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1.
Commun Biol ; 4(1): 381, 2021 Mar 22.
Artículo en Inglés | MEDLINE | ID: mdl-33753863

RESUMEN

Therapies for lethal castration-resistant prostate cancer (CRPC) are an unmet medical need. One mechanism underlying CRPC and resistance to hormonal therapies is the expression of constitutively active splice variant(s) of androgen receptor (AR-Vs) that lack its C-terminus ligand-binding domain. Transcriptional activities of AR-Vs and full-length AR reside in its N-terminal domain (NTD). Ralaniten is the only drug proven to bind AR NTD, and it showed promise of efficacy in Phase 1 trials. The peptidyl-prolyl isomerase Pin1 is frequently overexpressed in prostate cancer. Here we show that Pin1 interacted with AR NTD. The inhibition of Pin1 expression or its activity selectively reduced the transcriptional activities of full-length AR and AR-V7. Combination of Pin1 inhibitor with ralaniten promoted cell cycle arrest and had improved antitumor activity against CRPC xenografts in vivo compared to individual monotherapies. These findings support the rationale for therapy that combines a Pin1 inhibitor with ralaniten for treating CRPC.

2.
Cancers (Basel) ; 13(4)2021 Feb 12.
Artículo en Inglés | MEDLINE | ID: mdl-33673284

RESUMEN

The Glasgow prognostic score, a marker of systemic inflammation, is associated with clinical outcomes in different cancers including prostate cancer. However, there is no evidence for the relationship between the high-sensitivity modified Glasgow prognostic score (Hs-mGPS) in prostate cancer and its prognosis. This study aimed to investigate the prognostic significance of Hs-mGPS in castration-resistant prostate cancer (CRPC) treated with docetaxel. We retrospectively analyzed clinical datasets from 131 CRPC patients who received docetaxel treatment at Chiba University Hospital and a related hospital. Clinical factors including Hs-mGPS before docetaxel treatment were evaluated according to overall survival. The numbers of patients with Hs-mGPS of 0, 1, and 2 were 88, 30, and 13, respectively. The median prostate-specific antigen (PSA) level was 28.9 ng/mL. The median testosterone level was 13.0 ng/dL. The percentages of bone and visceral metastases were 80.8% and 10.2%, respectively. For overall survival, Hs-mGPS ≥ 1 (hazard ratio of 2.41; p = 0.0048), testosterone ≥ 13.0 ng/dL (hazard ratio of 2.23; p = 0.0117), and PSA ≥ 28.9 ng/mL (hazard ratio of 2.36; p = 0.0097) were significant poor prognostic factors in the multivariate analysis. The results of the two-group analysis showed that a higher Hs-mGPS was associated with high PSA, alkaline phosphatase, and testosterone levels. The median testosterone levels for Hs-mGPS of 0, 1, and 2 were 9.0, 16.5, and 23.0, respectively. Based on the multivariate analysis, we created a combined score with three prognostic factors: Hs-mGPS, testosterone, and PSA. The low-risk group (score of 0-1) showed a significantly longer overall survival compared to the intermediate-risk (score of 2-3) and high-risk (score of 4) groups (p < 0.0001). Our results demonstrated that an elevated Hs-mGPS was an independent prognostic factor in CRPC patients treated with docetaxel therapy. Risk classification based on Hs-mGPS, testosterone, and PSA may be useful in predicting the prognosis of CRPC patients.

3.
Rinsho Shinkeigaku ; 61(1): 33-38, 2021 Jan 29.
Artículo en Japonés | MEDLINE | ID: mdl-33328422

RESUMEN

A 44-year-old male was admitted to our hospital because of sudden weakness and sensory loss in both legs following left scapular pain. He had a history of lower back pain but no vascular risk factors. Neurological examination on admission revealed flaccid paraplegia, a loss of both pinprick and vibratory sensations below the Th6 level, and bladder and rectal disturbances. Tendon reflexes were absent in both lower limbs. Diffusion-weighted imaging performed 5 hours after onset revealed an extensive high-intensity lesion at the Th2-6 spine levels, accompanied by a vague high intensity on T2-weighted images. CT angiography showed no abnormalities of the aorta or the artery of Adamkiewicz. Laboratory test results were normal and there was no evidence of coagulopathy. Autoantibodies, including anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein antibodies, were negative. The cerebrospinal fluid test was normal. The lesion had expanded to the whole thoracic cord and was markedly swollen on T2-weighted imaging at 5 days after onset. Immunotherapies, including intravenous methylprednisolone pulse therapy and plasma exchange, were ineffective. Although there was no evidence of any source of embolism, we found degenerative calcified changes in the fibrocartilage of the intervertebral discs, with Schmorl's nodes in the thoracic spines. We clinically diagnosed the patient with spinal cord infarction caused by fibrocartilaginous embolism. He developed deep vein thrombosis and was treated with edoxaban. His neurological symptoms did not improve during 55 days of hospitalization. In a case with sudden-onset myelopathy, fibrocartilaginous embolism should be considered.

