[Risk Factors of Antiresorptive Agent-Related Osteonecrosis of the Jaw in Prostate Cancer Patients with Bone Metastases].

Antiresorptive agent-related osteonecrosis of the jaw (ARONJ) is a severe adverse event associated with use of bone resorption inhibitors (BRIs), such as zoledronic acid and denosumab. Based on the results of phase 3 clinical trials for BRIs, the frequency of ARONJ is reported to be 1 to 2%, but the actual frequency could be higher. We investigated 173 patients with prostate cancer with bone metastases who were treated either with zoledronic acid or denosumab at our hospital between July 2006 and June 2020. ARONJ occurred in 13 patients (8%); i.e., ten out of 159 patients (6%) who were treated with zoledronic acid, and three out of 14 patients (21%) who were treated with denosumab. Multivariate analysis showed that longer duration of BRI exposure and dental treatment before the initiation of BRI are associated with risk of ARONJ. ARONJ is associated with decreased mortality but the association is not significant. Generally, the occurrence of ARONJ may be underestimated; therefore, further studies are warranted to determine the actual frequency of ARONJ.

Impact of histological variants on outcomes in patients with urothelial carcinoma treated with pembrolizumab: a propensity score matching analysis.

OBJECTIVES: To assess the impact of histological variants on survival and response to treatment with pembrolizumab in patients with chemo-resistant urothelial carcinoma (UC). PATIENTS AND METHODS: The medical records of 755 patients with advanced UC who received pembrolizumab were reviewed retrospectively. Patients were classified into pure UC (PUC) and each variant. Best overall response (BOR) and overall survival (OS) were compared between the groups using a propensity score matching (PSM). RESULTS: Overall, 147 (19.5%) patients harboured any histological variant UC (VUC). After PSM, there were no significant differences in the objective response rate (ORR, 24.5% vs 17.3%, P = 0.098) or disease control rate (DCR, 36.7% vs 30.2%, P = 0.195) when comparing patients with any VUC and PUC. Furthermore, any VUC, as compared with PUC, was associated with a similar risk of death (hazard ratio [HR] 0.90, 95% confidence interval [CI] 0.68-1.20; P = 0.482). Squamous VUC, which was the most frequent variant in the cohort, had a comparable ORR, DCR and OS as compared with PUC or non-squamous VUC. The patients with sarcomatoid VUC (n = 19) had significantly better ORR (36.8%, P = 0.031), DCR (52.6%, P = 0.032), and OS (HR 0.37, 95% CI 0.15-0.90; P = 0.023) compared to patients with PUC. CONCLUSIONS: The presence of variant histology did not seem to affect BOR or OS after pembrolizumab administration in patients with chemo-resistant UC. The patients with sarcomatoid VUC achieved favourable responses and survival rates compared to PUC.

Impact of prior intravesical bacillus Calmette-Guerin therapy on the effectiveness of pembrolizumab for patients with metastatic urothelial carcinoma.

OBJECTIVE: The aim of this study was to determine whether a history of treatment for non-muscle invasive bladder cancer (NMIBC), including intravesical bacillus Calmette-Guerin (BCG) therapy, affects the treatment outcomes of pembrolizumab in patients with metastatic, chemo-resistant urothelial carcinoma (UC). MATERIALS AND METHODS: The clinicopathological data of 755 patients with metastatic, chemo-resistant UC who received pembrolizumab were retrospectively reviewed. Best overall response and overall survival (OS) from the initiation of pembrolizumab were analyzed with regard to the history of NMIBC treatment and BCG usage using propensity score matching (PSM). RESULTS: A total of 155 (20.5%) patients had a history of NMIBC treatment, of which 97 (12.8%) had received intravesical BCG therapy. When compared to patients without a NMIBC history (median 10.0 months), the OS from the initiation of pembrolizumab for patients with a NMIBC history (13.3 months, HR [95% CI] 0.79 [0.62-1.02], P = 0.073), those with a NMIBC history and BCG (12.1 months, HR 0.87 [0.64-1.17], P = 0.356), or those with a NMIBC history but not BCG (14.5 months, HR 0.68 [0.45-1.12], P = 0.061) were not significantly different. This tendency was robust after 1:1 or 1:2 PSMs. The objective response rate (ORR, 24.5% vs. 31.0%, P = 0.222) and disease control rate (DCR, 56.1% vs. 52.1%, P = 0.501) of the 155 patients with an NMIBC history did not differ from those of 155 matched patients without an NMIBC history. Among those with an NMIBC history, the prior use of BCG did not affect OS (with vs. without BCG, 12.1 vs. 14.5 months, HR 1.29 [0.80-2.09], P = 0.295), ORR (24.5% vs. 34.0%, P = 0.298) or DCR (57.1% vs. 56.0%, P = 0.908). The ORR in BCG-treated patients was significantly lower than that in those without a NMIBC history (19.8% vs. 33.3%, P = 0.042), whereas DCR between the 2 groups did not differ significantly (55.8% vs. 54.4%, P = 0.855). CONCLUSIONS: Our risk-adjusted analyses revealed that a history of prior NMIBC treatment, including intravesical BCG therapy, did not affect the treatment outcomes of pembrolizumab in metastatic UC patients.

