Metastatic castration resistant prostate cancer patients' experience with Radium-223 treatment in Japan.

Aim: We aimed to determine Japanese metastatic castration resistant prostate cancer (CRPC) patients' Ra-223 treatment experience. Patients & methods: Patients answered the Cancer Therapy Satisfaction Questionnaire (CTSQ domains: Satisfaction with Therapy [SWT], Expectations of Therapy [ET], Feelings about Side Effects [FSE]), the Memorial Anxiety Scale for Prostate Cancer (MAX-PC) and the FACT-Bone Pain (FACT-BP) Questionnaire at baseline, during (vists 3 and 5) and after treatment (end of observation; EOO). Results: Data from 72 patients were included. Baseline median CTSQ scores SWT: 66.1 (IQR19.7), ET: 75.0 (IQR45), and FSE 68.8 (IQR 34.4) were unchanged during vists 3 and 5, but the SWT (-3.57 [IQR17.9]) and ET (-5.0 [IQR30]) decreased while FSE was unchanged (0.0 [IQR31.25]) at EOO. The median MAX-PC (18.0 [IQR 49]) score was unchanged (0.0, IQR 6) while the median FACT BP (54.0 [IQR13]) score decreased by -1.0 (IQR 8) at EOO. Conclusion: Japanese metastatic castration resistant prostate cancer patients' experience is stable during Ra-223 treatment.

What is this study about? We wanted to know the treatment experience with Radium-223 (Ra-223) among Japanese prostate cancer patients. Ra-223 is a radioactive molecule used for the treatment of metastatic castration resistant prostate cancer. We asked patients to answer different questionnaires on treatment satisfaction, anxiety and quality of life before, during, and after treatment with Ra-223. What were the results? Based on the patients' answers to our questionnaires, treatment satisfaction, anxiety and quality of life remain stable while the patients undergo treatment with Ra-223, but in some aspects may decline after treatment. What do the results mean? The results mean that patients' experience during Ra-223 treatment is stable but patients should share any concerns they have about their treatment with their doctors.

Incidence and molecular characteristics of deficient mismatch repair conditions across nine different tumors and identification of germline variants involved in Lynch-like syndrome.

BACKGROUND: Based on molecular characteristics, deficient DNA mismatch repair (dMMR) solid tumors are largely divided into three categories: somatically MLH1-hypermethylated tumors, Lynch syndrome (LS)-associated tumors, and Lynch-like syndrome (LLS)-associated tumors. The incidence of each of these conditions and the corresponding pathogenic genes related to LLS remain elusive. METHODS: We identified dMMR tumors in 3609 tumors from 9 different solid organs, including colorectal cancer, gastric cancer, small-bowel cancer, endometrial cancer, ovarian cancer, upper urinary tract cancer, urinary bladder cancer, prostate cancer, and sebaceous tumor, and comprehensively summarized the characterization of dMMR tumors. Characterization of dMMR tumors were performed as loss of at least one of MMR proteins (MLH1, MSH2, MSH6, and PMS2), by immunohistochemistry, followed by MLH1 promotor methylation analysis and genetic testing for MMR genes where appropriate. Somatic variant analysis of MMR genes and whole exome sequencing (WES) were performed in patients with LLS. RESULTS: In total, the incidence of dMMR tumors was 5.9% (24/3609). The incidence of dMMR tumors and the proportion of the three categorized dMMR tumors varied considerably with different tumor types. One to three likely pathogenic/pathogenic somatic MMR gene variants were detected in 15 out of the 16 available LLS tumors. One patient each from 12 patients who gave consent to WES demonstrated non-MMR germline variants affect function (POLQ or BRCA1). CONCLUSIONS: Our data regarding the LS to LLS ratio would be useful for genetic counseling in patients who are suspected to have LS, though the genetic backgrounds for the pathogenesis of LLS need further investigation.

Prognostic significance of inflammatory markers in patients with advanced renal cell carcinoma receiving nivolumab plus ipilimumab.

