Tohru Nakagawa

Objectives: To investigate active surveillance (AS) continuation rates and associated clinical and institutional factors in Japanese patients with localized prostate cancer. Methods: We retrospectively analyzed 989 patients with localized prostate cancer from 92 institutions who initiated AS between 2016 and 2018. Institutions were categorized into three groups based on AS uptake for low‐risk disease. Discontinuation triggers and subsequent treatments were examined. Results: Median age was 70 years; 66.2%, 26.0%, and 7.8% of patients had low‐, intermediate‐, and high‐risk disease, respectively. Over a median follow‐up of 3.4 years, 47.0% discontinued AS (median AS continuation time: 3.0 years; 5‐year AS continuation rate: 33.7%). Multivariable analysis showed that ≥ 2 comorbidities, ≥ 3 positive biopsy cores, and T2b–c stage were associated with restricted mean continuation time differences (RMCTDs) of −0.6, −0.6, and −0.8 years, respectively (all p < 0.05). Conversely, intermediate‐ and high‐AS uptake institutions had significantly longer adjusted RMCTD (1.0 and 1.1 years, respectively; both p < 0.001). Triggers for discontinuation were more often multifaceted in high‐AS uptake institutions (39.1%) compared with low‐ or intermediate‐AS uptake institutions (16.2% and 15.1%, respectively). After discontinuation, 36.5%, 39.2%, and 24.3% of patients received prostatectomy, radiotherapy, and hormonal therapy, respectively. With advancing age, the proportion of patients whose AS was discontinued due to PSA elevation increased, as did the rate of subsequent hormonal therapy. Conclusions: In Japanese real‐world practice, AS continuation was limited. Beyond clinicopathological factors, institutional strategies for localized prostate cancer played a significant role in treatment choices following AS.

Purpose: To evaluate whether a simplified mutation‐based classification using archival formalin‐fixed paraffin‐embedded (FFPE) specimens provides prognostic information beyond pathological stage in patients with upper tract urothelial carcinoma (UTUC) undergoing nephroureterectomy. Materials and Methods: We retrospectively identified 107 UTUC patients who underwent nephroureterectomy between 2005 and 2020. DNA was extracted from FFPE specimens, and representative exons of FGFR3, KRAS, HRAS, and TP53 were analyzed by PCR followed by Sanger sequencing. Patients were classified into TP53, RAS, FGFR3, and triple‐negative groups according to mutation status. Non‐urothelial‐tract recurrence‐free survival (nutRFS) and overall survival (OS) were evaluated. To assess the incremental prognostic value of mutation‐based classification beyond pathological information, parsimonious Cox models including pT, pN, and nuclear grade were constructed, and model discrimination was assessed using the concordance index. Results: Mutation status could not be fully determined in 17 patients; thus, 90 patients comprised the final cohort. Mutations in TP53, KRAS, HRAS, and FGFR3 were identified in 20 (22%), 4 (4%), 3 (3%), and 32 (36%) patients, respectively. In general, alterations in TP53, KRAS/HRAS, and FGFR3 were mutually exclusive. In exploratory multivariable analyses, the FGFR3 group showed more favorable nutRFS and OS than the TP53 group. Addition of mutation‐based classification to a model including pT, pN, and nuclear grade modestly improved discrimination for nutRFS (c‐index, 0.782 to 0.804) and OS (0.726 to 0.754). Conclusions: Although the improvement in discrimination was modest, a simplified mutation‐based classification using archival FFPE specimens may provide additional prognostic information beyond pathological stage and contribute to postoperative risk stratification in UTUC.

Background: Avelumab maintenance therapy was approved in Japan in February 2021 for patients with unresectable locally advanced or metastatic urothelial carcinoma (la/mUC) without disease progression after platinum-based chemotherapy (PBC). We report subgroup analyses from the JAVEMACS chart review study of avelumab maintenance therapy in Japan by characteristics of first-line (1L) PBC. Methods: This multicenter, retrospective study collected data from medical charts of patients with la/mUC who received avelumab maintenance after 1L PBC. Protocol-specified subgroups defined by 1L PBC characteristics (PBC regimen, number of PBC cycles, and best overall response to PBC) were analyzed. Results: Between February 2021 and December 2023, 350 patients received avelumab maintenance. Patient characteristics were generally similar across subgroups defined by 1L PBC characteristics. In patients who received 1L gemcitabine + cisplatin ( n = 196) or gemcitabine + carboplatin ( n = 116), median overall survival (OS) was not reached (95% CI, 31.2 months-not estimable [NE]) and 24.3 months (95% CI, 19.5–30.6 months), respectively. In patients who received 1–3 cycles ( n = 68), 4 cycles ( n = 205), 5/6 cycles ( n = 61), or ≥ 7 cycles ( n = 16) of 1L PBC, median OS was 25.0 months (95% CI, 15.2 months-NE), not reached (95% CI, 29.3 months-NE), 31.2 months (95% CI, 18.0 months-NE), and 23.6 months (95% CI, 19.3 months-NE), respectively. In patients with complete response ( n = 32), partial response ( n = 180), or stable disease ( n = 138) as best response to 1L PBC, median OS was not reached (95% CI, 30.6 months-NE), 31.2 months (95% CI, 22.6 months-NE), and 26.5 months (95% CI, 20.2 months-NE), respectively. Across all subgroups, enfortumab vedotin was the most common second-line treatment after discontinuation of avelumab. Conclusions: Results from these descriptive subgroup analyses from JAVEMACS suggest that real-world outcomes with avelumab maintenance therapy are generally consistent regardless of 1L PBC regimen, number of 1L PBC cycles, or best response to 1L PBC. These findings further support the use of avelumab maintenance therapy as a standard of care for patients with la/mUC without disease progression after 1L PBC. Trial registration: NCT06412848.

