Purine-Rich Element Binding Protein Alpha, a Nuclear Matrix Protein, Has a Role in Prostate Cancer Progression.

Solid tumors as well as leukemias and lymphomas show striking changes in nuclear structure including nuclear size and shape, the number and size of nucleoli, and chromatin texture. These alterations have been used in cancer diagnosis and might be related to the altered functional properties of cancer cells. The nuclear matrix (NM) represents the structural composition of the nucleus and consists of nuclear lamins and pore complexes, an internal ribonucleic protein network, and residual nucleoli. In the nuclear microenvironment, the NM is associated with multi-protein complexes, such as basal transcription factors, signaling proteins, histone-modifying factors, and chromatin remodeling machinery directly or indirectly through scaffolding proteins. Therefore, alterations in the composition of NM could result in altered DNA topology and changes in the interaction of various genes, which could then participate in a cascade of the cancer process. Using an androgen-sensitive prostate cancer cell line, LNCaP, and its androgen-independent derivative, LN96, conventional 2D-proteomic analysis of the NM proteins revealed that purine-rich element binding protein alpha (PURα) was detected in the NM proteins and differentially expressed between the cell lines. In this article, we will review the potential role of the molecule in prostate cancer.

Roles of the PARP Inhibitor in BRCA1 and BRCA2 Pathogenic Mutated Metastatic Prostate Cancer: Direct Functions and Modification of the Tumor Microenvironment.

Cancer cells frequently exhibit defects in DNA damage repair (DDR), leading to genomic instability. Mutations in DDR genes or epigenetic alterations leading to the downregulation of DDR genes can result in increased dependency on other DDR pathways. Therefore, DDR pathways could be a treatment target for various cancers. In fact, polyadenosine diphosphatase ribose polymerase (PARP) inhibitors, such as olaparib (Lynparza®), have shown remarkable therapeutic efficacy against BRCA1/2-mutant cancers through synthetic lethality. Recent genomic analytical advancements have revealed that BRCA1/BRCA2 pathogenic variants are the most frequent mutations among DDR genes in prostate cancer. Currently, the PROfound randomized controlled trial is investigating the efficacy of a PARP inhibitor, olaparib (Lynparza®), in patients with metastatic castration-resistant prostate cancer (mCRPC). The efficacy of the drug is promising, especially in patients with BRCA1/BRCA2 pathogenic variants, even if they are in the advanced stage of the disease. However, olaparib (Lynparza®) is not effective in all BRCA1/2 mutant prostate cancer patients and inactivation of DDR genes elicits genomic instability, leading to alterations in multiple genes, which eventually leads to drug resistance. In this review, we summarize PARP inhibitors' basic and clinical mechanisms of action against prostate cancer cells and discuss their effects on the tumor microenvironment.

Prostate fibroblasts enhance androgen receptor splice variant 7 expression in prostate cancer cells.

BACKGROUND: Androgen receptor splice variant (AR-V) expression has been associated with prostate cancer (PCa) progression to castration-resistant PCa during androgen deprivation therapy, which reduces androgen production and inhibits androgen action in PCa cells. However, the mechanisms whereby aberrant AR-V expression is increased in PCa are still largely unknown. Fibroblasts in tumor stroma influence PCa initiation and aggressiveness, and which may play a crucial role in eliciting genetic changes during malignant transformation in human prostate epithelium. Here, our aim was to determine whether prostate fibroblasts in tumor stroma induce aberrant AR-V7 expression in PCa cells under low androgen concentration. METHODS: We performed in vitro experiments using androgen-sensitive, AR-positive PCa cell lines (LNCaP and 22Rv1 cells), commercially available prostate stromal cells (PrSC), and primary cultured prostate fibroblasts (pcPrF) from PCa specimens collected from biopsies of patients with advanced PCa. PCa cells were cocultured with each of the three fibroblast lines (PrSC, pcPrF-M37, and pcPrF-M48). RESULTS: The proliferation under low androgen concentration of LNCaP and 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48 was significantly increased compared to that of PCa cells cultured alone. Androgen receptor-full length (AR-FL) protein expression was increased in LNCaP and 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48. AR-V7 protein expression was increased in 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48. Under low androgen concentration, AR-V7 protein expression was slightly detected in LNCaP cells cocultured with PrSC or pcPrF-M37. Cytokine array analysis revealed that monocyte chemotactic protein-1 (MCP-1) and interleukin-8 (IL-8) levels in the conditioned medium of 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48 were increased under low androgen concentration. High IL-8 concentration (30 ng/ml) resulted in significantly increased protein expression of AR-FL, AR-V7, and phospho-NF-κB p65 in 22Rv1 cells. In contrast, IL-8 antibody (1 µg/ml) decreased AR-V7 protein expression in 22Rv1 cells cocultured with PrSC, pcPrF-M37, or pcPrF-M48. CONCLUSIONS: pcPrF from PCa specimens increase the expression of aberrant AR-V7 in PCa cells. IL-8 may be a target for preventing the expression of aberrant AR-Vs in PCa.