Risk stratification for the prognosis of patients with chemoresistant urothelial cancer treated with pembrolizumab.

The use of immune checkpoint inhibitors to treat urothelial carcinoma (UC) is increasing rapidly without clear guidance for validated risk stratification. This multicenter retrospective study collected clinicopathological information on 463 patients, and 11 predefined variables were analyzed to develop a multivariate model predicting overall survival (OS). The model was validated using an independent dataset of 292 patients. Patient characteristics and outcomes were well balanced between the discovery and validation cohorts, which had median OS times of 10.2 and 12.5 mo, respectively. The final validated multivariate model was defined by risk scores based on the hazard ratios (HRs) of independent prognostic factors including performance status, site of metastasis, hemoglobin levels, and the neutrophil-to-lymphocyte ratio. The median OS times (95% confidence intervals [CIs]) for the low-, intermediate-, and high-risk groups (discovery cohort) were not yet reached (NYR) (NYR-19.1), 6.8 mo (5.8-8.9), and 2.3 mo (1.2-2.6), respectively. The HRs (95% CI) for OS in the low- and intermediate-risk groups vs the high-risk group were 0.07 (0.04-0.11) and 0.23 (0.15-0.37), respectively. The objective response rates for in the low-, intermediate-, and high-risk groups were 48.3%, 28.8%, and 10.5%, respectively. These differential outcomes were well reproduced in the validation cohort and in patients who received pembrolizumab after perioperative or first-line chemotherapy (N = 584). In conclusion, the present study developed and validated a simple prognostic model predicting the oncological outcomes of pembrolizumab-treated patients with chemoresistant UC. The model provides useful information for external validation, patient counseling, and clinical trial design.

[A Case of Bladder Cancer Treated with Arterial Stent-Grafting to Prevent Uretero-Arterial Fistula Due to Radiation Therapy for Metastasis].

A 66-year-old male with bladder cancer underwent radical cystectomy and ileal conduit construction. The pathological diagnosis was urothelial carcinoma with squamous differentiation (pT3b). Computed tomography (CT) 18 months postoperatively revealed a right external iliac lymph node metastasis. He was treated with systemic chemotherapy after placement of bilateral ureteral stents, but CT following chemotherapy revealed an increase in the size of the metastasis, and the patient was diagnosed with progressive disease. Radiotherapy to the metastasis was selected as local therapy, but the patient was at risk of an uretero-arterial fistula because the right external iliac artery and the right ureter adjacent to the metastasis were involved in the irradiated field. The right external iliac lymph node metastasis was irradiated with a dose of 50 Gy after stent grafting for the right external iliac artery to prevent an ureteroarterial fistula. He had no adverse events, including hematuria after radiotherapy, but died of cancer cachexia 12 months after radiotherapy.

Impact of relative dose intensity in gemcitabine-cisplatin chemotherapy for metastatic urothelial carcinoma.

