The Detection and Negative Reversion of Circulating Tumor Cells as Prognostic Biomarkers for Metastatic Castration-Resistant Prostate Cancer with Bone Metastases Treated by Enzalutamide.

Enzalutamide is a second-generation androgen receptor inhibitor that increases overall survival (OS) rates in patients with metastatic castration-resistant prostate cancer (mCRPC). This study evaluates the efficacy of circulating tumor cell (CTC) status as a prognostic biomarker following enzalutamide administration. A retrospective subgroup analysis and prognostic survey were conducted on 43 patients with mCRPC and bone metastases treated in Juntendo University-affiliated hospitals from 2015 to 2022. Patients were treated with 160 mg enzalutamide daily. CTC analyses on blood samples were performed regularly before and every three months after treatment. The relationship between the patients' clinical factors and the OS rate was analyzed using the log-rank test; the median OS was 37 months. Patients with no detected CTCs at baseline showed significantly longer OS than those with detectable CTCs at baseline. Furthermore, patients demonstrating negative reversion of CTCs during enzalutamide treatment had significantly longer OS than patients with CTC-positivity. Two biomarkers-higher hemoglobin at baseline and achieving negative reversion of CTCs-were significantly associated with prolonged OS. This study suggests that patients achieving CTC-negative reversion during treatment for mCRPC with bone metastases exhibit improved long-term OS. Chronological measurement of CTC status might be clinically useful in the treatment of mCRPC.

T-Cell Receptor Repertoire as a Predictor of Immune-Related Adverse Events in Renal Cell Carcinoma.

Immune checkpoint inhibitors (ICIs) are effective in treating renal cell carcinoma (RCC) but can also cause immune-related adverse events (irAEs). The relationship between irAEs and the T-cell receptor (TCR) repertoire in RCC patients treated with ICIs remains unclear. We analyzed the relationship between the severity and diversity of irAEs and the TCR repertoire in RCC patients who received dual checkpoint inhibitors (ipilimumab + nivolumab). The TCRß (TRB) repertoires were characterized in peripheral blood samples from six patients with RCC before the initiation of ICI therapy. The diversity and clonality of the TCR repertoire were compared between patients with grade 2 and grade 3 irAEs. The median proportion of top 10 unique reads in the TCR repertoire was significantly higher in grade 3 compared with grade 2 irAEs in RCC patients receiving immune checkpoint inhibitors (grade 2: 0.196%; grade 3: 0.346%; p = 0.0038). We provide insight into the relationship between TCR repertoire and irAEs in RCC patients treated with ICIs. TCR repertoire clonality may be associated with the development of irAEs in RCC patients.

Extended versus standard pelvic lymph node dissection yields no difference in 3-year biochemical recurrence rates.

Background: extended pelvic lymph node dissection (ePLND) increases the detection rate of lymph node positive prostate cancer compared to a standard pelvic lymph node dissection (sPLND). However, improvement of patient outcomes remains questionable. Here we report and compare 3-year postoperative PSA recurrence rates between patients that underwent sPLND versus ePLND at the time of prostatectomy. Methods: 162 patients received a sPLND (which involvedremoval of periprostatic, external iliac, and obturator lymph nodes bilaterally), and 142 patients received an ePLND (which involved removal of periprostatic, external iliac, obturator, hypogastric, and common iliac nodes bilaterally). Decision to undergo ePLND versus sPLND at our institution was changed in 2016 based on the National Comprehensive Cancer Network guideline. The median follow-up time was 7 and 3 years for sPLND and ePLND patients, respectively. All node-positive patients were offered adjuvant radiotherapy. Kaplan-Meier analysis was carried out to assess the impact of a PLND on early postoperative PSA progression-free survival. Subgroup analyses were done for node-negative and node-positive patients, as well as Gleason score. Results: Gleason score and T stage were not significantly different between patients who received an ePLND and sPLND. The pN1 rate for ePLND and sPLND were 20% (28/142) and 6% (10/162), respectively. There was no difference in the use of adjuvant treatments in the pN0 patients. Significantly, more ePLND pN1 patients received adjuvant androgen deprivation therapy (25/28 vs. 5/10 P = 0.012) and radiation (27/28 vs. 4/10 P = 0.002). Yet, no difference in biochemical recurrence between ePLND and sPLND was observed (P = 0.44). This remained true in subgroup analyses of node-positive (P = 0.26), node-negative (P = 0.78), Gleason Score 6-7 (P = 0.51), and Gleason Score 8-10 (P = 0.77). Conclusions: PLND provided no additional therapeutic benefit, even though ePLND patients were significantly more likely to have node-positive disease and undergo adjuvant treatment, compared to a sPLND.