Dramatic response to pembrolizumab after pseudoprogression in a patient with advanced metastatic castration-resistant prostate cancer.

Introduction: Prostate cancer with a microsatellite instability-high or mismatch repair-deficient status is not common. Few reports of the response to pembrolizumab in metastatic castration-resistant prostate cancer in a real-world setting have been reported. This case report describes a dramatic response to pembrolizumab after initial pseudoprogression in a patient with microsatellite instability-high metastatic castration-resistant prostate cancer. Case presentation: A 70-year-old man was administered pembrolizumab for metastatic castration-resistant prostate cancer after the genetic evaluation of lymphadenectomy revealed a microsatellite instability-high status. His general condition dramatically improved after pseudoprogression. His favorable condition has been maintained for 1 year since the final dose. Conclusion: We experienced a case of dramatic response to pembrolizumab after pseudoprogression in a patient with advanced metastatic castration-resistant prostate cancer. In patients with metastatic castration-resistant prostate cancer and the microsatellite instability-high/mismatch repair-deficient phenotype, a few months follow-up is necessary to evaluate the efficacy of pembrolizumab.

Succinate dehydrogenase B-deficient renal cell carcinoma with a germline variant in a Japanese patient: a case report.

Succinate dehydrogenase (SDH)-deficient renal cell carcinoma (RCC) is a rare renal cancer. A 75-year-old Japanese female presented with gross hematuria. Computed tomography revealed two tumors in the left kidney, which were resected. Immunohistochemistry indicated negative staining for the B subunit of SDH (SDHB) in the resected specimen, leading to a final diagnosis of SDHB-deficient RCC. Genetic testing for SDHB showed a RCC germline variant in exon 6 (NM_003000.3:c.642 G > C) that was previously reported but associated with a novel phenotype (i.e., RCC). Twenty-six years prior, her daughter, who was 25 years old at the time, had undergone radical nephrectomy for a pathologic diagnosis of renal oncocytoma of the right kidney; SDHB immunostaining of her daughter's tumor was also negative retrospectively. We confirmed that her daughter carried the germline variant in SDHB exon 6, similar to the patient. The patient had no evidence of disease progression at 15 months after surgery.

The GP Score, a Simplified Formula (Bioptic Gleason Score Times Prostate Specific Antigen) as a Predictor for Biochemical Failure after Prostatectomy in Prostate Cancer.

OBJECTIVES: We used a new GP score (Gleason score multiplied by prostate-specific antigen) without the T stage as a predictive value for biochemical failure (BCF) after prostatectomy. MATERIALS AND METHODS: We assessed 459 prostate cancer patients who underwent prostatectomies at our institution. Three sub-groups were defined in terms of D'Amico classification risk (low, intermediate, and high) and Gleason score (low, < 50; intermediate, 50-100; and high GP score, > 100). Risk factors for BCF were evaluated by multivariate analysis with a Cox hazard model. A log-rank test was used to compare the BCF rate in the 2 groups. RESULTS: There was nosignificant difference in the non-BCF rate between the lowrisk and low GP score subgroups or the intermediate risk andintermediate GP score subgroups. In contrast, the non-BCFrate of the high GP score subgroup (42.1%) was significantlylower than that of the high-risk subgroup (66.1%, log-rankp = 0.008). Based on multivariate analysis, a high GP score(p = 0.001; HR 3.78; 95%CI 1.95-7.35) was a significant independent risk factor for BCF after prostatectomy. CONCLUSION: The GP score, consisting of two absolute numbers, may be a valuable predictive factor for BCF after prostatectomy, especially in the high-risk failure group.