OBJECTIVES: To evaluate the impact of relative dose intensity for gemcitabine-cisplatin chemotherapy in patients with metastatic urothelial carcinoma. METHODS: We retrospectively reviewed the medical records of 18 patients with metastatic urothelial carcinoma, who received gemcitabine-cisplatin regimen as the first-line chemotherapy between 2009 and 2015. The doses of gemcitabine and cisplatin were reduced or the intervals between treatment cycles were prolonged according to the treatment efficacy and adverse events during the first and second cycles. The individually optimal relative dose intensity was set as the actual dose per the standard dose in the first and second cycles. From the third course onward, patients received the gemcitabine-cisplatin chemotherapy with the same relative dose intensity. Overall survival was compared with the groups according to the value of relative dose intensity. RESULTS: The median age was 72.5 (range, 56-79) years and 15 men and 3 women were enrolled in the study. The median number of cycles of first-line gemcitabine-cisplatin chemotherapy was 8 (range, 2-17), and the median survival time from initiation of first-line chemotherapy was 20.1 (range, 3.5-32.8) months. The total median relative dose intensity of gemcitabine-cisplatin chemotherapy was 56.1%. The median survival time of 10 patients in the group with the relative dose intensity of less than 60% was significantly longer than that of 8 patients in the group with the relative dose intensity of more than 60% (19.2 and 11.0 months, respectively, p = 0.04). CONCLUSION: Individual low relative dose intensity management in the first-line gemcitabine-cisplatin chemotherapy may be an acceptable option for patients with metastatic urothelial carcinoma.

The Initial Case Report: Salvage Robotic Assisted Radical Prostatectomy After Heavy Ion Radiotherapy.

Salvage radical prostatectomy is one of treatments after radiation therapy to patients with prostate cancer. To date, no case of the salvage robotic assisted radical prostatectomy (RARP) following heavy ion radiotherapy (HIRT) has been published. We report on a 70-year-old man with a history of HIRT for prostate cancer in 2011. For 3 years after. HIRT, his serum PSA levels were permissible range. However, his PSA levels were increased. We had diagnosis localized prostate cancer after HIRT. We had carried out salvage RARP. Until 10 months after salvage RARP, his PSA level was not detectable.

Coincident detection of lung metastasis of prostate cancer and primary lung cancer: A case report.

We report an extremely rare case of 79-year-old man, who was discovered with coincidental lung metastasis of prostate cancer and primary lung cancer. The patient presented with low prostate-specific antigen and two lung lesions: one in the right lower lobe, and one in the right upper lobe, 3 years after he was treated with external beam radiotherapy for Gleason score 4+3=7, cT3aN0M0 prostate cancer. A computed tomography-guided needle biopsy of a nodule in the right lower lobe revealed suspicious metastasis of prostate cancer. Thoracoscopic excisions of both lesions were performed, and each lung lesion was diagnosed as being metastatic prostate cancer and primary lung cancer.

Combination of 5α-reductase inhibitor with combined androgen blockade (CAB) as a novel cytoreductive regimen before prostate brachytherapy: Ultra-CAB.

We report a first case of using a 5α-reductase inhibitor (5ARI) and combined androgen blockade (CAB) as a cytoreductive regimen before prostate brachytherapy. Prostate volume reduction with CAB is limited to approximately 40% in most cases, making it difficult to meet anatomical constraints to perform these procedures in cases with large prostate volume. With the added administration of 5ARI, further volume reduction can be expected. Here, we describe this cytoreductive regimen used in a 63 year-old prostate cancer patient who became eligible to receive brachytherapy after dutasteride (0.5 mg daily) was added to CAB and prostate volume reduction of 57% was achieved.

Torsades de pointes induced by garenoxacin in association with pacing failure in an elderly woman with VDD pacemaker.

An 86-year-old woman was admitted to the hospital for syncope and convulsion 4 days after starting antibiotic therapy for pneumonia with oral garenoxacin 400 mg/day. She had a VDD pacemaker for complete atrioventricular (AV) block. Her electrocardiogram showed marked QT prolongation and during pacemaker interrogation pacing failure probably due to battery depletion induced torsades de pointes. After cessation of garenoxacin, QTc returned to normal range subsequently and a new pacemaker was implanted. In patients with risks of QT prolongation, garenoxacin should be used cautiously with QT interval monitoring.