LOH without mutation was observed in RB1. CONCLUSION: These are the first reports of two cases of urinary tract metastasis of AIPC.

Antiplatelet therapy after percutaneous coronary intervention: current status and future perspectives.

Antiplatelet therapy after percutaneous coronary intervention (PCI) has been changing in parallel with the development of drug-eluting stents (DES) and antiplatelet agents. The recommendation of dual antiplatelet therapy duration is getting shorter due to the decreased risk of stent thrombosis in new-generation DES, the use of a P2Y12 inhibitor as a monotherapy, and the increasing prevalence of high bleeding risk patients. Antithrombotic therapy after PCI has also changed due to the introduction of direct oral anticoagulants. Aspirin-free P2Y12 inhibitor monotherapy is now being evaluated in several prospective studies as a novel strategy of antiplatelet therapy after PCI. This review shows a current status and provides future perspectives for the antiplatelet therapy after PCI.

First successful case of platinum-based chemotherapy for neuroendocrine prostate cancer with BRCA2 and PTEN alterations.

INTRODUCTION: Deoxyribonucleic acid repair gene mutations are now being studied in a variety of solid tumors, with the hope of predicting prognosis, pathogenesis, and treatment outcomes. CASE PRESENTATION: We report the case of a Japanese patient with advanced castration-resistant prostate cancer who exhibited a prominent response to platinum therapy and had coexisting BRCA2 and PTEN mutations according to retrospective multigene panel analysis. CONCLUSION: Through a review of clinical outcomes and genetic/pathologic profiling, the presented case provides insights into future management strategies based on the tumor genetic status.

Serum Albumin and Bleeding Events After Percutaneous Coronary Intervention in Patients With Acute Myocardial Infarction (from the HAGAKURE-ACS Registry).

Low serum albumin (SA) on admission in patients with acute myocardial infarction (AMI) has been reported to be associated with adverse cardiovascular events. The relation between low SA and post-AMI bleeding events is presently unknown. We analyzed 1,724 patients with AMI enrolled in the HAGAKURE-ACS registry who underwent primary percutaneous coronary intervention from January 2014 to December 2018. To assess the influence of low SA at admission, patients were divided into 3 groups according to the albumin tertiles: the low SA group (<3.8 g/100 ml), the middle SA (MSA) group (3.8 to 4.1 g/100 ml), and the normal SA (NSA) group (≥4.2 g/100 ml). The primary end point was the incidence of Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries moderate/severe bleeding. The cumulative 3-year incidence of the primary end point was significantly higher in the low SA group than in the MSA and NSA groups (30.8% and 11.9% vs 7.7%; p <0.001). In the landmark analysis at 30 days, the cumulative incidences of the primary end point were also significantly higher in the low SA group than in the MSA and NSA groups, both within and beyond 30 days (20.1% and 6.1% vs 3.5%; p <0.001, and 12.4% and 6.2% vs 4.5%; p <0.001, respectively). After adjusting for confounders, the low SA group showed excess risk of bleeding events relative to NSA (hazard ratio 1.56; 95% confidence interval 1.06 to 2.30; p = 0.026), whereas risk of bleeding was neutral in MSA relative to NSA (hazard ratio 0.94; 95% confidence interval 0.63 to 1.34; p = 0.752). In conclusion, low SA at admission was independently associated with higher risk for bleeding events in patients with AMI undergoing percutaneous coronary intervention.

CD8-positive T cells and CD204-positive M2-like macrophages predict postoperative prognosis of very high-risk prostate cancer.