[LEIOMYOSARCOMA ARISING FROM THE RENAL VEIN].

A 47-year-old female presented to a clinic complaining of right back pain. A CT scan revealed a right retroperitoneal mass and she was referred to our department for further evaluation. Contrast-enhanced CT and MRI revealed a right retroperitoneal mass (6 cm) in the hilum of the right kidney that invaded the right renal vein and inferior vena cava (IVC). Suspecting a tumor arising from retroperitoneal tissues involving the right renal vein and IVC, the decision was made to excise the tumor with the right kidney, renal vein, and a portion of the IVC. The histologic findings indicated that the tumor was a leiomyosarcoma originating from the renal vein wall. The tumor cells were spindle-shaped and stained positive for desmin, caldesmon and HHF35. The post-operative course was uneventful and she was recurrence-free 20 months after surgery. In addition to presenting a case of a leiomyosarcoma of the renal vein, a short review of the literature is provided.

Very high-risk prostate cancer: stratification by outcomes of radiotherapy and long-term androgen deprivation therapy.

AIM: The definition of very high-risk (VHR) prostate cancer is currently based on the study of radical prostatectomy. We aimed to identify a suitable definition for VHR group following external beam radiation therapy (EBRT) and long-term androgen-deprivation therapy (ADT). METHODS: This retrospective study included 356 high-risk patients treated with EBRT and long-term ADT. A median follow-up time was 68 months. At first, associations of previously described prognostic factors with biochemical disease-free survival (bDFS), clinical relapse-free survival (cRFS) and prostate cancer-specific survival (CSS) were examined. Second, the combination of significant adverse factors in the first analysis served as VHR test definitions. For each factor, a Cox proportional hazards model was used to calculate their hazard ratios for bDFS and cRFS. The logrank test was used to evaluate the association between each factor and CSS. RESULTS: Primary Gleason pattern 5, T4 and ≥ 5 or 4 cores with Gleason score 8-10 were risk factors associated with bDFS, cRFS and CSS. Eleven VHR test definitions composed of these adverse factors were associated significantly with bDFS, cRFS and CSS. The final definition was described by primary Gleason pattern 5 or T4 or ≥ 4 cores with Gleason score 8-10 because of the largest sample size of 38% among 11 test definitions. bDFS, cRFS and CSS of the VHR group were significantly lower compared with other high-risk patients (P < 0.001, P < 0.001 and P = 0.015, respectively). CONCLUSION: These VHR criteria were best fitted following EBRT with long-term ADT.

[A Case of Intrascrotal Liposarcoma].

A 69-year-old man was referred to our hospital with the chief complaint of a painless right scrotal swelling gradually increasing in size during the past 10 years. Testicular tumor markers were within the normal range. Ultrasonography showed an intrascrotal homogeneous mass. Computed tomography and magnetic resonance imaging revealed an inguinal mass, which mainly consisted of fat signal area and partially well enhanced in vascular density. Pre-surgical diagnosis was liposarcoma of spermatic cord estimated by radiographic examination and resection of the right intrascrotal tumor with high inguinal orchitectomy was performed. Histopathological diagnosis revealed well-differentiated liposarcoma. No recurrence phenomenon has been observed after 12 months without any adjuvant therapy. This case is the 129th report of intrascrotal liposarcoma in the Japanese literature.

High-dose radiotherapy with helical tomotherapy and long-term androgen deprivation therapy for prostate cancer: 5-year outcomes.

