L-type amino acid transporter 1 inhibitor JPH203 prevents the growth of cabazitaxel-resistant prostate cancer by inhibiting cyclin-dependent kinase activity.

L-type amino acid transporter 1 (LAT1, SLC7A5) is an amino acid transporter expressed in various carcinomas, and it is postulated to play an important role in the proliferation of cancer cells through the uptake of essential amino acids. Cabazitaxel is a widely used anticancer drug for treating castration-resistant prostate cancer (CRPC); however, its effectiveness is lost when cancer cells acquire drug resistance. In this study, we investigated the expression of LAT1 and the effects of a LAT1-specific inhibitor, JPH203, in cabazitaxel-resistant prostate cancer cells. LAT1 was more highly expressed in the cabazitaxel-resistant strains than in the normal strains. Administration of JPH203 inhibited the growth, migration, and invasive ability of cabazitaxel-resistant strains in vitro. Phosphoproteomics using liquid chromatography-mass spectrometry to comprehensively investigate changes in phosphorylation due to JPH203 administration revealed that cell cycle-related pathways were affected by JPH203, and that JPH203 significantly reduced the kinase activity of cyclin-dependent kinases 1 and 2. Moreover, JPH203 inhibited the proliferation of cabazitaxel-resistant cells in vivo. Taken together, the present study results suggest that LAT1 might be a valuable therapeutic target in cabazitaxel-resistant prostate cancer.

The LAT1 inhibitor JPH203 suppresses the growth of castration-resistant prostate cancer through a CD24-mediated mechanism.

L-type amino acid transporter 1 (LAT1) is specifically expressed in many malignancies, contributes to the transport of essential amino acids, such as leucine, and regulates the mammalian target of rapamycin (mTOR) signaling pathway. We investigated the expression profile and functional role of LAT1 in prostate cancer using JPH203, a specific inhibitor of LAT1. LAT1 was highly expressed in castration-resistant prostate cancer (CRPC) cells, including C4-2 and PC-3 cells, but its expression level was low in castration-sensitive LNCaP cells. JPH203 significantly inhibited [14C] leucine uptake in CRPC cells but had no effect in LNCaP cells. JPH203 inhibited the proliferation, migration, and invasion of CRPC cells but not of LNCaP cells. In C4-2 cells, Cluster of differentiation (CD) 24 was identified by RNA sequencing as a novel downstream target of JPH203. CD24 was downregulated in a JPH203 concentration-dependent manner and suppressed activation of the Wnt/ß-catenin signaling pathway. Furthermore, an in vivo study showed that JPH203 inhibited the proliferation of C4-2 cells in a castration environment. The results of this study indicate that JPH203 may exert its antitumor effect in CRPC cells via mTOR and CD24.

Testosterone bounce predicts favorable prognoses for prostate cancer patients treated with degarelix.

BACKGROUND: To clarify the clinical roles of changes in testosterone (T) levels with a cut-off level of 20 ng/dL as predictive factors for prostate cancer patients treated with degarelix acetate. METHODS: A total of 120 prostate cancer patients who received hormone therapies with gonadotropin-releasing hormone antagonist degarelix acetate were retrospectively analyzed. The predictive values of nadir T levels, max T levels, T bounce, and other clinical factors were evaluated for overall survival (OS), cancer-specific survival (CSS), and progression-free survival (PFS). T bounce was defined as satisfying both nadir serum T levels of <20 ng/dL and max serum T levels of ≥20 ng/dL during hormone therapies. RESULTS: In 120 prostate cancer patients, 16 (13%) patients did not achieve nadir T < 20 ng/dL, and 76 (63%) patients had max T ≥ 20 ng/dL. The median times to nadir T and max T are 108 and 312 days, respectively. T bounce was shown in 60 (50%) patients and is associated with favorable prognoses both for OS (p = 0.0019) and CSS (p = 0.0013) but not for PFS (p = 0.92). While in the subgroup analyses of the patients with the progression of the first-line hormone therapies, T bounce predicts favorable OS (p = 0.0015) and CSS (p = 0.0013) after biochemical recurrence. CONCLUSIONS: The present study revealed that T bounce with cut-off levels of 20 ng/dL is a promising biomarker that predicts OS and CSS for prostate cancer patients treated with degarelix acetate.