4.
Int J Urol ; 2020 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-33258172

RESUMEN

OBJECTIVES: To investigate whether the result of the 1-mg dexamethasone suppression test can predict the improvement of comorbidities after adrenalectomy in patients with subclinical Cushing syndrome. METHODS: This retrospective study included 117 subclinical Cushing syndrome patients who underwent adrenalectomy. The numbers of prescribed drugs for metabolic comorbidities and the clinical variables at diagnosis were compared with those at the follow up. Patients were classified into subgroups according to the result of the 1-mg dexamethasone suppression test. RESULTS: Significant improvements in blood pressure, serum cholesterol and body mass index were observed. Furthermore, a significant improvement in glycated hemoglobin was observed in patients with diabetes mellitus. These improvements led to a discontinuation or reduction of prescribed drugs after surgery. In addition, the greatest reduction of prescribed drugs was observed in patients whose serum cortisol levels were between 1.8 and 3.0 µg/dL after the 1-mg dexamethasone suppression test. CONCLUSIONS: The result of the 1-mg dexamethasone suppression test can be a useful factor predicting the improvement of comorbidities after adrenalectomy. Current data might give us a new insight into the decision-making for the treatment of subclinical Cushing syndrome.

5.
Transl Oncol ; 14(1): 100915, 2020 Oct 20.
Artículo en Inglés | MEDLINE | ID: mdl-33096335

RESUMEN

Primary prostate cancer (PC) progresses to castration-resistant PC (CRPC) under androgen deprivation therapy, by mechanisms e.g. expression of androgen receptor (AR) splice variant-7 (AR-V7). Here we conducted comprehensive epigenome and transcriptome analyses comparing LNCaP, primary PC cells, and LNCaP95, AR-V7-expressing CRPC cells derived from LNCaP. Of 399 AR-V7 target regions identified through ChIP-seq analysis, 377 could be commonly targeted by hormone-stimulated AR, and 22 were specifically targeted by AR-V7. Among genes neighboring to these AR-V7 target regions, 78 genes were highly expressed in LNCaP95, while AR-V7 knockdown led to significant repression of these genes and suppression of growth of LNCaP95. Of the 78 AR-V7 target genes, 74 were common AR/AR-V7 target genes and 4 were specific AR-V7 target genes; their most suppressed genes by AR-V7 knockdown were NUP210 and SLC3A2, respectively, and underwent subsequent analyses. NUP210 and SLC3A2 were significantly upregulated in clinical CRPC tissues, and their knockdown resulted in significant suppression of cellular growth of LNCaP95 through apoptosis and growth arrest. Collectively, AR-V7 contributes to CRPC proliferation by activating both common AR/AR-V7 target and specific AR-V7 target, e.g. NUP210 and SLC3A2.

6.
Int J Urol ; 2020 Oct 27.
Artículo en Inglés | MEDLINE | ID: mdl-33111429

RESUMEN

Prostate cancer is a major cause of cancer-related deaths among men worldwide. In addition to genomic alterations, epigenetic alterations accumulated in prostate cancer have been elucidated. While aberrant deoxyribonucleic acid hypermethylation in promoter CpG islands inactivates crucial genes associated with deoxyribonucleic acid repair, cell cycle, apoptosis or cell adhesion, aberrant deoxyribonucleic acid hypomethylation can lead to oncogene activation. Acetylation of histone is also deregulated in prostate cancer, which could cause aberrant super-enhancer formation and activation of genes associated with cancer development. Deregulations of histone methylation, such as an increase of trimethylation at position 27 of histone H3 by enhancer of zeste homolog2 overexpression, or other modifications, such as phosphorylation and ubiquitination, are also involved in prostate cancer development, and inhibitors targeting these epigenomic aberrations might be novel therapeutic strategies. In this review, we provide an overview of epigenetic alterations in the development and progression of prostate cancer, focusing on deoxyribonucleic acid methylation and histone modifications.