PURPOSE: We aimed to examine outcomes of high-dose radiotherapy with helical tomotherapy (HT) and long-term androgen deprivation therapy (ADT) for T1-4N0M0 prostate cancer. METHODS: A total of 391 patients treated with HT between June 2006 and December 2013 were included in this retrospective study. All patients received neoadjuvant ADT for a median duration of 10 months followed by HT at a median dose of 78 Gy [interquartile range (IQR) 78-78]. The times of median adjuvant and total ADT were 19 and 27 months (IQR 20-31), respectively. The risk stratification followed the 2015 National Comprehensive Cancer Network criteria. Biochemical disease-free survival (bDFS) followed the Phoenix definition. Toxicity was scored according to the Radiation Therapy Oncology Group morbidity grading scale. RESULTS: Median follow-up from HT start was 60 months (IQR 42-81). Five-year bDFS rates for low-, intermediate-, high-, and very-high-risk groups were 100, 98.2, 97.7, and 87.9 %, respectively. We observed clinical relapse in nine very-high-risk patients and one high-risk patient, resulting in a 5-year clinical relapse-free survival of 100, 100, 99.4, and 91.7 %, respectively, for each risk group. Three patients died of prostate cancer, resulting in a 5-year prostate cancer-specific survival of 99.6 %. The late grade 2 or higher gastrointestinal and genitourinary toxicities were 9.7 and 10.7 %. No cardiovascular fatal events were observed. CONCLUSIONS: This report confirmed the excellent outcomes with acceptable late toxicities with the combination of HT and long-term ADT. Longer follow-up is crucial to further determine the treatment effect and toxicity.

Clinical Effect of Switching from a Luteinizing Hormone-Releasing Hormone Agonist to an Antagonist in Patients with Castration-Resistant Prostate Cancer and Serum Testosterone Level ≥ 20 ng/dl.

INTRODUCTION: The efficacy of conversion from a luteinizing hormone-releasing hormone agonist to an antagonist was evaluated prospectively in patients with castration-resistant prostate cancer. MATERIALS AND METHODS: From October 2012 to December 2014, 8 cases with a serum testosterone level ≥ 20 ng/dl during following androgen deprivation therapy were enrolled and received degarelix monthly. The primary end-pointgoal was to determine the effective prostate-specific antigen response rate. The secondary end-pointgoal was to assess the proportion of cases with a decrease in serum testosterone level to < 20 ng/ml. RESULTS: One patient achieved a complete response, with a prostate-specific antigen level of 0.02 ng/ml at the nadirend of the study. The effective response rate was 25.0% (2/8), and the proportion of cases with prostate-specific antigen decline was 62.5% (5/8). In 5/8 cases (5/8, 62.5%), serum testosterone levels declined to < 20 ng/dl. CONCLUSION: Switching to a luteinizing hormone-releasing hormone antagonist in patients with testosterone levels ≥ 20 ng/dl may be an option in sequential androgen deprivation therapy for some patients.

Review of Bioptic Gleason Scores by Central Pathologist Modifies the Risk Classification in Prostate Cancer.

OBJECTIVES: The Gleason score (GS) is the primary classification of clinical risk in prostate cancer (PCa). Here, we estimated the factors predictive of accordance of local and central pathologist-dependent GS and clinical risk classification in an increased number of cases. METHODS: Between January 2009 and December 2013, 388 patients were diagnosed with PCa by 80 independent pathologists from local communities and were referred to our hospital. Validation of the GS with needle-core biopsy specimens was carried out by a single central pathologist, and clinical risk, according to the D'Amico risk classification, was determined. Discrepancies between the GS and risk classification, based on the GS estimated by the local or central pathologist, were reviewed, and predictive factors for accordance of clinical risk classification were estimated. RESULTS: When pathological results were compared, 59.5% of cases were given concordant GSs by local and central pathologists. A significant discrepancy existed in the classification of intermediate risk (p < 0.0001). Multivariate analysis indicated that local pathologist-dependent GS7, lower prostate-specific antigen (≤ 10 ng/ml), and lower T stage (T1 or T2a) were significant predictive factors for discordance with the central pathologist-dependent risk classification. CONCLUSION: Review of bioptic GSs by central pathologists affected discrepancies in risk classification in patients with PCa.