Bone scan index (BSI) scoring by using bone scintigraphy and circulating tumor cells (CTCs): predictive factors for enzalutamide effectiveness in patients with castration-resistant prostate cancer and bone metastases.

Reports of Bone Scan Index (BSI) calculations as imaging biomarkers to predict survival in patients with metastatic castration-resistant prostate cancer (mCRPC) have been mainly from retrospective studies. To evaluate the effectiveness of enzalutamide (ENZ) in Japanese patients with mCRPC and bone metastases using BSI (bone scintigraphy) and circulating tumor cell (CTC) analysis. Prospective, single-arm study at Juntendo University affiliated hospitals, Japan. Patients were administered 160 mg ENZ daily, with 3 monthly assessments: BSI, prostate specific antigen (PSA), CTC and androgen receptor splicing variant-7 (AR-V7) status. Primary endpoint: BSI-decreasing rate after ENZ treatment. Secondary endpoints: PSA-decreasing rate and progression free survival (PFS). Statistical analyses included the Wilcoxon t-test, Cox proportional hazard regression analysis, and log-rank test. Median observation period: 17.9 months, and median PFS: 13.8 (2.0-43.9) months (n = 90 patients). A decrease in BSI compared to baseline as best BSI change on ENZ treatment was evident in 69% patients at the end of the observation period (29% patients showed a complete response, BSI 0.00). At 3 months 67% patients showed a ≥ 50% PSA reduction, and 70% after ENZ treatment. PSA decline (3 months) significantly associated with a prolonged median PFS: 18.0 (estimated) versus 6.4 months (HR 2.977 [95% CI 1.53-5.78], p = 0.001). Best BSI decline response significantly associated with a prolonged PFS: 18.1(estimated) versus 7.8 months (HR 2.045 [95% CI: 1.07-3.90], p = 0.029). CTC negative status (n = 20) significantly associated with a prolonged PFS: 13.4 [estimated] vs 8.6 months (HR 2.366, 95% CI 0.97-5.71, p = 0.041). CTC positive/AR-V7 positive status significantly associated with a shorter PFS: 5.9 months (HR 8.56, 95% CI 2.40-30.43, p = 0.0087). -reduction (3 months) and BSI-reduction (on ENZ treatment) were significant response biomarkers, and a negative CTC status was a predictive factor for ENZ efficacy in patients with mCRPC.

Kidney Transplantation for a Patient With Protein C Deficiency Using Activated Protein C Concentrate: A Case Report.

BACKGROUND: Thrombophilia causes thrombosis after kidney transplantation (KT). Protein C deficiency is a rare form of hereditary thrombophilia. To our knowledge, there are few reports on KT for patients with protein C deficiency, and there are no reports of KT in patients with protein C deficiency administered with activated protein C concentrate. METHOD: Here we reported the case of a patient with protein C deficiency who underwent KT without the occurrence of any fresh thrombosis after administration of an activated protein C concentrate. The patients was a 49-year-old woman diagnosed with immunoglobulin A nephropathy at 20 years of age. During pregnancy, she experienced deep vein thrombosis of the lower extremities and pulmonary embolism for which she was started on warfarin. After a thorough examination, the patient was diagnosed with protein C deficiency. The patient had end-stage kidney disease and received a preemptive living donor kidney transplant from her mother. RESULTS: To prevent thrombosis, we switched from oral warfarin to continuous heparin 7 days before surgery. Heparin was discontinued 6 hours before surgery, and continuous activated protein C concentrate was administered 12 hours before surgery. Heparin administration was resumed 6 hours after the surgery. Warfarin administration was restarted 3 days after the surgery, and heparin was discontinued 11 days post-surgery. The surgery was performed without complications. After the KT, the patient's renal function steadily improved, and no fresh thrombosis were observed. CONCLUSIONS: Thrombosis can cause graft loss and pulmonary embolism, thus appropriate administration of activated protein C concentrate may help prevent thrombosis.