7.
Int J Urol ; 27(11): 1024-1030, 2020 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-32875619

RESUMEN

OBJECTIVES: To evaluate the relationship between residual urine volume, pyuria and bladder carcinoma recurrence. METHODS: The clinical data of 305 patients who had post-void residual urine volume measured and preoperative pyuria were retrospectively collected. The patients were classified into three risk groups based on the presence of residual urine and pyuria: good (negative residual urine and pyuria), intermediate (positive residual urine or pyuria) and poor (positive residual urine and pyuria). Predictive factors for intravesical recurrence-free survival were statistically analyzed using Cox proportional hazard models and Kaplan-Meier methods. The propensity score matching method was used to adjust the patients' backgrounds. RESULTS: The median follow-up period for all patients was 44 months. The presence of residual urine (P = 0.0164) and pyuria (P = 0.0233) were two independent prognostic factors for recurrence. After patients were classified into risk groups, the poor-risk group showed significantly shorter recurrence-free survival compared with that of the good- (P = 0.0002) and intermediate-risk groups (P = 0.0090). Even after matching, the presence of residual urine was related to short recurrence-free survival in male patients (P = 0.0012). When stratified by European Organization for Research and Treatment of Cancer risk groups, the presence of pyuria was related to short recurrence-free survival, especially for intermediate-risk patients without bacillus Calmette-Guérin treatment. CONCLUSIONS: Post-void residual urine and preoperative pyuria are two risks for recurrence-free survival in non-muscle-invasive bladder cancer.

8.
IJU Case Rep ; 3(2): 33-35, 2020 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-32743464

RESUMEN

Introduction: When ileal conduit construction is performed for urinary tract drainage during radical cystectomy, the conduit is usually constructed in the right lower abdomen. However, no reports have described ileal conduit construction in the left lower abdomen when it cannot be performed on the right side. In addition, some ingenuity is necessary for construction on the left. Case presentation: A 75-year-old woman visited our hospital with chief complaint of gross hematuria. Computed tomography and cystoscopy showed a huge bladder tumor, and blood analysis showed anemia. The patient was treated by radical cystectomy with ileal conduit construction. An ileal conduit was constructed in the left lower abdomen; it was impossible to construct in the right lower abdomen because of the abdominal wall scar hernia due to the past open surgery. Conclusion: We herein reported a patient who underwent ileal conduit for urinary diversion on the left side of low abdominal wall.

9.
Am J Cardiol ; 128: 35-44, 2020 08 01.
Artículo en Inglés | MEDLINE | ID: mdl-32650922

RESUMEN

The immune response after transcatheter aortic valve implantation (TAVI) in comparison to that after surgical aortic valve replacement (SAVR) remains to be fully elucidated. In a 2-part study, we assessed laboratory data obtained before, immediately after, and 24 and 48 hours after SAVR (128 patients; age ≥80 [mean 82] years) or transfemoral TAVI (102 patients; age ≥80 [mean 86] years) performed for aortic stenosis. In-hospital mortalities were similar (3% vs 0%), but leukocyte counts and aspartate aminotransferase and creatine kinas concentrations were decreased immediately and 24 hours after surgery (all, p <0.001). We performed cytokine profiling in a SAVR group (11 patients; mean age, 77 years) and transfemoral TAVI group (12 patients; mean age, 84 years). By measuring normalized concentrations of 71 cytokines at 3 time points, we found a significant difference (defined as fold change >1.7 and p <0.05 [by Mann-Whitney U-test]) in 23 cytokines. The differentially expressed cytokines fell into 3 hierarchical clusters: cluster A (high increase after SAVR and suppressed increase after TAVI only immediately after surgery [CCL2, CCL4, and 2 others]), cluster B (high increase after SAVR and suppressed increase after TAVI at 2 time points [IL-1Ra, IL-6, IL-8, IL-10, and 5 others]), and cluster C (various patterns [TRAIL, CCL11, and 8 others]). Gene enrichment analysis identified multiple pathways associated with the inflammatory responses in SAVR and altered responses in TAVI, including cellular responses to tumor necrosis factor (p = 0.0035) and interleukin-1 (p = 0.0062). In conclusion, a robust inflammatory response follows SAVR, and a comparatively attenuated response follows TAVI.