BACKGROUND: A useful biomarker for the efficacy of immune checkpoint inhibitors (ICIs) in advanced renal cell carcinoma (RCC) has not yet been established. This study aims to investigate whether inflammatory markers are associated with the efficacy of nivolumab plus ipilimumab therapy before and during treatment. METHODS: Data from patients with advanced clear cell RCC who received a combination treatment of nivolumab plus ipilimumab were retrospectively analyzed. The neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and C-reactive protein (CRP) levels were assessed at baseline and 3, 6, and 9 weeks after treatment initiation. The correlation between these inflammatory markers and the patient's prognosis was investigated. RESULTS: Eighty-four patients were identified. The multivariate analysis identified NLR at week 3, CRP at week 6, and NLR and CRP at week 9 as the consistent predictor associated with poor overall survival (OS) at each time point. The survival analysis and receiver operating characteristic (ROC) curve analysis revealed that an NLR of ≥ 2.4 at week 3, CRP of ≥ 1.4 mg/dL at week 6, and NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 were associated with worse OS (hazard ratios (HR) = 5.70, P = 0.008, HR = 3.23, P = 0.004, HR = 7.38, P < 0.001 and HR = 3.55, P = 0.002). CONCLUSIONS: Both NLR and CRP were considered useful biomarkers for understanding the prognosis during nivolumab plus ipilimumab therapy. Furthermore, an NLR of ≥ 4.8 and CRP of ≥ 1.0 mg/dL at week 9 are helpful in reconsidering treatment continuation.

Association between immune-related adverse events and survival in patients with renal cell carcinoma treated with nivolumab plus ipilimumab: immortal time bias-corrected analysis.

BACKGROUND: Immune-related adverse events (irAEs) in patients treated with immune check inhibitors are associated with favourable response rate and survivals in multiple cancers, including renal cell carcinoma (RCC). The aim of this study was to investigate how irAEs were associated with improved survivals in advanced RCC patients treated with nivolumab plus ipilimumab. MATERIALS AND METHODS: This retrospective study included patients who received nivolumab plus ipilimumab at six centres, institutions, or hospitals between September 2018 and February 2022. We assessed associations of the development and the number of irAEs with overall survival (OS) and progression-free survival (PFS). To eliminate immortal time bias, landmark analysis and a Cox model with time-dependent variables were used. RESULTS: This study included 129 patients with a median follow-up of 12.3 months. The 2-year OS and PFS rates were 55% and 42%, respectively. Ninety six patients experienced irAEs. The development of irAEs was positively associated with OS and PFS rates (hazard ratio [HR] 0.328, 95% confidence interval [CI] 0.165-0.648, p = 0.001; HR 0.334, 95% CI 0.151-0.737, p = 0.007). Patients who experienced multiple irAEs had longer OS (HR 0.507, 95% CI 0.235-1.097, p = 0.085 or HR 0.245, 95% CI 0.110-0.544, p < 0.001) and PFS (HR 0.572, 95% CI 0.316-1.036, p = 0.085 or HR 0.267, 95% CI 0.113-0.628, p = 0.002) compared with those who experienced single or zero irAE. CONCLUSIONS: Developing irAEs, particularly multiple irAEs, is associated with favourable survivals in advanced RCC patients treated with nivolumab plus ipilimumab.

Clinical outcomes of nivolumab plus ipilimumab in patients with metastatic non-clear cell renal cell carcinoma: Real-world data from a Japanese multicenter retrospective study.

OBJECTIVES: Although nivolumab plus ipilimumab has become a standard treatment regimen for metastatic clear cell renal cell carcinoma (ccRCC), its efficacy in non-clear cell carcinoma (nccRCC) has not been fully examined. In the current study, we evaluated the clinical outcomes of nivolumab plus ipilimumab in nccRCC compared with ccRCC. METHODS: We retrospectively analyzed 22 patients with metastatic and/or locally advanced unresectable nccRCC who received nivolumab plus ipilimumab as a first-line therapy and compared them with 107 patients with ccRCC. Objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and toxicity were compared between the nccRCC and ccRCC groups. RESULTS: The histology of nccRCC included eight papillary, six unclassified, three chromophobe, two collecting duct carcinoma, and three other subtypes. Best objective response in nccRCC patients included three complete responses and five partial responses, resulting in an ORR of 36%, while that in ccRCC patients was 50% (p = 0.22). With a median follow-up of 11.9 months, OS was significantly shorter in patients with nccRCC than in those with ccRCC (median 20.8 months vs. not reached, p = 0.04), while there was no significant difference in PFS (median 6.3 vs. 10.8 months, p = 0.21). Treatment-related adverse events occurred in 14 (64%) nccRCC patients and 81 (76%) ccRCC patients. CONCLUSIONS: Combination treatment with nivolumab and ipilimumab demonstrated modest clinical efficacy in patients with nccRCC compared with patients with ccRCC, suggesting it could be a therapeutic option for metastatic nccRCC patients.