Efficacy of cabazitaxel and androgen splicing variant-7 status in circulating tumor cells in Asian patients with metastatic castration-resistant prostate cancer.

Androgen receptor splice variant-7 (AR-V7) expression in circulating tumor cells (CTCs) in metastatic castration-resistant prostate cancer (mCRPC) is associated with abiraterone and enzalutamide resistance. We determine whether cabazitaxel (CBZ) is equally effective in AR-V7-positive and -negative CRPC and whether AR-V7-positive patients retain CBZ sensitivity. This is the first prospective, open-label, Asian validation study of CBZ in Japanese patients with mCRPC after docetaxel (n = 48; four CBZ cycles; 2017-2020, Juntendo University Hospitals). Primary endpoint was prostate-specific antigen response rate (PSA-RR); secondary endpoints included overall survival (OS), bone scan index (BSI) PSA-RR (≥ 50% decline from baseline) for CTC-/ARV7-, CTC+ /ARV7-, and CTC +/ARV7+ groups. PSA-RR ≥ - 30% was 38% (18/48) and ≥ - 50% was 26% (12/48). BSI-change rate ≥ - 30% was 19% (9/41) and ≥ - 50% was 17% (8/41). Median OS was 13.7(12.2-18.9) months. PSA decline in early CBZ treatment associated with OS (p = 0.00173). BSI decline associated with OS (p = 0.0194). PSA-RR(≥ 50%) was 43%(6/14) in CTC-/ARV7-, 19%(5/26) in CTC+ ARV7-, and 12%(1/8) in CTC+/ARV7+ ( p > 0.05). AR-V7 in CTCs at baseline not associated with OS. AR-V7 was not associated with CBZ resistance in CTCs. Reductions in BSI and PSA in early stages of CBZ treatment may predict OS.

RNA-seq profile of African American men with a clinically localized prostate cancer.

BACKGROUND: Prostate cancer in African American (AA) men has a poor prognosis. This study aimed to identify potential genetic risk factors for prostate cancer in AA men. METHODS: We used prostate cancer tissue from 61 patients who underwent radical prostatectomy. We compared somatic gene expression in Caucasian (CA) and AA men using RNA sequencing. RESULTS: By comparing the RNA-seq data obtained from prostate cancer tissue between AA and CA men, this study showed a significant difference in expression levels of 45 genes. Pathway analysis of 45 genes using Kyoto Encyclopedia of Genes and Genomesenrichment analysis revealed a neuroactive ligand-receptor interaction signal. In addition, the results of the Ingenuity Pathway Analysis showed pathways involved sphingosine-1-phosphate signaling. Furthermore, validating 45 genes in the The Cancer Genome Atlas (TCGA) Provisional cohort, cholinergic receptor muscarinic 3 expression level was significantly lower in AA than in CA men, and the results showed a significantly higher rate of biochemical recurrence in patients with low expression. CONCLUSIONS: We identified genetic differences of clinically localized prostate cancer in AAs and CAs by RNA sequencing.

Transcription factor 4 expression in circulating tumor cells from castration-resistant prostate cancer.

INTRODUCTION: Neuroendocrine differentiation is partly caused by antiandrogen therapy and exhibits an androgen receptor-independent growth mechanism. We hypothesized that the expression of transcription factor 4, an inducer of neuroendocrine differentiation, in circulating tumor cells is related to drug resistance in castration-resistant prostate cancer. CASE PRESENTATION: We evaluate the messenger ribonucleic acid expression of transcription factor 4 in circulating tumor cells from 17 patients with castration-resistant prostate cancer and compared these levels between patients receiving antiandrogen therapies and those who were resistant to antiandrogen therapies and receiving chemotherapies. The expression of transcription factor 4 in circulating tumor cells was significantly higher among patients receiving chemotherapies. CONCLUSION: This study shows that transcription factor 4 is higher in the group of patients who were judged by their physicians to need chemotherapy treatment.