Asunto(s)
Estenosis de la Válvula Aórtica/cirugía , Citocinas/inmunología , Implantación de Prótesis de Válvulas Cardíacas/métodos , Reemplazo de la Válvula Aórtica Transcatéter/métodos , Anciano , Anciano de 80 o más Años , Estenosis de la Válvula Aórtica/sangre , Estenosis de la Válvula Aórtica/inmunología , Aspartato Aminotransferasas/sangre , Estudios de Casos y Controles , Creatina Quinasa/sangre , Forma MB de la Creatina-Quinasa/sangre , Femenino , Mortalidad Hospitalaria , Humanos , L-Lactato Deshidrogenasa/sangre , Recuento de Leucocitos , Masculino , Periodo Perioperatorio
10.
Prostate ; 80(11): 850-858, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32501559

RESUMEN

BACKGROUND: Oligometastatic cancer has been suggested as an intermediate state between localized disease and wide-ranging metastases. The clinical significance of local treatment in oligometastatic prostate cancer (PCa) has been a recent topic of interest. However, standard definitions of oligometastasis are lacking. Here we studied risk factors among Japanese de novo oligometastatic patients with PCa. METHODS: We retrospectively assessed clinical data from 264 patients, including locally advanced (T3 or T4N0M0) cancer, lymph-node-positive cancer (Tany N1M0), and cancer with ≤10 bone metastases. All patients received androgen deprivation therapy only. The number of bone metastases and clinical factors were evaluated in association with overall survival (OS) and progression-free survival (PFS). The Mann-Whitney U test, Cox proportional hazard models, and Kaplan-Meier methods were used as statistical analyses. RESULTS: Median age, PSA at baseline and OS were 74 years, 55.2 ng/mL, and 129.0 months, respectively. The cutoff for the number of bone metastases having the greatest impact on OS was ≥3 (hazard ratio [HR]: 2.67; P = .0001). In multivariate analysis, non-regional lymph node (LN) metastases (HR: 2.15; P = .0222), ISUP grade group (GG) 5 (HR: 2.04; P = .0186) and ≥3 bone metastases (HR: 1.82; P = .0390) were independent predictors of OS. In risk classification based on these factors, OS and PFS were significantly classifiable into poor (2-3 factors), intermediate (1 factor), and good (no factors) risk groups (P < .0001). CONCLUSION: Not only the number of bone metastases, but also non-regional LN metastases predict OS in patients with de novo oligometastatic PCa.


Asunto(s)
Neoplasias Óseas/mortalidad , Neoplasias Óseas/secundario , Neoplasias de la Próstata/mortalidad , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Antagonistas de Andrógenos/uso terapéutico , Humanos , Japón/epidemiología , Estimación de Kaplan-Meier , Metástasis Linfática , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Supervivencia sin Progresión , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Tasa de Supervivencia
11.
Prostate ; 80(7): 559-569, 2020 05.
Artículo en Inglés | MEDLINE | ID: mdl-32134137

RESUMEN

BACKGROUND: The inflammatory process has been reported to be involved in the formation and progression of various types of cancer. Recently, a peripheral inflammatory index, combining the derived neutrophils/(leukocytes minus neutrophils) ratio (dNLR) and the lactate dehydrogenase (LDH) level, was proposed as a useful prognostic marker in advanced nonsmall cell lung cancer. The prognostic value of inflammatory markers in prostate cancer has not been established. We aimed to validate the prognostic significance of this peripheral inflammatory index in metastatic castration-resistant prostate cancer (mCRPC). METHODS: Clinical data of 196 mCRPC patients were retrospectively collected from multiple institutions. Clinical factors and inflammatory markers at the development of CRPC, including white blood cell count, absolute neutrophil count, dNLR, neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, C-reactive protein (CRP), and LDH levels, were evaluated. The patients were classified into three groups based on the inflammatory index: Good (low dNLR and LDH), Intermediate (high dNLR or LDH), and Poor (high dNLR and LDH). Overall survival (OS) and cancer-specific survival after CRPC were analyzed using Cox proportional hazard models and Kaplan-Meier methods. RESULTS: The median age and baseline prostate-specific antigen level were 75 years and 397.15 ng/mL, respectively. On multivariate analysis, dNLR (≥1.51; hazard ratio [HR] = 1.624; P = .0173), LDH (≥upper limit of normal; HR = 2.065; P = .0004), alkaline phosphatase (≥310 U/L; HR = 2.546; P < .0001), and positive N stage (HR = 1.621; P = .048) were associated with poor OS after CRPC, whereas other inflammatory markers including the NLR were not. The Good inflammatory index group showed significantly longer OS after CRPC compared to the Intermediate and Poor groups, with median survivals of 46.2, 28.9, and 16.6 months, respectively. CONCLUSIONS: The novel inflammatory index combining dNLR and LDH was a useful prognostic parameter in patients with mCRPC. Our analysis suggested that dNLR emerged as a more valuable prognostic marker than NLR.