Olaparib in patients with mCRPC with homologous recombination repair gene alterations: PROfound Asian subset analysis.

BACKGROUND: The Phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control; randomized 2:1 to olaparib or control) in men with homologous recombination repair gene alterations and metastatic castration-resistant prostate cancer whose disease progressed on prior next-generation hormonal agent. METHODS: We present efficacy and safety data from an exploratory post hoc analysis of olaparib in the PROfound Asian subset. Analyses were not planned, alpha controlled or powered. Of 101 Asian patients enrolled in Japan (n=57), South Korea (n=29) and Taiwan (n=15), 66 and 35 patients received olaparib and control, respectively. RESULTS: Radiographic progression-free survival (rPFS) and overall survival (OS) favored olaparib versus control in Cohort A [rPFS 7.2 vs. 4.5 months, HR 0.58, 95% CI 0.29-1.21, P = 0.14 (nominal); OS 23.4 vs. 17.8 months, HR 0.81, 95% CI 0.40-1.74, P = 0.57 (nominal)] and Cohorts A+B [rPFS 5.8 vs. 3.5 months, HR 0.69, 95% CI 0.42-1.16, P = 0.13 (nominal); OS 18.6 vs. 16.2 months, HR 0.96, 95% CI 0.56-1.70, P = 0.9 (nominal)]. Olaparib showed greatest improvement in patients harboring BRCA alterations [rPFS 9.3 vs. 3.5 months, HR 0.17, 95% CI 0.06-0.49, P = 0.0003 (nominal); OS 26.8 vs. 14.3 months, HR 0.62, 95% CI 0.24-1.79, P = 0.34 (nominal)]. Safety data were consistent with the known profile of olaparib, with no new safety signals identified. CONCLUSION: In PROfound, there was a statistically significant improvement in outcomes reported in the global population of patients with metastatic castration-resistant prostate cancer and alterations in homologous recombination repair genes whose disease progressed on prior next-generation hormonal agent compared with control. For the subset of Asian patients reported here, exploratory analysis suggested that there was also an improvement in outcomes versus control. The safety and tolerability of olaparib in Asian patients were similar to that of the PROfound global population. CLINICAL TRIAL NUMBER: ClinicalTrials.gov NCT02987543.

Nomogram predicting testicular torsion in Japanese patients with acute scrotal pain using physical examination findings and environmental conditions: Development and prospective external validation.

OBJECTIVES: To develop a prediction tool based on physical findings and environmental conditions without utilizing color Doppler ultrasonography to guide non-urologists and patients' families in determining the testicular torsion possibility among patients with acute scrotal pain. METHODS: Overall, 110 consecutive patients aged ≤30 years with acute scrotal pain at Saitama Medical Center between 2012 and 2014 were retrospectively evaluated. Physical examination results, including scrotal inspection, palpation and gait observation, and environmental conditions at pain onset (time range and ambient temperature) were collected. Multivariate analysis identified significant and independent risk factors for testicular torsion, and a nomogram predicting testicular torsion was constructed. The model underwent prospective validation in an independent set of 123 consecutive patients admitted with acute scrotal pain to our institution between 2015 and 2017. RESULTS: Testicular torsion diagnosis rates were 27% (30/110) and 26% (32/123) in the training and validation cohorts, respectively. Logistic regression analysis showed four risk factors for developing testicular torsion: abnormal testicular position, walking difficulty, midnight to early morning onset and ambient temperature <15°C at pain onset. The constructed nomogram showed that the areas under the receiver operating characteristic curves were 0.92 and 0.84 for the training and validation cohorts, respectively. The calibration plot showed an acceptable fitness between the predicted probability and the observed rate of testicular torsion. CONCLUSIONS: A novel nomogram was developed solely based on physical findings and environmental conditions to predict testicular torsion in Japanese patients with acute scrotal pain.

Risk factors for disease progression in Japanese patients with COVID-19 with no or mild symptoms on admission.

