Pathological lymph node involvement (pN1) after a pelvic lymph node dissection represents one of the most unfavorable prognostic factors for disease recurrence and cancer-specific mortality in ...prostate cancer. However, optimal management for pN1 patients remains unclear. Thus, the guideline from the European Association of Urology recommends discussing three following management options with pN1 patients after an extended pelvic lymph node dissection, based on nodal involvement characteristics: (i) offer adjuvant androgen-deprivation therapy, (ii) offer adjuvant androgen-deprivation therapy with additional radiotherapy and (iii) offer observation (expectant management) to a patient with ≤2 nodes and a prostate-specific antigen <0.1 ng/mL. Treatment intensification may reduce risks of recurrence and cancer-specific mortality, but it may increase adverse events and impair quality of life. Few randomized control trials for pN1 are under investigation. In addition, there are limited reports on the quality of life and patient-reported outcomes in patients with pN1. Therefore, more research is needed to establish an optimal therapeutic strategy for patients with pN1. This review summarizes current evidence on the treatments available for men with pN1, summarizes randomized control trials that included pN1 prostate cancer, and discusses future perspectives.
The prognostic significance of germline variants in homologous recombination repair genes in advanced prostate cancer (PCa), especially with regard to hormonal therapy, remains controversial.
...Germline DNA from 549 Japanese men with metastatic and/or castration-resistant PCa was sequenced for 27 cancer-predisposing genes. The associations between pathogenic variants and clinical outcomes were examined. Further, for comparison, DNA from prostate biopsy tissue samples from 80 independent patients with metastatic PCa were analysed.
Forty-four (8%) patients carried germline pathogenic variants in one of the analysed genes. BRCA2 was most frequently altered (n = 19), followed by HOXB13 (n = 9), PALB2 (n = 5) and ATM (n = 5). Further, the BRCA1, BRCA2, PALB2 and ATM variants showed significant association with a short time to castration resistance and overall survival (hazard ratio = 1.99 and 2.36; 95% CI, 1.15-3.44 and 1.23-4.51, respectively), independent of other clinical variables. Based on log-rank tests, the time to castration resistance was also significantly short in patients with BRCA1, BRCA2, PALB2 or ATM somatic mutations and TP53 mutations.
Germline variants in BRCA1, BRCA2, PALB2 or ATM are independent prognostic factors of the short duration of response to hormonal therapy in advanced PCa.
Mesenchymal stem cells (MSCs), including adipose-derived mesenchymal stem cells (ADSCs), have been shown to attenuate organ damage in acute respiratory distress syndrome (ARDS) and sepsis; however, ...the underlying mechanisms are not fully understood. In this study, we aimed to explore the potential roles and molecular mechanisms of action of ADSCs in histone-induced endothelial damage.
Male C57BL/6 N mice were intravenously injected with ADSCs, followed by histones or a vehicle. The mice in each group were assessed for survival, pulmonary vascular permeability, and histological changes. A co-culture model with primary human umbilical vein endothelial cells (HUVECs) exposed to histones was used to clarify the paracrine effect of ADSCs. Overexpression and inhibition of miR-126 ADSCs were also examined as causative factors for endothelial protection.
The administration of ADSCs markedly improved survival, inhibited histone-mediated lung hemorrhage and edema, and attenuated vascular hyper-permeability in mice. ADSCs were engrafted in the injured lung and attenuated histone-induced endothelial cell apoptosis. ADSCs showed endothelial protection (via a paracrine effect) and Akt phosphorylation in the histone-exposed HUVECs. Notably, increased Akt phosphorylation by ADSCs was mostly mediated by exosomes in histone-induced cytotoxicity and lung damage. Moreover, the expression of miR-126 was increased in exosomes from histone-exposed ADSCs. Remarkably, the inhibition of miR-126 in ADSCs failed to increase Akt phosphorylation in histone-exposed HUVECs.
ADSC-derived exosomes may exert protective effects on endothelial cells via activation of the PI3K/Akt pathway.