Asunto(s)
Inflamación/patología , Neoplasias de la Próstata Resistentes a la Castración/patología , Anciano , Anciano de 80 o más Años , Proteína C-Reactiva/metabolismo , Humanos , Inflamación/sangre , L-Lactato Deshidrogenasa/sangre , Linfocitos/patología , Masculino , Persona de Mediana Edad , Metástasis de la Neoplasia , Estadificación de Neoplasias , Neutrófilos/patología , Pronóstico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Estudios Retrospectivos
13.
Prostate ; 80(5): 432-440, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32017175

RESUMEN

BACKGROUND: Recent landmark randomized trials (CHAARTED and LATITUDE studies) have highlighted potent upfront therapy for "high-volume" and "high-risk" metastatic castration-naïve prostate cancer (mCNPC). However, treatment response shows racial differences. We aimed to propose a novel definition for "high-volume" prostate cancer in Asians. METHODS: We retrospectively pursued 426 patients with de novo mCNPC from multiple institutions between 1999 and 2017. All patients received androgen deprivation therapy alone as initial treatment. We evaluated the number of bone metastases at diagnosis to clarify the clinical significance for progression-free survival and overall survival (OS). Statistical analyses were conducted using the Mann-Whitney U test, Cox proportional hazard models, and Kaplan-Meier methods. RESULTS: Median age and prostate-specific antigen level were 73 years and 266.2 ng/ml, respectively. Median OS was 55.5 months in patients who met the CHAARTED high criteria (vs 33.1 months in the trial). We evaluated 5 thresholds in the number of bone metastases (≥4, ≥6, ≥11, ≥16, and ≥21) to investigate the prognostic values. Patients with ≥11 bone metastases showed the highest HR for OS (2.766). Patients with 11 to 20 bone metastases had a significantly shorter OS than those with ≤10 metastases (P = .0001). We, therefore, proposed modified CHAARTED and LATITUDE high criteria (extending bone metastases ≥11). In multivariate analysis, the modified criteria were the only independent prognostic factors for OS (P = .0272 and P = .042, respectively). Conversely, no significant differences in OS were seen between patients with 1 to 3 bone metastases and 4 to 10 (P = .7513). CONCLUSION: Our exploratory study suggested ≥11 bone metastases as a suitable definition for "high-volume" prostate cancer in Asians. A larger, prospective study is warranted to verify our findings.


Asunto(s)
Neoplasias Óseas/secundario , Neoplasias de la Próstata/patología , Anciano , Anciano de 80 o más Años , Anilidas/administración & dosificación , Grupo de Ascendencia Continental Asiática/estadística & datos numéricos , Estudios de Cohortes , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Humanos , Japón/epidemiología , Masculino , Persona de Mediana Edad , Nitrilos/administración & dosificación , Pronóstico , Supervivencia sin Progresión , Neoplasias de la Próstata/epidemiología , Neoplasias de la Próstata/terapia , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Compuestos de Tosilo/administración & dosificación
14.
Sci Rep ; 10(1): 1292, 2020 Jan 28.
Artículo en Inglés | MEDLINE | ID: mdl-31992742