BACKGROUND: Although the risk factors for coronavirus disease 2019 (COVID-19) mortality have been identified, there is limited information about the risk factors for disease progression after hospitalization among Japanese patients with COVID-19 exhibiting no or mild symptoms. METHODS: All 302 consecutive patients who were admitted to our institutions and diagnosed with COVID-19 between March and December 2020 were retrospectively assessed. Ultimately, 210 adult patients exhibiting no or mild symptoms on admission were included in the analysis. They were categorized into the stable (no oxygen needed) and worsened (oxygen needed) groups, and their characteristics and laboratory data were compared. RESULTS: Among 210 patients, 49 progressed to a severe disease stage, whereas 161 did not. The mean patient age was 52.14 years, and 126 (60.0%) patients were male. The mean body mass index (BMI) was 23.0 kg/m2, and 71 patients were overweight (BMI ≥ 25 kg/m2). Multivariate logistic analysis showed that old age, overweight, diabetes mellitus (DM), and high serum ferritin levels were independent risk factors for disease progression. CONCLUSIONS: Clinicians should closely observe patients with COVID-19, especially those with risk factors such as old age, overweight, DM, and high serum ferritin levels, regardless of whether they have no or mild symptoms.

Prevalence and clinicopathological/molecular characteristics of mismatch repair protein-deficient tumours among surgically treated patients with prostate cancer in a Japanese hospital-based population.

BACKGROUND: The prevalence and molecular characteristics of deficient mismatch repair prostate cancer in the Japanese population have scarcely been investigated. METHODS: Immunohistochemistry for mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from resected primary prostate cancers in patients who underwent prostatectomy at our institution between January 2001 and May 2016. Genetic and/or epigenetic alterations of mismatch repair genes were investigated in patients with any loss of mismatch repair protein expression in the tumour. RESULTS: Of the 337 patients, four (1.2%) showed loss of mismatch repair protein expression on immunohistochemistry. All four patients showed loss of both MSH2 and MSH6 protein expression. Genetic testing was performed in two of the four patients, demonstrating no pathogenic germline alterations were present. In each of these two patients, at least one somatic alteration inactivating MSH2 without MSH2 hypermethylation was identified, leading to the diagnosis of supposed 'Lynch-like syndrome'. Patients with deficient mismatch repair prostate cancer were at a significantly higher stage (pT2pN0 vs. pT3-4pN0/pTanypN1, P = 0.02) and had a greater Gleason score (<8 vs. ≥8, P < 0.01) than those with proficient mismatch repair prostate cancer. CONCLUSIONS: The prevalence of deficient mismatch repair prostate cancer in the Japanese hospital-based prostatectomized population was extremely low. To improve screening efficacy for deficient mismatch repair prostate cancer, screening candidates can be limited to patients with locally advanced, node-positive and/or Gleason score of 8 or greater prostate cancer. Universal tumour screening for Lynch syndrome seems ineffective in patients with prostate cancer.

Identification of Lynch syndrome-associated DNA mismatch repair-deficient bladder cancer in a Japanese hospital-based population.

BACKGROUND: The prevalence of Lynch syndrome (LS)-associated DNA mismatch repair (MMR)-deficient bladder cancer (BC) has scarcely been investigated. METHODS: Immunohistochemistry for four MMR proteins (MLH1, MSH2, MSH6, and PMS2) was performed in formalin-fixed paraffin-embedded (FFPE) sections prepared from the resected specimens of 618 consecutive newly diagnosed BC cases. Genetic/epigenetic analyses were performed in patients displaying the loss of any MMR proteins in the tumor. RESULTS: Of the 618 patients, 9 (1.5%) showed the loss of MMR protein expression via immunohistochemistry; specifically, 3, 3, 2, and 1 patients displayed the loss of MLH1/PMS2, PMS2, MSH6, and MSH2/MSH6, respectively. All nine patients were male with a median age of 68 years (63-79 years). One had been previously diagnosed as having LS with an MSH2 variant. Genetic testing demonstrated the presence of a pathogenic PMS2 variant (n = 1), a variant of uncertain significance in MSH2 (n = 1), and no pathogenic germline variants of the MMR genes (n = 1). One patient with MSH6-deficient BC did not complete the genetic testing because of severe degradation of DNA extracted from the FFPE specimen, but the patient was strongly suspected to have LS because of their history of colon cancer and MSH6-deficient upper urinary tract cancer. There remained a possibility that the remaining four patients who refused genetic testing had LS. CONCLUSIONS: The prevalence of LS-associated MMR-deficient BC was estimated to be 0.6-1.1% among unselected BC cases.

ALDH1A1 in patient-derived bladder cancer spheroids activates retinoic acid signaling leading to TUBB3 overexpression and tumor progression.