Fourteen-Core Systematic Biopsy That Includes Two Anterior Cores in Men With PI-RADS Lesion ≥ 3 is Comparable With Magnetic Resonance Imaging-ultrasound Fusion Biopsy in Detecting Clinically Significant Prostate Cancer: A Single-institution Experience.

INTRODUCTION: Magnetic resonance imaging (MRI)-ultrasound fusion targeted prostate biopsy (FB) has been advocated by many experts as a replacement for the standard template biopsy. Herein, we compared pathology results and cancer detection rates of FB with our standard 14-core systematic prostate biopsy (SB) that includes 2 anterior cores. MATERIALS AND METHODS: One hundred two men with elevated prostate-specific antigen and suspicious lesions on multiparametric MRI, Prostate Imaging Reporting And Data System (PI-RADS) v2 score ≥ 3, underwent FB. Each target lesion was biopsied 3 times; our SB was performed concurrently. Biopsy results were compared for overall and clinically significant (cs), defined as Gleason score ≥ 7, cancer detection. RESULTS: Fifty-two percent of patients had positive biopsy results, and of those, 44 had cs prostate cancer (PCa). The overall detection rates for FB and SB were 39% and 50%, respectively, and there was no statistical difference in the detection rate of csPCa detection rate (P = .42). Of 17 patients diagnosed with a high-risk PCa, defined as Gleason score ≥ 8, SB identified 15, whereas FB identified 10. Within the SB group, 21 had positive anterior core biopsies, of which 11 were cs. CONCLUSION: Expanding the standard template prostate biopsies to include 2 anterior horn sampling may be just as effective as FB in men with PI-RADS lesion ≥ 3, thereby mitigating the increased cost associated with FB.

Effects of MTX-23, a Novel PROTAC of Androgen Receptor Splice Variant-7 and Androgen Receptor, on CRPC Resistant to Second-Line Antiandrogen Therapy.

Although second-line antiandrogen therapy (SAT) is the standard of care in men with castration-resistant prostate cancer (CRPC), resistance inevitably occurs. One major proposed mechanism of resistance to SAT involves the emergence of androgen receptor (AR) splice variant-7, AR-V7. Recently, we developed MTX-23 using the principle of proteolysis targeting chimera (PROTAC) to target both AR-V7 and AR-full length (AR-FL). MTX-23 has been designed to simultaneously bind AR's DNA binding domain (DBD) and the Von Hippel-Lindau (VHL) E3 ubiquitin ligase. Immunoblots demonstrated that MTX-23's degradation concentration 50% (DC50) for AR-V7 and AR-FL was 0.37 and 2 µmol/L, respectively. Further studies revealed that MTX-23 inhibited prostate cancer cellular proliferation and increased apoptosis only in androgen-responsive prostate cancer cells. The antiproliferative effect of MTX-23 was partially reversed when either AR-V7 or AR-FL was overexpressed and was completely abrogated when both were overexpressed. To assess the potential therapeutic value of MTX-23, we next generated 12 human prostate cancer cell lines that are resistant to the four FDA-approved SAT agents-abiraterone, enzalutamide, apalutamide, and darolutamide. When resistant cells were treated with MTX-23, decreased cellular proliferation and reduced tumor growth were observed both in vitro and in mice. These results collectively suggest that MTX-23 is a novel PROTAC small molecule that may be effective against SAT-resistant CRPC by degrading both AR-V7 and AR-FL.

CXC Chemokine/Receptor Axis Profile and Metastasis in Prostate Cancer.

In this study, the effects of the CXC chemokine/receptor axis on lymph node and distant metastases of prostate cancer (PC) were analyzed. Further, mRNA expression data of metastatic PC were extracted from the Stand Up To Cancer-Prostate Cancer Foundation Dream Team database and differences between metastatic sites were comprehensively analyzed. CXC chemokine/receptor mRNA expression data of primary PC included in the Cancer Genome Atlas were used to analyze the relationships of CXC chemokine/receptor expression with lymph node metastasis and cancer progression. In metastatic PC, significantly higher expression of ELR+ CXC chemokines/receptors and significantly lower expression of ELR- CXC chemokines/receptors were observed in bone metastases relative to lymph node metastases. In primary PC, significantly higher ELR- CXC chemokine/receptor expression and significantly lower ELR+ CXC chemokine/receptor expression were observed in patients with lymph node metastasis relative to those without. Multivariate logistic regression analysis identified CXCL10 expression as an independent predictor of lymph node metastasis. Furthermore, the log-rank test results revealed that co-expression of CXCL10/CXCR3 was associated with postoperative recurrence. These findings demonstrate heterogeneous expression of CXC chemokine/receptor genes in primary PC as well as differences in expression patterns according to the metastatic site.