RESUMEN

L-type amino acid transporter 1 (LAT1) plays a role in transporting essential amino acids including leucine, which regulates the mTOR signaling pathway. Here, we studied the expression profile and functional role of LAT1 in bladder cancer. Furthermore, the pharmacological activity of JPH203, a specific inhibitor of LAT1, was studied in bladder cancer. LAT1 expression in bladder cancer cells was higher than that in normal cells. SiLAT1 and JPH203 suppressed cell proliferative and migratory and invasive abilities in bladder cancer cells. JPH203 inhibited leucine uptake by > 90%. RNA-seq analysis identified insulin-like growth factor-binding protein-5 (IGFBP-5) as a downstream target of JPH203. JPH203 inhibited phosphorylation of MAPK / Erk, AKT, p70S6K and 4EBP-1. Multivariate analysis revealed that high LAT1 expression was found as an independent prognostic factor for overall survival (HR3.46 P = 0.0204). Patients with high LAT1 and IGFBP-5 expression had significantly shorter overall survival periods than those with low expression (P = 0.0005). High LAT1 was related to the high Grade, pathological T stage, LDH, and NLR. Collectively, LAT1 significantly contributed to bladder cancer progression. Targeting LAT1 by JPH203 may represent a novel therapeutic option in bladder cancer treatment.


Asunto(s)
Regulación Neoplásica de la Expresión Génica , Transportador de Aminoácidos Neutros Grandes 1/biosíntesis , Sistema de Señalización de MAP Quinasas , Proteínas de Neoplasias/biosíntesis , Neoplasias de la Vejiga Urinaria/metabolismo , Neoplasias de la Vejiga Urinaria/microbiología , Benzoxazoles/farmacología , Línea Celular Tumoral , Supervivencia sin Enfermedad , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Femenino , Humanos , Masculino , Proteínas de Neoplasias/antagonistas & inhibidores , Tasa de Supervivencia , Serina-Treonina Quinasas TOR/metabolismo , Tirosina/análogos & derivados , Tirosina/farmacología , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología
15.
Prostate ; 80(3): 247-255, 2020 02.
Artículo en Inglés | MEDLINE | ID: mdl-31816126

RESUMEN

BACKGROUND: The role of testosterone as a prognostic factor for castration-resistant prostate cancer treated with docetaxel in Japan was investigated. METHODS: A total of 164 patients with castration-resistant prostate cancer who received docetaxel treatment at Chiba University Hospital and an affiliated hospital were retrospectively analyzed. Testosterone and other clinical factors at the start of docetaxel treatment were evaluated with respect to overall survival and progression-free survival. RESULTS: Of the 164 patients, 69 had high-volume tumors. The median prostatic-specific antigen was 27.0 ng/mL. The median testosterone was 13.0 ng/dL. The rates of bone and visceral metastases were 80.1% and 8.8%, respectively. For progression-free survival, testosterone ≥13 ng/dL was an independent prognostic factor only on univariate analysis (hazard ratio, 1.81; P = .0108). For overall survival, testosterone ≥ 1.3 ng/dL (hazard ratio, 3.37; P < .0001), high volume (hazard ratio, 3.06; P = .0009), and prostate-specific antigen ≥ 27.0 ng/mL (hazard ratio, 2.75; P = .0013) were independent prognostic factors on multivariate analysis. When assessing related clinical factors, higher serum testosterone was associated with visceral metastasis, high volume, and prostate-specific antigen. Based on three prognostic factors (testosterone, high volume, prostate-specific antigen), a risk classification was developed. The high-risk group (3 risk factors) showed a significantly shorter overall survival compared to the moderate-risk (2 risk factors) and low-risk (0-1 risk factor) groups (P < .0001). CONCLUSIONS: The present study identified higher serum testosterone (≥13 ng/dL) as a significant prognostic factor in castration-resistant prostate cancer patients treated with docetaxel therapy.


Asunto(s)
Docetaxel/uso terapéutico , Neoplasias de la Próstata Resistentes a la Castración/sangre , Neoplasias de la Próstata Resistentes a la Castración/tratamiento farmacológico , Testosterona/sangre , Anciano , Antineoplásicos/uso terapéutico , Humanos , Masculino , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos
16.
Sci Rep ; 9(1): 16776, 2019 11 20.
Artículo en Inglés | MEDLINE | ID: mdl-31748583