Acquired chemoresistance is a critical issue for advanced bladder cancer patients during long-term treatment. Recent studies reveal that a fraction of tumor cells with enhanced tumor-initiating potential, or cancer stem-like cells (CSCs), may particularly contribute to acquired chemoresistance and recurrence. Thus, CSC characterization will be the first step towards understanding the mechanisms underlying advanced disease. Here we generated long-term patient-derived cancer cells (PDCs) from bladder cancer patient specimens in spheroid culture, which is favorable for CSC enrichment. Pathological features of bladder cancer PDCs and PDC-dependent patient-derived xenografts (PDXs) were basically similar to those of their corresponding patients' specimens. Notably, CSC marker aldehyde dehydrogenase 1A1 (ALDH1A1), a critical enzyme that synthesizes retinoic acid (RA), was abundantly expressed in PDCs. ALDH1A1 inhibitors and shRNAs repressed both PDC proliferation and spheroid formation, whereas all-trans RA could rescue ALDH1A1 shRNA-suppressed spheroid formation. ALDH inhibitor also reduced the in vivo growth of PDC-derived xenografts. ALDH1A1 knockdown study showed that tubulin beta III (TUBB3) was one of the downregulated genes in PDCs. We identified functional RA response elements in TUBB3 promoter, whose transcriptional activities were substantially activated by RA. Clinical survival database reveals that TUBB3 expression may associate with poor prognosis in bladder cancer patients. Moreover, TUBB3 knockdown was sufficient to suppress PDC proliferation and spheroid formation. Taken together, our results indicate that ALDH1A1 and its putative downstream target TUBB3 are overexpressed in bladder cancer, and those molecules could be applied to alternative diagnostic and therapeutic options for advanced disease.

Prevalence of Lynch syndrome among patients with upper urinary tract carcinoma in a Japanese hospital-based population.

BACKGROUND: The prevalence of Lynch syndrome and the use of universal tumor screening to identify Lynch syndrome among unselected patients with upper urinary tract urothelial carcinoma, which is associated with Lynch syndrome, have not been closely investigated yet. METHODS: A total of 166 tumors from 164 upper urinary tract urothelial carcinoma patients were tested for microsatellite instability and expression of mismatch repair proteins (MLH1, MHS2, MSH6 and PMS2) by immunohistochemistry. Genetic testing was performed for patients suspected of having Lynch syndrome. Clinicopathological factors, including familial and personal cancer history associated with mismatch repair deficiency, were evaluated. RESULTS: The frequency of high-level microsatellite instability and loss of at least one mismatch repair protein was 2.4% (4/164); the microsatellite instability and immunohistochemistry results showed complete concordance. Of these four patients, three were genetically proven to have Lynch syndrome, while the remaining one was highly suggestive for Lynch syndrome based on their personal cancer history. Univariate analysis showed that age<70 years (P = 0.04), ureter as the tumor location (P = 0.052), previous history/synchronous diagnosis of colorectal cancer (P < 0.01) and fulfillment of the criteria per the revised Bethesda guideline (P < 0.01) tended to be or were significantly associated with high-level microsatellite instability/mismatch repair loss. CONCLUSIONS: The prevalence of Lynch syndrome among unselected upper urinary tract urothelial carcinoma patients was at least 1.8% in our study population. The screening efficacies of the microsatellite instability test and immunohistochemistry appear equivalent. Universal tumor screening may be a valid approach; however, selective screening methods that consider factors associated with mismatch repair loss/high-level microsatellite instability tumors require further investigation.

The single-base-pair deletion, MSH2 c.2635-3delC affecting intron 15 splicing can be a cause of Lynch syndrome.

The proband was a 62-year-old man with ureter cancer. He had a history of metachronous colorectal and gastric cancer. Immunohistochemical staining showed the absence of both MSH2 and MSH6 proteins in the ureter cancer and other available cancer tissue specimens. Genetic testing was conducted to identify the causative genes of hereditary gastrointestinal cancer syndromes including mismatch repair genes. We detected a germline variant, c.2635-3delC, within the splice acceptor site of exon 16, in the MSH2 gene. To investigate whether this variant affected splicing of the gene, RNA sequencing was performed using blood samples. We observed a substantial amount of the transcripts that lacked proper splicing of intron 15 in the indexed case, whereas, a very low amount of such aberrant transcripts was detected in the controls, strongly indicating an association between the variant and splicing defect. These results indicate that MSH2 c.2635-3delC affects normal splicing and might be a cause of Lynch syndrome.