Abiraterone Rechallenge Based on Sequential Testing of Androgen Receptor Splice Variant 7 Expression in Circulating Tumor Cells: A Case Report.

Serial analysis of circulating tumor cells (CTCs) such as androgen receptor splice variant 7 is useful in selecting treatments for castration-resistant prostate cancer (CRPC). We report a case who had been positive for androgen receptor splice variant 7 in CTCs before docetaxel, and was subsequently treated with abiraterone rechallenge because of the negative conversion of androgen receptor splice variant 7 following docetaxel. Although, the rechallenge of anti-androgen agent based on CTCs analysis is expected to be an effective approach, it is yet to be reported. Thus, we chose the candidate for abiraterone rechallenge based on serial CTCs analyses by the AdnaTest. As a result, the patient responded to abiraterone that he once had developed resistance to. Our findings reinforce the utility of AR-V7 as a biomarker in the setting of post-chemo androgen-targeted-therapy rechallenge.

Prostate-specific membrane antigen in circulating tumor cells is a new poor prognostic marker for castration-resistant prostate cancer.

The aim of this study is to elucidate the clinical significance of prostate-specific membrane antigen (PSMA) expression in circulating tumor cells (CTCs) from castration-resistant prostate cancer (CRPC) patients. We analyzed a total of 203 CTC samples from 79 CRPC patients to investigate the proportion of positive mRNA expressions at different treatment phases. Among them, we elected to focus on specimens from 56 CRPC patients who progressed on therapy and were subsequently provided a new treatment (treatment-switch cohort). In this cohort, we investigated the association between PSMA expression in CTCs and treatment response. CTCs were detected in 55/79 patients and median serum PSA in CTC-positive patients was 67.0 ng/ml. In the treatment-switch cohort of 56 patients, 20 patients were positive for PSMA in CTCs. PSMA expression was inversely associated with percentage of change in prostate-specific antigen (PSA). The median PSA progression-free survival and overall survival were significantly shorter in the PSMA-positive cohort. Furthermore, PSMA expression was predictive of poorer treatment response, shorter PSA progression-free survival and overall survival. PSMA expression in circulating tumor cells may be a novel poor prognostic marker for CRPC.

Movement of target organs and anatomical landmarks caused by body position change during urological laparoscopic surgery.

INTRODUCTION: The aim of our study was to elucidate the impact of patients' physical characteristics on the movement of target organs and anatomical landmarks by comparing supine and lateral CT images. METHODS: This study consisted of 55 patients who underwent laparoscopic surgery in the lateral position. CT images of the area between the abdomen and pelvis were taken preoperatively with patients in both supine and lateral positions. We measured the moving distance of target organs and anatomical landmarks on the body surface used for access port settings. We investigated which covariates from patients' body composition most affected moving distance in correlation analysis. Then, using multiple linear regression analysis, we examined whether we could predict the movement of target organs and anatomical landmarks solely based on information obtained from supine CT images. RESULTS: The moving distance of both the hilum of the kidney and the outer edge of the rectus abdominis muscle were significantly associated with some physical characteristics. Multiple regression analysis showed that a larger visceral fat area could be a useful index for predicting the movement of the kidney toward the counter side. Lower CT density of back muscles and higher BMI could be useful indexes for predicting the movement of the rectus abdominis muscle. CONCLUSION: Our results suggested that body composition characteristics obtained from preoperative CT images can help predict the movement of target organs and anatomical landmarks used to determine proper port-site placement for laparoscopic surgery performed with the patient in the lateral position.

DNA Damage Response Pathway Alteration in Locally Advanced Clear-Cell Renal-Cell Carcinoma Is Associated With a Poor Outcome.