Contractile behaviour of the urinary bladder and its sympathetic inhibition during storage phases are not well understood. Here, we explore muscularis mucosae (MM) as a predominant mucosal ...contractile element and the capability of sympathetic nerves to relax detrusor smooth muscle (DSM) or MM. Distribution of α-smooth muscle actin (α-SMA)-immunoreactive cells was compared in pig, human, guinea pig, rat and mouse bladders by immunohistochemistry, while contractility of the bladder mucosa was compared in these species by isometric tension recordings. In pig, human and guinea pig bladders, DSM and MM located in the lamina propria expressed α-SMA immunoreactivity, while both rat and mouse bladders lacked a MM. Consistent with this presence or absence of MM, bladder mucosa of pig, human and guinea pig but not rat and mouse developed spontaneous phasic contractions (SPCs). Distribution of tyrosine hydroxylase (TH)-immunoreactive sympathetic nerve fibres was compared in pig DSM, MM, trigone and urethra, as were their sympathetic nerve-evoked contractile/relaxing responses examined. In pig DSM or MM, where TH-immunoreactive sympathetic fibres exclusively projected to the vasculature, sympathetic relaxations were difficult to demonstrate. In contrast, sympathetic contractions were invariably evoked in pig trigone and urethra where the smooth muscle cells receive TH-immunoreactive sympathetic innervations. Thus, SPCs of bladder mucosa appear to predominantly arise from the MM displaying species differences. Despite the currently accepted concept of sympathetic nerve-mediated DSM relaxation during the storage phase, it is unlikely that neurally released noradrenaline acts on β-adrenoceptors to relax either DSM or MM due to the anatomical lack of sympathetic innervation.
Objectives
To determine the association between hormone therapy and outcomes in a cohort of prostate cancer patients with a family history of prostate cancer.
Methods
Data of patients with prostate ...cancer who had received hormone therapy were extracted from a nationwide community‐based database established by the Japan Study Group for Prostate Cancer. Family history of prostate cancer was available for 13 346 of these patients, who thus comprised the study cohort. Prognostic variables, including progression‐free survival, cancer‐specific survival and overall survival, were compared between men with familial and men with sporadic prostate cancer.
Results
A positive family history was identified in 220 patients (1.6%). Patients with a positive family history were younger than those without; however, other clinicopathological characteristics and prognoses were comparable. In subgroup analysis, family history was identified as a possible favorable prognostic factor for overall survival among patients with a prostate‐specific antigen level at diagnosis <100 ng/mL and those with low or intermediate Japan Cancer of the Prostate Risk Assessment.
Conclusions
Our findings show that familial prostate cancer has an early‐onset feature or is diagnosed earlier than sporadic prostate cancer. However, the prognosis of individuals with familial prostate cancer undergoing hormone therapy is comparable to those with sporadic prostate cancer.
To develop and validate deep convolutional neural network (DCNN) models for the diagnosis of adrenal adenoma (AA) using CT.
This retrospective study enrolled 112 patients who underwent abdominal CT ...(non-contrast, early, and delayed phases) with 107 adrenal lesions (83 AAs and 24 non-AAs) confirmed pathologically and with 8 lesions confirmed by follow-up as metastatic carcinomas. Three patients had adrenal lesions on both sides. We constructed six DCNN models from six types of input images for comparison: non-contrast images only (Model A), delayed phase images only (Model B), three phasic images merged into a 3-channel (Model C), relative washout rate (RWR) image maps only (Model D), non-contrast and RWR maps merged into a 2-channel (Model E), and delayed phase and RWR maps merged into a 2-channel (Model F). These input images were prepared manually with cropping and registration of CT images. Each DCNN model with six convolutional layers was trained with data augmentation and hyperparameter tuning. The optimal threshold values for binary classification were determined from the receiver-operating characteristic curve analyses. We adopted the nested cross-validation method, in which the outer fivefold cross-validation was used to assess the diagnostic performance of the models and the inner fivefold cross-validation was used to tune hyperparameters of the models.