[HUGE RENAL ANGIOMYOLIPOMA COMPLICATED WITH COMMON ILIAC VEIN THROMBUS BECAUSE OF THE TUMOR PRESSURE].

A 47-year-old woman was transferred to our hospital in June 2014 in hemorrhagic shock due to rupture of a huge right renal angiomyolipoma (AML). Selective right renal arterial embolization performed that same day reversed the shock immediately. Despite the huge abdominal tumor, the patient was discharged 2 weeks later after refusing any further treatment.Two weeks later she noticed the abdominal tumor growing. One month after discharge, she was readmitted due to dyspnea caused by restriction of her breathing by the growing tumor mass. A CT revealed a massive increase in tumor size with internal liquefaction, a thrombus in the left common iliac vein, and a 12 mm aneurysm in the right renal artery. The patient requested removal of the abdominal tumor since her ADL had deteriorated. We decided to perform a right nephrectomy with consideration of the left common iliac vein thrombus and right renal arterial aneurysm.As a precaution against pulmonary embolism in case the left common iliac vein thrombus dislodged, a retrievable inferior vena cava (IVC) filter was inserted before surgery. We were also concerned about possible rupture of the right renal aneurysm, so the right renal artery was embolized before surgery. After these procedures, a right nephrectomy was performed via a transperitoneal approach.The surgery was uneventful. The tumor weighed about 11 kg including 7,000 mL of bloody fluid. The IVC filter was removed the day after surgery, but the thrombus in the left common iliac vein remained, and an anticoagulant was started. Three months later, the thrombus had disappeared, and the anticoagulant was discontinued six months after surgery.According to the treatment guidelines for deep vein thrombosis, anticoagulants are the drugs of choice. IVC filters are seldom used to prevent pulmonary embolism. We initially administered an anticoagulant for the thrombus in the left iliac vein. However, an increase in abdominal tumor size suggested the drug had caused internal rebleeding and it had to be discontinued. Ultimately, we used a temporary retrievable IVC filter during the right nephrectomy with success.There is currently no consensus on when to use an IVC filter. Moreover, very little data exists on the use of an IVC filter during the perioperative period. Therefore, given the risk of potential thromboembolism, although we were able to use it successfully in our surgery, it should not be employed without a thorough benefit-risk assessment.

Candidate selection for quadrant-based focal ablation through a combination of diffusion-weighted magnetic resonance imaging and prostate biopsy.

OBJECTIVES: To identify prostatic quadrants that could be preserved without intervention, using diffusion-weighted magnetic resonance imaging (DWI) and extended core biopsy, as a step toward implementation of quadrant-based focal ablation with potential preservation of erectile and ejaculatory functions, based on comparisons with unilateral hemi-gland ablation. PATIENTS AND METHODS: We conducted a prebiopsy DWI study including 648 quadrants in 162 men who underwent 14-core biopsy including anterior sampling and radical prostatectomy (RP) for localised cancer. Imaging and pathology were analysed on a quadrant basis. Each quadrant was assessed through four-core sampling. Predictive performance of DWI and biopsy for quadrant status was analysed. RESULTS: On RP specimens, 170 anterior (52.5%) and 172 posterior quadrants (53.1%) harboured significant cancer. Negative predictive values of DWI, biopsy, and their combination for significant cancer were 79.7%, 70.6%, and 91.1%, respectively, in anterior quadrants, and 78.5%, 81.3%, and 91.7%, respectively, in posterior quadrants. DWI incrementally improved the negative predictive values of biopsy in anterior (P < 0.001) and posterior quadrants (P = 0.025), without untoward impacts on positive predictive values. Negative findings on both DWI and biopsy were identified in posterior quadrants of 109 sides (33.6%), but in entire hemi-glands of 54 sides (16.7%). CONCLUSIONS: The combination of DWI and 14-core biopsy including anterior sampling efficiently identifies quadrants without significant cancer in men with localised prostate cancer; the remaining quadrants, therefore, could be potential candidate areas for focal ablation. Focal therapy designed based on quadrant-based assessment could be superior to unilateral hemi-gland ablation for preservation of posterior quadrants and retaining of sexual function in more sides.

ASSOCIATION BETWEEN THE RISK OF TESTICULAR TORSION AMONG ACUTE SCROTUM AND AMBIENT TEMPERATURE.