BACKGROUND: Advanced clear-cell renal-cell carcinoma (ccRCC), which is the most common subtype of kidney cancer, is considered to be lethal despite recent advancements in therapeutic agents. The benefit of adjuvant or neoadjuvant therapy with currently available agents remains controversial. We investigated the clinical implications of DNA damage response (DDR) pathway for locally advanced ccRCC. PATIENTS AND METHODS: Localized ccRCC cases were selected from the Provisional TCGA (The Cancer Genome Atlas) database. Presence of mutation or copy-number alteration of DDR pathway-related genes were evaluated. Disease-free survival and overall survival according to disease progression were evaluated. RESULTS: From TCGA database, 312 cases were identified of a localized ccRCC with full data on mutation and copy-number alteration. Alteration in the DDR pathway was present in 25.0% of cases. Female subjects were more likely to have alterations in the DDR pathway (34.6% vs. 48.7%, P = .026). DDR pathway alteration was associated with decreased disease-free survival in cases of locally advanced T3-4 disease (median, 123.7 vs. 23.0 months, T3 and T4 disease, P = .031). The association was more prominent in cases of T3a disease (normal group median not reached, altered group median 17.7 months, P < .001). DDR pathway alteration was an independent factor predicting a shorter disease-free survival on Cox regression analysis (odds ratio = 4.41; 95% confidence interval, 1.47∼13.28; P = .008). CONCLUSION: Alteration in the DDR pathway was associated with increased recurrence in locally advanced ccRCC, and investigation of therapeutic agents targeting the DDR pathway for this population should be considered.

Dihydrotestosterone Increases Cytotoxic Activity of Macrophages on Prostate Cancer Cells via TRAIL.

Although androgen deprivation therapy (ADT) and immunotherapy are potential treatment options in men with metastatic prostate cancer (CaP), androgen has conventionally been proposed to be a suppressor of the immune response. However, we herein report that DHT activates macrophages. When the murine macrophage cell line (RAW 264.7), human monocyte cell line (THP-1), and human peripheral blood monocytes were cultured with androgen-resistant CaP cell lines, DHT increased cytotoxicity of macrophages in a concentration-dependent manner. Further studies revealed that DHT induced M1 polarization and increased the expression levels of TNF-related apoptosis-inducing ligand (TRAIL) in macrophages and that this effect was abrogated when TRAIL was neutralized with a blocking antibody or small interfering RNA. Subsequent experiments demonstrated that induction of TRAIL expression was regulated by direct binding of androgen receptor to the TRAIL promoter region. Finally, an in vivo mouse study demonstrated that castration enhanced the growth of an androgen-resistant murine CaP tumor and that this protumorigenic effect of castration was blocked when macrophages were removed with clodronate liposomes. Collectively, these results demonstrate that DHT activates the cytotoxic activity of macrophages and suggest that immunotherapy may not be optimal when combined with ADT in CaP.

[Endocrine therapy for prostate cancer.]

Endocrine therapy for prostate cancer is androgen deprivation therapy and antiandrogens, which are the standard treatment for advanced prostate cancer. Endocrine therapy is effective in most prostate cancers, but as treatment continues, most patients eventually experience resistant to endocrine therapy and disease progression. Patients in this state are said to have castration-resistant prostate cancer. This review outlines the types of endocrine therapy for prostate cancer, the physiological mechanisms of endocrine therapy, its clinical use in Japan and the United States and Europe, new endocrine therapy for castration-resistant prostate cancer, and the side effects to be noted in endocrine therapy.

The Surge in the Number of Circulating Tumor Cells Following Treatment with Sunitinib for Metastatic Renal Cell Carcinoma.

Circulating tumor cells (CTCs) are a promising biomarker for several cancers. We streamlined the experimental procedure of CTC immunofluorescent staining. We encountered a 72-year-old woman with metastatic right renal cell carcinoma (RCC) (clinical stage: T4N0M1), whose CTC number rapidly increased after the administration of sunitinib and then gradually decreased. The change in the CTC number appeared to coincide with laboratory data and hypertension, suggesting that a CTC analysis may be useful for promptly monitoring the treatment response. Our data provided the first evidence of an association between the CTC numbers and the treatment response in a metastatic RCC patient.