Summary of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma 2023 by the Japanese Urological Association.

This article is an English translation of the Clinical Practice Guidelines for Upper Tract Urothelial Carcinoma (2nd edition) published in June 2023. The Japanese Urological Association's (JUA) Guidelines Committee on Upper Tract Urothelial Carcinoma (UTUC) created a 2023 update guideline to support clinicians' current evidence-based management of UTUC and to incorporate its recommendations into clinical practice. The new guideline adhered as closely as possible to the Minds Manual for Guideline Development 2020 ver. 3.0. Findings related to epidemiological, pathological, diagnosis, treatment, and follow-up were reviewed. In addition, seven clinical questions (CQs) were set to determine the grade of recommendation and level of evidence. Preconceptions and biases were removed from the preparation process, the overall evidence was evaluated appropriately, and recommendations were made after fully considering the balance between benefits and harms. Although the evidence is still insufficient to be taken up as a CQ, the latest important information is described in seven columns, and clinical issues that should be resolved in the future related to the CQ are described as recommendations for tomorrow. We hope that these guidelines will help medical professionals, patients, and their families involved in the treatment of UTUC in their decision-making, and hope that a critical review of these guidelines will lead to further refinements in the next edition.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

Detection of intraductal carcinoma in prostate cancer patients with small tumor volume.

OBJECTIVES: The purpose of this study was to investigate intraductal carcinoma of the prostate (intraductal carcinoma) and significant cancer (SC) in patients with small tumor volume (<0.5 cm3 ) in prostatectomy specimens. METHODS: Data from 639 patients undergoing radical prostatectomy between April 2006 and December 2017 at Chiba University Hospital and 2 affiliated institutions were retrospectively reviewed. Tumor volume in prostatectomy specimens was measured, and with a tumor volume of less than 0.5 cm3 , the presence of intraductal carcinoma and SC was examined. SC was defined as one that did not meet the definition of pathological insignificant cancer (organ-confined cancer, Grade Group 1, tumor volume < 0.5 cm3 ). The number of patients who met four active surveillance (AS) protocols was also examined. RESULTS: A total of 83 patients with tumor volume < 0.5 cm3 were identified in this study population (SC: 43 patients [52%], intraductal carcinoma: 5 patients [6%]). The median follow-up was 34.6 months (range: 18-57 months). Four (5%) developed biochemical recurrence. The number of positive biopsy cores ≥ 2 was an independent predictor of SC in patients with tumor volume < 0.5 cm3 (hazard ratio: 4.39; 95% confidence interval: 1.67-11.56; p = 0.003). In tumor volume < 0.5 cm3 , tumor volume was significantly correlated with the International Society of Urological Pathology Grade Group (1 vs. 4-5, p = 0.002) and the presence of intraductal carcinoma (p = 0.004). In intraductal carcinoma-positive cases, four of five patients (80%) had the predictor of SC, which was two or more positive biopsy cores. Of the four AS protocols, the criteria for Prostate Cancer Research International: Active Surveillance were met most frequently in 46 cases (55%) of tumor volume less than 0.5 cm3 if targeted biopsy by magnetic resonance imaging was available. CONCLUSION: The results of the present study suggest that intraductal carcinoma was present even in cases with small tumor volumes. Grade Group and intraductal carcinoma showed a positive correlation with tumor volume.

Clinical utility of the prognostic nutritional index in patients with metastatic hormone-sensitive prostate cancer: A retrospective, multicenter, cohort study.