(Objectives) Testicular torsion (TT) is a socially and clinically important urological emergency condition because delayed diagnosis and treatment can lead to testicular loss. Although a possible association between TT and low ambient temperature has been argued, the clinical significance of the association has not been fully elucidated. We retrospectively collected acute scrotum cases and investigated the association between the risk of TT among acute scrotums and ambient temperatures on the day of onset. (Patients and methods) We studied 105 consecutive acute scrotum patients with suspected TT who underwent urgent surgical exploration between October 2004 and October 2014. The patients' age, residential area, time and date of onset, laboratory findings, and operative findings were collected from their medical records. Climate data, including daily mean ambient temperature (DMAT), diurnal temperature change (DTC), humidity, and atmospheric pressure at the time of onset, were obtained from the Japan Meteorological Agency website. The chi-square and Wilcoxon rank sum tests were used to evaluate statistical differences. Logistic regression analysis used to identify significant predictors of TT. (Results) The median age of the patients was 13 years (range, 1-43 years). The affected side was the right/left/bilateral side in 46/58/1 of the patients. Surgical exploration revealed TT in 67 patients. The remaining 38 non-TT patients included 12 with testicular appendage torsions, 12 with epididymal appendage torsions, 9 with epididymitis, 2 with orchitis, 2 with idiopathic hematomas, and 1 with allergic purpura. The median DMATs at the day of onset were 10.8°C (1.8-29.4°C) in the TT patients and 19.4°C (1.9-29.1°C) in the non-TT patients. The incidence of TT among the patients with acute scrotum explored surgically (TT incidence) in days with DMATs <15°C (80%) was significantly higher than that in days with DMATs ≥ 15°C (45%; p<0.001). During days with DMATs ≥15°C, the TT incidence in days with DTCs ≥10°C (62%) was significantly higher than that in days with DTCs <10°C (32%; p=0.037). Multivariate analysis revealed higher age (≥14), low serum C-reactive protein level (<0.5 ng/ml) and low DMAT (<15°C) were significant risk factor for TT in patients with acute scrotum undergoing surgery. (Conclusions) It should be noted that in this study, the onset of acute scrotum during days with low ambient temperatures or large DTCs was associated with a moderate to high possibility of TT.

Diagnostic performance and safety of a three-dimensional 14-core systematic biopsy method.

OBJECTIVE: To investigate the diagnostic performance and safety of a three-dimensional 14-core biopsy (3D14PBx) method, which is a combination of the transrectal six-core and transperineal eight-core biopsy methods. PATIENTS AND METHODS: Between December 2005 and August 2010, 1103 men underwent 3D14PBx at our institutions and were analysed prospectively. Biopsy criteria included a PSA level of 2.5-20 ng/mL or abnormal digital rectal examination (DRE) findings, or both. The primary endpoint of the study was diagnostic performance and the secondary endpoint was safety. We applied recursive partitioning to the entire study cohort to delineate the unique contribution of each sampling site to overall and clinically significant cancer detection. RESULTS: Prostate cancer was detected in 503 of the 1103 patients (45.6%). Age, family history of prostate cancer, DRE, PSA, percentage of free PSA and prostate volume were associated with the positive biopsy results significantly and independently. Of the 503 cancers detected, 39 (7.8%) were clinically locally advanced (≥cT3a), 348 (69%) had a biopsy Gleason score (GS) of ≥7, and 463 (92%) met the definition of biopsy-based significant cancer. Recursive partitioning analysis showed that each sampling site contributed uniquely to both the overall and the biopsy-based significant cancer detection rate of the 3D14PBx method. The overall cancer-positive rate of each sampling site ranged from 14.5% in the transrectal far lateral base to 22.8% in the transrectal far lateral apex. As of August 2010, 210 patients (42%) had undergone radical prostatectomy, of whom 55 (26%) were found to have pathologically non-organ-confined disease, 174 (83%) had prostatectomy GS ≥7 and 185 (88%) met the definition of prostatectomy-based significant cancer. CONCLUSIONS: This is the first prospective analysis of the diagnostic performance of an extended biopsy method, which is a simplified version of the somewhat redundant super-extended three-dimensional 26-core biopsy. As expected, each sampling site uniquely contributed not only to overall cancer detection, but also to significant cancer detection. 3D14PBx is a feasible systematic biopsy method in men with PSA <20 ng/mL.

Long-term oncological outcome in men with T3 prostate cancer: radical prostatectomy versus external-beam radiation therapy at a single institution.