RESUMEN

Large neutral amino acid transporter 1 (LAT1, SLC7A5) is abundantly expressed in various types of cancer, and it has been thought to assist cancer progression through its activity for uptake of neutral amino acids. However, the roles of LAT1 in renal cell carcinoma (RCC) prognosis and treatment remain uncharacterized. Therefore, we first retrospectively examined the LAT1 expression profile and its associations with clinical factors in RCC tissues (n = 92). The results of immunohistochemistry showed that most of the tissues examined (92%) had cancer-associated LAT1 expression. Furthermore, the overall survival (OS) and progression-free survival (PFS) were shorter in patients with high LAT1 expression levels than in those with low LAT1 expression levels (P = 0.018 and 0.014, respectively), and these associations were further strengthened by the results of univariate and multivariate analyses. Next, we tested the effects of JPH203, which is a selective LAT1 inhibitor, on RCC-derived Caki-1 and ACHN cells. It was found that JPH203 inhibited the growth of these cell types in a dose-dependent manner. Moreover, JPH203 clearly suppressed their migration and invasion activities. Thus, our results show that LAT1 has a great potential to become not only a prognosis biomarker but also a therapeutic target in RCC clinical settings.


Asunto(s)
Carcinoma de Células Renales/metabolismo , Neoplasias Renales/metabolismo , Transportador de Aminoácidos Neutros Grandes 1/metabolismo , Benzoxazoles/farmacología , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Renales/tratamiento farmacológico , Carcinoma de Células Renales/patología , Línea Celular Tumoral , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Femenino , Humanos , Neoplasias Renales/tratamiento farmacológico , Neoplasias Renales/patología , Masculino , Persona de Mediana Edad , Pronóstico , Supervivencia sin Progresión , Estudios Retrospectivos , Tirosina/análogos & derivados , Tirosina/farmacología
17.
Int J Urol ; 26(12): 1106-1112, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31522458

RESUMEN

OBJECTIVE: To examine the impact of post-void residual urine volume on the risk of postoperative recurrence of intravesical carcinoma in patients with upper urinary tract urothelial carcinoma undergoing nephroureterectomy. METHODS: We retrospectively reviewed the data of 81 patients who were admitted to Chiba University Graduate School of Medicine Hospital and underwent nephroureterectomy for upper urinary tract urothelial carcinoma without bladder carcinoma. We assessed the predictive factors for intravesical recurrence after nephroureterectomy in all patients. Next, we compared patients with and without a residual urine volume using propensity score-matching analysis. The presence of a residual urine volume was defined as ≥30 mL. RESULTS: The median follow-up period among all patients was 48 months. The presence of pyuria and a residual urine volume were associated with bladder recurrence in the multivariate analysis. A total of 19 patients each were selected after matching, and we confirmed a significant difference between the presence and absence of a residual urine volume (P = 0.0291). The 2-year postoperative recurrence-free rate of patients with and without a residual urine volume was 32% and 82%, respectively. CONCLUSIONS: This is the first study to evaluate the post-void residual urine volume and intravesical recurrence rate after nephroureterectomy for upper urinary tract urothelial carcinoma. The presence of residual urine might be a risk factor for postoperative recurrence of intravesical carcinoma.


Asunto(s)
Carcinoma de Células Transicionales/cirugía , Neoplasias Renales/cirugía , Recurrencia Local de Neoplasia/epidemiología , Nefroureterectomía , Neoplasias Ureterales/cirugía , Vejiga Urinaria/diagnóstico por imagen , Adulto , Anciano , Anciano de 80 o más Años , Carcinoma de Células Transicionales/mortalidad , Cistoscopía , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Neoplasias Renales/mortalidad , Masculino , Persona de Mediana Edad , Periodo Posoperatorio , Estudios Retrospectivos , Medición de Riesgo/métodos , Factores de Riesgo , Neoplasias Ureterales/mortalidad , Vejiga Urinaria/fisiopatología , Micción/fisiología
18.
Angew Chem Int Ed Engl ; 58(35): 12159-12163, 2019 08 26.
Artículo en Inglés | MEDLINE | ID: mdl-31211483

RESUMEN

1-Hydroxytaxinine (1) is a cytotoxic taxane diterpenoid. Its central eight-membered B-ring possesses four oxygen-functionalized centers (C1, C2, C9, and C10) and two quaternary carbon centers (C8 and C15), and is fused with six-membered A- and C-rings. The densely functionalized and intricately fused structure of 1 makes it a highly challenging synthetic target. Reported here is an efficient radical-based strategy for assembling 1 from A- and C-ring fragments. The A-ring bearing an α-alkoxyacyl telluride moiety underwent intermolecular coupling with the C-ring fragment by a Et3 B/O2 -promoted decarbonylative radical formation. After construction of the C8-quaternary stereocenter, a pinacol coupling reaction using a low-valent titanium reagent formed the B-ring with stereoselective installation of the C1,C2-diol. Subsequent manipulations at the A- and C-rings furnished 1 in 26 total steps.