BACKGROUND: The prognostic nutritional index (PNI) based on the serum albumin level and the lymphocyte count has been investigated as a prognostic factor in patients with malignant tumors. However, it has been poorly studied in prostate cancer (PCa), and little is known about its clinical utility. METHODS: Clinical data of 353 patients with de novo, metastatic, hormone-sensitive PCa (mHSPC) who received androgen deprivation therapy (ADT) were obtained from multiple institutions between 2000 and 2019. The impacts of the pretreatment PNI level on treatment response and survival, together with clinical parameters, were examined. The Mann-Whitney U test, Cox proportional hazards models, and Kaplan-Meier methods were used to evaluate significance. RESULTS: The median age and initial prostate-specific antigen level were 73 and 266.18 ng/mL, respectively. Patients with a low PNI had shorter progression-free survival (PFS), cancer-specific survival (CSS), and overall survival (OS) (p < 0.0001). On multivariate analysis, low PNI was an independent prognostic factor for OS (p = 0.0027, HR = 1.65), as well as advanced age (p = 0.049, HR = 1.38), the International Society of Urological Pathology (ISUP) grade group (GG) 5 (p = 0.0027, HR = 1.69), and elevated lactate dehydrogenase (LDH) (p < 0.0001, HR = 2.08). A propensity score-matching analysis showed that the PNI level remained a significant prognostic biomarker for PFS (p = 0.0263), CSS (p = 0.0006), and OS (p = 0.0015). Furthermore, a novel risk classification using PNI, LDH, and the ISUP GG was established to stratify patients' prognosis. An increase in the number of risk factors was significantly correlated with poor outcomes. CONCLUSIONS: A low pretreatment PNI might be an effective biomarker of poor treatment response and survival in patients with mHSPC undergoing ADT.

Extracellular vesicles in bone homeostasis: key roles of physiological and pathological conditions.

Extracellular vesicles (EVs) are small particles with lipid bilayer membranes that are secreted by all cell types and are widely known as crucial intercellular communication mediators, shuttling biologically active molecules. The bone is a typically preferred site of cancer metastasis due to its unique cellular compositions and dynamics. Bone cell-derived EVs serve as regulators that orchestrate harmonious bone homeostasis. Cancer cells secrete specific EVs in a series of the bone metastatic process to dominate the bone microenvironment. Additionally, cancer cell-related EVs contribute to pre-metastatic niche formation, bone homeostasis disruption, and tumor bone progression and survival. Here, we investigated recent studies on EV-mediated crosstalk in the bone tumor microenvironment. Furthermore, this review aimed to elucidate the EV-based therapeutic perspectives for bone metastasis.

Challenges in the diagnosis of the enigmatic primary adrenal leiomyosarcoma: two case reports and review of the literature.

BACKGROUND: Primary adrenal leiomyosarcoma is a rare and aggressive mesenchymal tumor derived from the smooth muscle wall of a central adrenal vein or its tributaries; therefore, tumors tend to invade the inferior vena cava and cause thrombosis. The great majority of tumors grow rapidly, which makes the disease difficult to diagnose in its early clinical stages and needs differentiation from adrenocortical carcinomas for the selection of chemotherapy including mitotane which causes adrenal insufficiency. CASE PRESENTATION: We presented two patients with adrenal leiomyosarcoma who were referred to our hospital with abdominal pain and harboring large adrenal tumors and inferior vena cava thrombosis. The endocrine findings, including serum catecholamine levels, were unremarkable. These two patients were considered clinically inoperable, and CT-guided core needle biopsy was performed to obtain the definitive histopathological diagnosis and determine the modes of therapy. The masses were subsequently diagnosed as primary adrenal leiomyosarcoma based on the histological features and positive immunoreactivity for SMA (smooth muscle actin), desmin, and vimentin. CONCLUSIONS: Adrenal leiomyosarcoma derived from the smooth muscle wall of a central adrenal vein or its tributaries is rare but should be considered a differential diagnosis in the case of nonfunctioning adrenal tumors extending directly to the inferior vena cava. CT-guided biopsy is considered useful for histopathological diagnosis and clinical management of patients with inoperable advanced adrenal tumors without any hormone excess.

Delayed postrenal failure due to progression of asymptomatic hydronephrosis following hysterectomy.

Asymptomatic hydronephrosis following hysterectomy is generally transient. Here, we present the case of a 52-year-old woman who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy for benign indications. Computed tomography (CT) to examine bleeding on the second postoperative day incidentally revealed bilateral grade II hydronephrosis. Asymptomatic hydronephrosis was not reevaluated, and gynecological outpatient follow-up was terminated with a normal creatinine level on postoperative day 43. On postoperative day 107, the patient noticed weight gain of 10 kg, decreased urine output, and generalized edema. The serum creatinine level was elevated to 5.4 mg/dL, and CT revealed bilateral grade III hydronephrosis. Urgent bilateral ureteral stenting was performed to treat stenosis of the distal ureters that caused postrenal failure. Ureteroneocystostomy was performed for strict stenosis of the right ureter at 10 months postoperatively. Histological examination of the resected distal ureter showed inflammation and fibrosis. Asymptomatic hydronephrosis developing after hysterectomy progress to delayed postrenal failure.