The areas under the curve with 95% confidence intervals of Models A-F were 0.94 0.90, 0.98, 0.80 0.69, 0.89, 0.97 0.94, 1.00, 0.92 0.85, 0.97, 0.99 0.97, 1.00 and 0.94 0.86, 0.99, respectively. Model E showed high area under the curve greater than 0.95.
DCNN models may be a useful tool for the diagnosis of AA using CT.
The current study demonstrates a deep learning-based approach could differentiate adrenal adenoma from non-adenoma using multiphasic CT.
The nuclear receptor (NR) superfamily consists of 48 members that are divided into seven subfamilies. NRs are transcription factors that play an important role in a number of biological processes. ...The NR superfamily includes androgen receptor, which is a key player in prostate cancer pathogenesis, suggesting the functional roles of other NRs in prostate cancer. The findings on the roles of NRs in prostate cancer thus far have shown that several NRs such as vitamin D receptor, estrogen receptor β, and mineralocorticoid receptor play antioncogenic roles, while other NRs such as peroxisome proliferator-activated receptor γ and estrogen receptor α as well as androgen receptor play oncogenic roles. However, the roles of other NRs in prostate cancer remain controversial or uninvestigated. Further research on the role of NRs in prostate cancer is required and may lead to the development of novel preventions and therapeutics for prostate cancer.
Recent advances in stem cell biology have enabled the generation of kidney organoids in vitro, and further maturation of these organoids is observed after experimental transplantation. However, the ...current organoids remain immature and their precise maturation stages are difficult to determine because of limited information on developmental stage-dependent gene expressions in the kidney in vivo. To establish relevant molecular coordinates, we performed single-cell RNA sequencing (scRNA-seq) on developing kidneys at different stages in the mouse. By selecting genes that exhibited upregulation at birth compared with embryonic day 15.5 as well as cell lineage-specific expression, we generated gene lists correlated with developmental stages in individual cell lineages. Application of these lists to transplanted embryonic kidneys revealed that most cell types, other than the collecting ducts, exhibited similar maturation to kidneys at the neonatal stage in vivo, revealing non-synchronous maturation across the cell lineages. Thus, our scRNA-seq data can serve as useful molecular coordinates to assess the maturation of developing kidneys and eventually of kidney organoids.
•Single-cell RNA sequencing of mouse embryonic kidneys at various developmental stages.•Identification of maturation-dependent genes in nephron and collecting duct segments.•Non-synchronous maturation of transplanted embryonic kidneys.
Objective
To investigate the somatic mutation profiles of testicular germ cell tumors in Japanese men.
Methods
We analyzed the somatic missense mutation profile of testicular germ cell tumors among ...21 Japanese men with seminoma (n = 14), pure embryonic carcinoma (n = 3) and mixed testicular germ cell tumor (n = 4) by targeted next‐generation sequencing of 409 cancer‐related genes covering 1.23 Mb of the genome.
Results
We identified a total of 22 missense mutations in 21 primary testicular germ cell tumor samples (0.89 mutations/Mb), of which seven mutations were confirmed to be absent from the germline. KIT:p.Asn822Tyr, KIT:p.Leu576Pro, PIK3CA:p.Glu542Lys and FBXW7:p.Arg505His were statistically and functionally potential. A total of 18 missense mutations were previously unknown in testicular germ cell tumors. PDGFRA amplification from one patient with seminoma was detected. KIT, BCR,PIK3CG, PIK3CA and PDGFRA mutations involved in aberrant signaling of the KIT–PI3K–AKT pathway was detected in 27.3% of detected mutations.
Conclusions
The present investigation identified a low mutation rate in testicular germ cell tumors among Asian patients, 18 novel mutations and PDGFRA amplification. Limitations of the present study are the small sample and missing normal DNA for some testicular germ cell tumors.
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