19.
Int J Urol ; 26(8): 791-796, 2019 08.
Artículo en Inglés | MEDLINE | ID: mdl-31081198

RESUMEN

OBJECTIVES: To examine the effectiveness of intravesical irrigation with physiological saline solution or distilled water for the prevention of bladder recurrence in patients undergoing laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma. METHODS: This retrospective study involved 109 upper urinary tract urothelial carcinoma patients who underwent laparoscopic nephroureterectomy, and were evaluated at Chiba University Hospital and Yokohama Rosai Hospital between 2001 and 2018. We investigated the outcomes and analyzed various clinical factors including with or without intravesical irrigation related to bladder carcinoma recurrence after surgery. Physiological saline solution or distilled water was used for irrigation, which was carried out only during surgery. RESULTS: The median follow-up period after surgery was 26.1 months. Bladder recurrence was confirmed within 2 years for 45 of the 109 patients in the present study. Irrigation was carried out for 48 cases (distilled water, 26 patients; physiological saline solution, 22 patients). Tumor grade (G1-2 vs G3; P = 0.05) and intravesical irrigation (yes vs no; P = 0.0058) were related to bladder recurrence on univariate analyses. On multivariate analyses, intravesical irrigation was the independent factor involved in the prevention of bladder recurrence (P = 0.0051). Comparison between the irrigation and non-irrigation groups showed that bladder recurrence rates were significantly lower in the irrigation group (irrigation group vs non-irrigation group: 25.0% vs 52.5%, P = 0.0066). There was no significant difference in the recurrence rate between the two solutions used for irrigation. CONCLUSIONS: Intravesical irrigation during surgery of upper urinary tract urothelial carcinoma might decrease postoperative bladder recurrence rates.


Asunto(s)
Carcinoma de Células Transicionales/cirugía , Neoplasias Renales/cirugía , Recurrencia Local de Neoplasia/prevención & control , Nefroureterectomía/métodos , Solución Salina/administración & dosificación , Neoplasias Ureterales/cirugía , Administración Intravesical , Anciano , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Recurrencia Local de Neoplasia/epidemiología , Siembra Neoplásica , Estudios Retrospectivos , Irrigación Terapéutica/métodos , Vejiga Urinaria , Agua/administración & dosificación
20.
Postepy Kardiol Interwencyjnej ; 15(4): 431-438, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31933659

RESUMEN

Introduction: Transcatheter aortic valve implantation (TAVI) has grown to be an alternative treatment for severe symptomatic aortic valve stenosis (AS) in elderly patients. Although TAVI is a less invasive surgery than surgical aortic valve replacement, some patients may require prolonged hospitalization. Aim: To find the determinants of prolonged hospitalization in patients who underwent trans-femoral TAVI. Material and methods: A total of 94 AS patients who underwent trans-femoral TAVI were included as the final study population, and divided into the conventional hospitalization group (≤ 21 days) (n = 74) and prolonged hospitalization group (> 21 days) (n = 20). We compared clinical characteristics between the two groups, and multivariate logistic regression analysis was performed to find the determinants of prolonged hospitalization. Results: In multivariate logistic regression analysis, moderate or severe mitral regurgitation (OR = 4.49, 95% CI: 1.16-17.47, p = 0.03), taking statins or angiotensin converting enzyme (ACE) inhibitors/angiotensin II receptor blockers (ARB) on admission (statins: OR = 0.13, 95% CI: 0.02-0.71, p = 0.02, ACE inhibitors/ARB: OR = 0.25, 95% CI: 0.06-0.96, p = 0.04), estimated glomerular filtration rate (eGFR) (per 15 ml/min/1.73 m2 incremental) (OR = 0.49, 95% CI: 0.26-0.90, p = 0.02) and current chopsticks user (OR = 0.05, 95% CI: 0.01-0.41, p < 0.01) were significantly associated with prolonged hospitalization. Conclusions: Moderate or severe mitral regurgitation was significantly associated with prolonged hospitalization, while current chopsticks user, eGFR (per 15 ml/min/1.73 m2 incremental), taking ACE inhibitors/ARB or statins before the procedure were inversely associated with prolonged hospitalization in patients who underwent trans-femoral TAVI.

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