Development and validation of novel nomogram to identify the candidates for extended pelvic lymph node dissection for prostate cancer patients in the robotic era.

OBJECTIVES: To determine candidates for extended pelvic lymph node dissection using a novel nomogram to assess the risk of lymph node invasion in Japanese prostate cancer patients in the robotic era. METHODS: A total of 538 patients who underwent robot-assisted radical prostatectomy with extended pelvic lymph node dissection in three hospitals were retrospectively analyzed. Medical records were reviewed uniformly and the following data collected: prostate-specific antigen, age, clinical T stage, primary and secondary Gleason score at prostate biopsy, and percentage of positive core numbers. Finally, data from 434 patients were used for developing the nomogram and data from 104 patients were used for external validation. RESULTS: Lymph node invasion was detected in 47 (11%) and 16 (15%) patients in the development and validation set, respectively. Based on multivariate analysis, prostate-specific antigen, clinical T stage ≥3, primary Gleason score, grade group 5, and percentage of positive cores were selected as variables to incorporate into the nomogram. The area under the curve values were 0.781 for the internal and 0.908 for the external validation, respectively. CONCLUSIONS: The present nomogram can help urologists identify candidates for extended pelvic lymph node dissection concomitant with robot-assisted radical prostatectomy among patients with prostate cancer.

Contribution of the L-Type Amino Acid Transporter Family in the Diagnosis and Treatment of Prostate Cancer.

The L-type amino acid transporter (LAT) family contains four members, LAT1~4, which are important amino acid transporters. They mainly transport specific amino acids through cell membranes, provide nutrients to cells, and are involved in a variety of metabolic pathways. They regulate the mTOR signaling pathway which has been found to be strongly linked to cancer in recent years. However, in the field of prostate cancer (PCa), the LAT family is still in the nascent stage of research, and the importance of LATs in the diagnosis and treatment of prostate cancer is still unknown. Therefore, this article aims to report the role of LATs in prostate cancer and their clinical significance and application. LATs promote the progression of prostate cancer by increasing amino acid uptake, activating the mammalian target of rapamycin (mTOR) pathway and downstream signals, mediating castration-resistance, promoting tumor angiogenesis, and enhancing chemotherapy resistance. The importance of LATs as diagnostic and therapeutic targets for prostate cancer was emphasized and the latest research results were introduced. In addition, we introduced selective LAT1 inhibitors, including JPH203 and OKY034, which showed excellent inhibitory effects on the proliferation of various tumor cells. This is the future direction of amino acid transporter targeting therapy drugs.

Targeting L-type amino acid transporter 1 in urological malignancy: Current status and future perspective.

Amino acid transporters are responsible for the uptake of amino acids, critical for cell proliferation. L-type amino acid transporters play a major role in the uptake of essential amino acids. L-type amino acid transporter 1 (LAT1) exerts its functional properties by forming a dimer with 4F2hc. Utilizing this cancer-specificity, research on diagnostic imaging and therapeutic agents for malignant tumors targeting LAT1 progresses in various fields. In hormone-sensitive prostate cancer, the up-regulation of L-type amino acid transporter 3 (LAT3) through the androgen receptor (AR) has been identified. On the other hand, in castration-resistant prostate cancer, the negative regulation of LAT1 through AR has been determined. Furthermore, 4F2hc: a binding partner of LAT1, was identified as the specific downstream target of Androgen Receptor Splice Variant 7: AR-V7. LAT1 has been suggested to contribute to acquiring castration resistance in prostate cancer, making LAT1 a completely different therapeutic target from anti-androgens and taxanes. Increased expression of LAT1 has also been found in renal and bladder cancers, suggesting a contribution to acquiring malignancy and progression. In Japan, clinical trials of LAT1 inhibitors for solid tumors are in progress, and clinical applications are now underway. This article will summarize the relationship between LAT1 and urological malignancies.

External validation of the Candiolo nomogram for high-risk prostate cancer patients treated with carbon ion radiotherapy plus androgen deprivation therapy: a retrospective cohort study.