To stratify the heterogeneity of prostate cancer (PCa) with seminal vesicle invasion (SVI) immunologically after radical prostatectomy focusing on the tumor microenvironment. We retrospectively reviewed the clinicopathological data of 71 PCa patients with SVI, which is known as a factor of very high-risk PCa. Preoperative clinical variables and postoperative pathological variables were evaluated as predictors of biochemical recurrence (BCR) with a multivariate logistic regression. Immune cell infiltration including the CD8-positive cell (CD8+ cell) and CD204-positive M2-like macrophage (CD204+ cell) was investigated by immunohistochemistry. The cumulative incidence and risk of BCR were assessed with a Kaplan-Meier analysis and competing risks regression. A higher CD8+ cell count in the SVI area significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). A lower CD204+ cell count in the SVI area also significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). Furthermore, the combination of the CD8+ and CD204+ cell infiltration ratio of the SVI area to the main tumor area was a significant factor for BCR in the patients with the PCa with SVI (p = 0.001). In PCa patients with SVI, the combination of CD8+ and CD204+ cell infiltration is useful to predict the prognosis.

Vasohibin-1 expression as a biomarker of aggressive nature in ductal adenocarcinoma of the prostate: a retrospective cohort study at two centres in Japan.

OBJECTIVES: Vasohibin-1 (VASH1) is an endogenous angiogenesis regulator expressed in activated vascular endothelial cells. We previously reported that high VASH1 expression is a predictor of progression in acinar adenocarcinoma of the prostate. In this study, we evaluated the characteristics of ductal adenocarcinoma of the prostate by comparing the level of VASH1 expression between ductal and acinar adenocarcinoma specimens. DESIGN AND SETTING: A retrospective cohort study at two centres in Japan. PARTICIPANTS: Among the 1495 patients who underwent radical prostatectomy or transurethral resection for the past 15 years, a total of 14 patients diagnosed with ductal adenocarcinoma and 20 patients diagnosed with acinar adenocarcinoma with a Gleason score of 4+4 were included. INTERVENTIONS: We immunohistochemically examined the CD34 expression as the microvessel density (MVD) and activated endothelial cells as the VASH1 density (vessels per mm2). PRIMARY AND SECONDARY OUTCOME MEASURES: The primary outcome was the association of MVD and VASH1 density between ductal and acinar adenocarcinoma, and the secondary outcome was their oncological outcomes. RESULTS: Nine patients (64.3%) with ductal adenocarcinoma were diagnosed at an advanced clinical stage, and five patients (35.7%) died from cancer during a median follow-up of 56.0 months. The VASH1 densities (mean±SD) in ductal and acinar adenocarcinoma were 45.1±18.5 vs 16.1±21.0 (p<0.001), respectively, while the MVD (mean±SD) in ductal and acinar adenocarcinoma were 65.3±21.9 vs 80.8±60.7 (p=0.666), respectively. The 5-year cancer-specific survival rates for high and low VASH1 expression were 70.0% and 100.0% (p=0.006), respectively. High VASH1 expression and a diagnosis of ductal adenocarcinoma were significant predictors of cancer-specific survival. CONCLUSIONS: Ductal adenocarcinoma was more aggressive and had higher VASH1 expression than acinar adenocarcinoma, although MVD was equivalent. These results indicate that VASH1 expression may serve as a novel biomarker for the aggressive nature of ductal adenocarcinoma.

Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways.

Cabazitaxel (CBZ) is approved for the treatment of docetaxel-resistant castration-resistant prostate cancer (CRPC). However, its efficacy against CRPC is limited, and there are no effective treatments for CBZ-resistant CRPC. This study explored the optimal treatment for CRPC in the post-cabazitaxel setting. PC3 (CBZ-sensitive) and PC3CR cells (CBZ-resistant) were used in this study. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of PC3CR cells. The in vivo effect of the drug combination was tested in xenograft mice models. We identified etoposide (VP16) as a promising treatment candidate for CBZ-resistant CRPC. The WST assay revealed that VP16 had a significant antitumor effect on PC3CR cells. PC3CR cells exhibited significantly higher topoisomerase II alpha (TOP2A) expression than PC3 cells. Higher TOP2A expression was a poor prognostic factor in The Cancer Genome Atlas prostate cancer cohort. In the Fred Hutchinson Cancer Research Center dataset, docetaxel-exposed tissues and metastatic tumors had higher TOP2A expression. In addition, VP16 significantly inhibited the growth of tumors generated from both cell lines. Based on these findings, VP16-based chemotherapy may be an optimal treatment for CPRC in the post-CBZ setting.