BACKGROUND: This study was designed to compare the long-term oncological outcome of patients with clinical T3 (cT3) prostate cancer (PCA) treated with either radical prostatectomy (RP) or external-beam radiation therapy (EBRT) and to identify predictors of oncological outcomes. METHODS: A total of 231 patients with cT3 PCA underwent either RP (n = 112) or EBRT (n = 119). Local progression-free (LPFS), distant metastasis-free (DMFS), cancer-specific (CSS), and overall survival curves were generated with the Kaplan-Meier method, and the differences in survival rates between the two groups were assessed with a log-rank test. Cox proportional stepwise multivariate analysis was used to assess the association of variables to the oncological outcomes. RESULTS: The median follow-up of the RP and EBRT groups was 93 and 85 months, respectively (p = 0.004).The 10-year LPFS, DMFS, and CSS rates were not statistically different between the two groups (90.2, 73.9, and 93.7 % in the RP group and 82.7, 88.2, and 85.1 % in the EBRT group; p = 0.25, 0.10, and 0.10, respectively). The Cox proportional multivariate analysis revealed that clinical T3b (cT3b) (p = 0.001) and a biopsy Gleason score of 7-10 (p = 0.043) were significant predictors of cancer-specific mortality and that cT3b was also a significant predictor of local progression and all-cause mortality. CONCLUSION: In cT3 PCA, both RP and EBRT provide an excellent long-term oncological outcome. cT3b was the strongest predictor of oncological outcome for the patients with locally advanced PCA who underwent the definitive therapy.

Clinical Outcomes of Patients with High-risk Metastatic Hormone-naïve Prostate Cancer: A 3-year Interim Analysis of the Observational J-ROCK Study.

BACKGROUND: Androgen deprivation therapy (ADT), administered alone, as combined androgen blockade (CAB) or as ADT plus androgen receptor signalling inhibitors (ARSIs) or ADT plus docetaxel, is the standard treatment for metastatic hormone-naïve prostate cancer (mHNPC) in Japanese real-world practice. OBJECTIVE: To investigate treatment patterns and clinical outcomes in LATITUDE criteria high-risk mHNPC. DESIGN, SETTING, AND PARTICIPANTS: The longitudinal, multicentre, J-ROCK registry study enrolled patients initiating ADT in Japan after May 2019, and categorised them as cohort 1 (ADT or CAB) or cohort 2 (ADT plus ARSIs or docetaxel). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate-specific antigen (PSA) response, progression-free survival (PFS), time to castrate-resistant prostate cancer (CRPC), overall survival (OS), and safety were evaluated. PFS, time to CRPC, and OS were estimated via the Kaplan-Meier method and between-cohort comparisons via multivariate Cox regression models. RESULTS AND LIMITATIONS: In total, 974 patients were included (cohort 1: 38.1%, cohort 2: 61.9%). CAB was preferred (67.4%) to ADT alone in cohort 1, and abiraterone acetate plus prednisolone was used most frequently in cohort 2 (59.4%). The proportion of patients with ≥50%/≥90% PSA decline or who achieved PSA ≤0.2/≤0.1 ng/ml tended to be higher in cohort 2. PFS (adjusted hazard ratio 0.42; 95% confidence interval [CI] 0.31-0.55), time to CRPC (0.28; 95% CI 0.23-0.36), and OS (0.54; 95% CI 0.35-0.82) were longer in cohort 2. In cohorts 1 and 2, adverse drug reactions of special interest (ADRSIs) occurred in 1.3% and 15.1%, and fatal adverse events occurred in 1.9% and 1.7%, respectively. Limitations included nonrandomised design, varying time since marketing authorisation for ARSIs, and limited safety assessments. CONCLUSIONS: ADT plus ARSIs or docetaxel was used more frequently to treat high-risk mHNPC than standard ADT/CAB and was associated with more favourable clinical outcomes. Although ADRSIs were reported more in cohort 2, the safety profile was considered tolerable. PATIENT SUMMARY: Although many treatment options are available for high-risk metastatic prostate cancer, there are limited reports on real-world clinical experience with different therapies outside of the clinical trial setting. In this study, we compared clinical and safety outcomes with different treatment regimens, using a large series of patients with high-risk metastatic hormone-naïve prostate cancer across Japan. We found that androgen deprivation therapy in combination with newer androgen receptor signalling inhibitors resulted in improved response compared with androgen deprivation therapy alone or in combination with a first-generation antiandrogen.