The aim of this study was to reclassify high-risk prostate cancer patients treated with carbon-ion radiotherapy and androgen deprivation therapy using the Candiolo nomogram and evaluate usefulness to predict the following 10-year biochemical recurrence. Six hundred seventy-two high-risk prostate cancer patients were reclassified according to the Candiolo nomogram. The cumulative incidence curves for biochemical recurrence were compared by Gray's test. Furthermore, five predictors of the Candiolo nomogram in our patients were evaluated by Fine and Gray regression hazards model. The higher the Candiolo risk, the worse the biochemical recurrence, especially in high- and very high-risk patients. Out of five predictors, age ≥70 years, cT3 stage, biopsy Gleason score ≥9 or the percentage of positive biopsy cores ≥50% had significant impacts on 10-year biochemical recurrence in our patients. The Candiolo nomogram can reclassify our high-risk prostate cancer patients treated with carbon-ion radiotherapy and androgen deprivation therapy and evaluate the biochemical recurrence preciously.

A clinical investigation of recurrence and lost follow-up after renal cell carcinoma surgery: a single-center, long-term, large cohort, retrospective study.

BACKGROUND: Late recurrence of renal cell carcinoma (RCC) is observed in some postoperative patients. In addition, some of these patients are lost to long-term postoperative follow-up. We reviewed the treatment results and prognosis of postoperative patients with RCC at Chiba University Hospital, with the aim of clarifying the proportion and background of patients lost to follow-up. METHODS: This retrospective study included 1176 RCC patients who underwent radical or/and partial nephrectomy. Overall survival (OS), cancer-specific survival (CSS), recurrence-free survival (RFS), and lost follow-up free survival (LFFS) were evaluated and the risk factors for LFFS identified. RESULTS: The median RFS for stage II and II cases was 188.3 and 104.0 months, respectively. Even in stage I, recurrence was observed in about 20% of patients 20 years after surgery. The Kaplan-Meier curve for LFFS showed a linear descent over time, with 50% of patients lost to follow-up within 25 years. Older age (≥ 62 years), histological type (clear cell RCC), and no recurrence were significant risk factors for lost follow-up. CONCLUSIONS: Long-term follow-up is necessary after RCC surgery because late recurrence cases are not uncommon. We believe that lifelong follow-up with imaging studies is recommended for postoperative RCC patients. Early detection of recurrence in postoperative patients is a very important issue, and it may be worthwhile for improving the prognosis of postoperative patients to focus on patients lost to follow-up who may have been overlooked.

Carbon-ion radiotherapy for urological cancers.

Carbon-ions are charged particles with a high linear energy transfer, and therefore, they make a better dose distribution with greater biological effects on the tumors compared with photons and protons. Since prostate cancer, renal cell carcinoma, and retroperitoneal sarcomas such as liposarcoma and leiomyosarcoma are known to be radioresistant tumors, carbon-ion radiotherapy, which provides the advantageous radiobiological properties such as an increasing relative biological effectiveness toward the Bragg peak, a reduced oxygen enhancement ratio, and a reduced dependence on fractionation and cell-cycle stage, has been tested for these urological tumors at the National Institute for Radiological Sciences since 1994. To promote carbon-ion radiotherapy as a standard cancer therapy, the Japan Carbon-ion Radiation Oncology Study Group was established in 2015 to create a registry of all treated patients and conduct multi-institutional prospective studies in cooperation with all the Japanese institutes. Based on accumulating evidence of the efficacy and feasibility of carbon-ion therapy for prostate cancer and retroperitoneal sarcoma, it is now covered by the Japanese health insurance system. On the other hand, carbon-ion radiotherapy for renal cell cancer is not still covered by the insurance system, although the two previous studies showed the efficacy. In this review, we introduce the characteristics, clinical outcomes, and perspectives of carbon-ion radiotherapy and our efforts to disseminate the use of this new technology worldwide.

Predictive factors for the effectiveness of novel androgen receptor axis-targeted agents in patients with metastatic prostate cancer.

