市川 智彦

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.

Introduction: Plasmacytoid variant bladder cancer is a rare variant of urothelial carcinoma that accounts for 1% of bladder cancers. Plasmacytoid variant urothelial carcinoma is characterized by an aggressive phenotype and poor clinical outcomes. Case presentation: A 61-year-old woman presented with gross hematuria. Cystoscopy showed a 16-mm solid tumor. Transurethral resection of the bladder tumor was performed, and the pathological diagnosis was invasive plasmacytoid variant urothelial carcinoma. Although the pathological T stage was pT1, computed tomography showed right obturator lymph node swelling. Since previous reports indicate poor response to chemotherapy for this disease, clinical sequencing was performed. Based on the high tumor mutation burden revealed, pembrolizumab was administered for 4 cycles, and computed tomography showed a partial response. Robot-assisted radical cystectomy was performed, and a pathological complete response including the pelvic lymph node was observed. Conclusion: Pembrolizumab may be a treatment option for plasmacytoid variant urothelial carcinoma following genomic analysis.

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.

Abstract 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.

▼唯一のがん免疫チェックポイント阻害薬2剤での複合免疫療法である。▼長期観察やサブグループ解析がされた大規模臨床試験がある。▼奏効後の長期間の効果持続が期待できる。(著者抄録)

BACKGROUND/AIM: This study aimed to evaluate the therapeutic benefit of novel androgen receptor-targeted agents (ARTAs) in castration-resistant prostate cancer (CRPC) with bone metastases in Japan. PATIENTS AND METHODS: In followup to our prospective observational study (PROSTAT-BSI) from 2012 to 2018 on metastatic hormone-sensitive prostate cancer (mHSPC) and metastatic CRPC (mCRPC) before docetaxel initiation, we conducted this sub-analysis to investigate the benefit of ARTAs after clinical recurrence on overall survival (OS) in the real-world clinical setting in Japan. In this study, we compared patients who were treated with ARTA with those who received only vintage hormone therapy including docetaxel after clinical recurrence. RESULTS: In the mHSPC group, 69 patients became mCRPC and were treated with or without ARTAs. No significant difference was observed in prostate-specific antigen (PSA) progression-free survival between the ARTA (+) and ARTA (-) groups; however, OS after clinical recurrence was significantly better in the ARTA (+) group than in the ARTA (-) group (median OS 31.9 vs. 23.0 months; p<0.01). CONCLUSION: The ARTAs are beneficial even after mHSPC recurrence in Japanese patients in the real-world clinical setting. Since ARTAs are beneficial after clinical recurrence, it may be better to switch to ARTAs whenever necessary based on PSA response after combined androgen blockade therapy, considering the adverse effects and cost. This approach may be suitable to reduce overtreatment in Japanese patients with mHSPC.

In bronchial asthma patients, mucous cell metaplasia (MCM) and fibrosis occur in the bronchial epithelium and interstitium, respectively. The mucus and collagen fibers are identified by Periodic acid-Schiff stain (PAS) or Sirius red stain on optical microscopy. On a scanning electron microscope (SEM) observation, formalin-fixed-paraffin-embedded specimens have high insulation, thereby attenuating the scattered electron signals leading to insufficient contrast. Moreover, there were no staining methods for SEM observation, which characterizes the changes in epithelium and interstitium by enhancing the scattered electrons. In this study, we established a method of coating osmium thin film on pathological tissue specimens using plasma chemical vapor deposition technology. This method ensured the intensity of scattered electron signals and enabled SEM observation. Furthermore, we found that morphological changes in MCM and interstitial fibrosis could be characterized by Grocott stain, which we optimized to evaluate pathological remodeling in bronchial asthma. Using these techniques, we compared asthma-induced mice with Amphiregulin (Areg) knockout mice, and found that Areg induce MCM, but the production of Grocott-stain-positive substrate in the interstitium is Areg-independent. The method developed in this study provides an understanding of the pathological spatial information linked to the ultrastructural changes in cells and interstitium due to disease-related signaling abnormalities.

Abstract 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.

Background/Aim: To assess the efficacy of novel therapeutic agents, such as androgen receptor axis-targeted agents (ARATs) and cabazitaxel, for relapse of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel in real-world practice, we performed a subanalysis using database from PROSTAT-BSI, a prospective observational study to evaluate the utility of software for quantifying bone metastases on bone scintigraphy. Patients and Methods: Patients with clinically relapsed mCRPC after docetaxel treatment who received the new agents (NEW group) and those who did not (standard of care, SOC group) were included; patients who received ARAT before DOC treatment were excluded. Overall survival (OS) after docetaxel treatment was compared between the NEW and SOC groups. Results: Patients in the NEW group had significantly better OS from the start of docetaxel than those in the SOC group (the median OS in NEW and SOC was 28.9 months vs. 14.5 months, respectively). Furthermore, regardless of the time from androgen-deprivation therapy to the start of docetaxel at mCRPC, the NEW group had a better OS from relapse after docetaxel than the SOC group. Conclusion: In clinical practice, OS of patients with relapse after docetaxel was significantly improved in the NEW group over the SOC group.

BACKGROUND/AIM: To assess the efficacy of novel therapeutic agents, such as androgen receptor axis-targeted agents (ARATs) and cabazitaxel, for relapse of metastatic castration-resistant prostate cancer (mCRPC) after docetaxel in real-world practice, we performed a subanalysis using database from PROSTAT-BSI, a prospective observational study to evaluate the utility of software for quantifying bone metastases on bone scintigraphy. PATIENTS AND METHODS: Patients with clinically relapsed mCRPC after docetaxel treatment who received the new agents (NEW group) and those who did not (standard of care, SOC group) were included; patients who received ARAT before DOC treatment were excluded. Overall survival (OS) after docetaxel treatment was compared between the NEW and SOC groups. RESULTS: Patients in the NEW group had significantly better OS from the start of docetaxel than those in the SOC group (the median OS in NEW and SOC was 28.9 months vs. 14.5 months, respectively). Furthermore, regardless of the time from androgen-deprivation therapy to the start of docetaxel at mCRPC, the NEW group had a better OS from relapse after docetaxel than the SOC group. CONCLUSION: In clinical practice, OS of patients with relapse after docetaxel was significantly improved in the NEW group over the SOC group.