Avelumab maintenance therapy is approved in Japan for patients with aUC without progression after PBC. This report presents subgroup analysis data from the JAVEMACS chart review of avelumab maintenance in patients who received 1L ddMVAC and GC. This retrospective study reviewed medical charts of patients with aUC (February 2021–December 2023). Overall, 350 patients (ddMVAC, n = 32 and GC, n = 196) were included in the study. Baseline characteristics were balanced between the two PBC groups. Median duration from PBC start to avelumab start was 13.2 and 21.1 weeks; median overall survival (OS) was not reached (both groups), progression-free survival (PFS) was 12.0 and 7.4 months, and PFS2 was 27.6 and 21.3 months for the ddMVAC and GC groups, respectively. At data cutoff (June 2024), 25.0% of patients in the ddMVAC and 17.3% in the GC groups were ongoing avelumab treatment. Second-line treatments included EV (64.3% ddMVAC; 64.5% GC), pembrolizumab (21.4% ddMVAC; 8.3% GC), and PBC (14.3% ddMVAC and 21.5% GC). This real-world data from patients with aUC in Japan showed consistent OS patterns with avelumab maintenance across treatment subgroups vs. the overall population despite their inherent heterogeneity. Although patients were not resistant to PBC, 2L EV was more common than 2L PBC.

A 42-year-old man presented with sudden abdominal pain during self-injurious sexual activity including the injection of high-pressure hot water into his urethra. He also self-injected carbon dioxide gas under the skin of the anterior chest. He was diagnosed with intraperitoneal bladder rupture and extensive subcutaneous emphysema. The bladder was surgically repaired, and then hyperbaric oxygen therapy was administered as an adjunctive treatment. The injury healed successfully, and the subcutaneous emphysema and pigmentation resolved promptly. This case suggests that hyperbaric oxygen therapy may be useful as an adjunct to surgical treatment and antibiotics for wound healing and as a treatment for subcutaneous emphysema.

ESS2 (ess-2 splicing factor homolog, also known as DGCR14 or DGS-I) is a member of the deletion gene cluster in the 22q11.2 deletion syndrome (22q11.2DS, also known as DiGeorge syndrome or CATCH 22 syndrome). The ESS2 gene is not part of a gene family, and the coded protein has a coiled-coil structure (Es domain), which is conserved from yeast to humans. Recent studies have shown that ESS2 is involved in splicing C and C* complex, but other interactants, such as transcription factors and U1 snRNP, are also reported. Although the molecular mechanism is still under investigation, ESS2 plays a pivotal role in cell differentiation and proliferation. ESS2 knockout mice show embryonic lethal in the early stage, and recent studies show the association of ESS2 with cancer, autoimmune disease, and neurodevelopmental disorders. ESS2 can regulate mRNA splicing and transcriptional activity through interactions with other proteins, and ESS2-dependent gene expression regulation seems to be cell type-selective. In this review, we summarized the cloning history and functions of ESS2, including recent findings.

Background: Dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) regimen has been established as a systemic chemotherapy for patients with urothelial carcinoma. However, it is rarely used in Japan owing to the challenges associated with managing the related adverse events. This study aimed to optimize the dd-MVAC protocol for Japanese patients. Methods: Criteria were developed to adjust the doses of anticancer drugs used in dd-MVAC. In this regimen, the initial cycle of methotrexate and cisplatin was administered at 75% of the full dose. Patients who did not experience significant toxicities during the first cycle subsequently received the full dose starting from the second cycle. Additionally, the doses of methotrexate and cisplatin were adjusted according to the Cockcroft-Gault creatinine clearance. Based on these criteria, patients with urothelial carcinoma underwent dd-MVAC between August 2018 and May 2023, and all patients were scheduled to undergo six cycles. Results: A total of 86 patients received dd-MVAC, with 36, 15, and 35 patients receiving it as neoadjuvant, adjuvant, and salvage chemotherapy, respectively. Fifty-nine patients (68.6%) completed the six scheduled cycles. Grade ≥ 3 toxicities of Common Terminology Criteria for Adverse Events were observed in 76 (88.4%) patients; however, most were manageable. In the neoadjuvant cohort, the pathological complete response rate was 52.2% among patients with clinical N0 lower tract urothelial carcinoma. High levels of alkaline phosphatase at the initiation of treatment were correlated with failure to complete six cycles of dd-MVAC. Conclusion: Adjusting the dd-MVAC regimen based on renal function and significant adverse events may result in a high completion rate of scheduled treatments in Japanese patients with urothelial carcinoma.

Background: Salvage robot-assisted radical prostatectomy (sRARP) after PSA failure in patients who underwent initial radiotherapy or focal therapy has rarely been reported in Japan. We aimed to report the oncologic and functional outcomes of the first 10 cases of sRARP. Methods: Ten patients underwent sRARP after failing to respond to initial radiotherapy or focal therapy. Initial definitive treatment included volumetric modulated arc therapy, intensity-modulated radio therapy, stereotactic body radiotherapy, heavy-ion radiotherapy, low-dose-rate brachytherapy, and high-intensity focused ultrasound. We retrospectively investigated 10 cases on oncologic and functional outcomes of sRARP. Results: The median PSA level at sRARP, amount of blood loss, and console time were 2.17 ng/mL, 100 mL, and 136 min, respectively. Positive surgical margins were found in half of the cases. Median follow-up was 1.1 years. There were no 30-day major complications. No patients had erections after sRARP. Urinary continence and biochemical recurrence (BCR) rate were 40% and 30% at 1 year after sRARP, respectively. Conclusions: Salvage RARP may be a feasible option after PSA failure in patients who underwent radiotherapy or focal therapy as initial treatment, showing acceptable BCR rate.