OBJECTIVE: Novel androgen receptor axis-targeted agents (ARATAs) have been developed for mCRPC and improved overall survival (OS). Here, we aimed to find predictors who will receive the greatest benefits from ARATAs. METHODS: We previously performed a multicenter study to identify prognostic factors for metastatic hormone-sensitive prostate cancer (mHSPC, n = 148) and mCRPC (n = 99), and showed that the bone scan index (BSI) was one of the significant prognostic factors for 3-year OS (PROSTAT-BSI study). mHSPC progressed to mCRPC (n = 101), for which 69 patients were treated with (n = 39) or without ARATAs (n = 30, prior to the approval of ARATAs). The 69 patients were divided into two groups according to patient factors, and these cohorts were further divided into two subgroups by usage of ARATAs. OS was compared between subgroups in each group. RESULTS: The predictors were age (<71.4 years), serum levels of C-reactive protein (≥0.16 ng/ml) and alkaline phosphatase (≥548 U/L), time to PSA progression after ADT (<8.9 months), the lowest PSA level (≥1 ng/ml) after ADT, and the rate of PSA decline 3 months after ADT (<0.987), whereas hemoglobin levels, PSA before ADT, Gleason scores, existence of visceral metastases, and BSI were not. CONCLUSIONS: The present study identified predictors for the effectiveness of ARATAs. The number of bone metastases (≒BSI), existence of visceral metastases, and Gleason scores, which were identified as high-risk factors in the LATITUDE study and disease volume in CHAARTED criteria, did not appear to be useful for predicting effectiveness from ARATAs.

Long-term clinical outcomes after 12-fractionated carbon-ion radiotherapy for localized prostate cancer.

There are no clinical reports of long-term follow-up after carbon-ion radiotherapy (CIRT) using a dose of 51.6 Gy (relative biological effectiveness [RBE]) in 12 fractions for localized prostate cancer, or of a comparison of clinical outcomes between passive and scanning beam irradiation. A total of 256 patients with localized prostate cancer who received CIRT at a dose of 51.6 Gy (RBE) in 12 fractions using two different beam delivery techniques (passive [n = 45] and scanning [n = 211]), and who were followed for more than 1 year, were analyzed. The biochemical relapse-free (bRF) rate was defined by the Phoenix definition, and the actuarial toxicity rates were evaluated using the Kaplan-Meier method. Of the 256 patients, 41 (16.0%), 111 (43.4%), and 104 (40.6%) were classified as low, intermediate, and high risk, respectively, after a median follow-up of 7.0 (range 1.1-10.4) years. Androgen deprivation therapy was performed in 212 patients (82.8%). The 5-year bRF rates of the low-, intermediate-, and high-risk patients were 95.1%, 90.9%, and 91.1%, respectively. The 5-year rates of grade 2 late gastrointestinal and genitourinary toxicities in all patients were 0.4% and 6.3%, respectively. No grade ≥3 toxicities were observed. There were no significant differences in the rates of bRF or grade 2 toxicities in patients who received passive irradiation versus scanning irradiation. Our long-term follow-up results showed that a CIRT regimen of 51.6 Gy (RBE) in 12 fractions for localized prostate cancer yielded a good therapeutic outcome and low toxicity rates irrespective of the beam delivery technique.

Functional analysis of LAT3 in prostate cancer: Its downstream target and relationship with androgen receptor.

L-type amino acid transporter 3 (LAT3, SLC43A1) is abundantly expressed in prostate cancer (PC) and is thought to play an essential role in PC progression through the cellular uptake of essential amino acids. Here, we analyzed the expression, function, and downstream target of LAT3 in PC. LAT3 was highly expressed in PC cells expressing androgen receptor (AR), and its expression was increased by dihydrotestosterone treatment and decreased by bicalutamide treatment. In chromatin immunoprecipitation sequencing of AR, binding of AR to the SLC43A1 region was increased by dihydrotestosterone stimulation. Knockdown of LAT3 inhibited cell proliferation, migration, and invasion, and the phosphorylation of p70S6K and 4EBP-1. Separase (ESPL1) was identified as a downstream target of LAT3 by RNA sequencing analysis. In addition, immunostaining of prostatectomy specimens was performed. In the multivariate analysis, high expression of LAT3 was an independent prognostic factor for recurrence-free survival (hazard ratio: 3.24; P = .0018). High LAT3 expression was correlated with the pathological T stage and a high International Society of Urological Pathology grade. In summary, our results suggest that LAT3 plays an important role in the progression of PC.

Epigenetic modifications in prostate cancer.

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.