A cross-species analysis of fecal microbiomes in humans and mice reveals similarities and dissimilarities associated with prostate cancer risk.

BACKGROUND: Prostate cancer is a complex disease that develops over time and is influenced by several lifestyle factors that also impact gut microbes. Gut dysbiosis is intricately linked to prostate carcinogenesis, but the precise mechanisms remain poorly understood. Mice are crucial for studying the relationships between gut microbes and prostate cancer, but discovering similarities between humans and mice may aid in elucidating new mechanisms. METHODS: We used 16s rRNA sequencing data from stool samples of tumor-bearing prostate-specific conditional Pten-knockout mice, disease-free wildtype mice, and a human cohort suspected of having prostate cancer to conduct taxonomic and metagenomic profiling. Features were associated with prostate cancer status and low risk (a negative biopsy of Gleason grade <2) or high risk (Gleason grade ≥2) in humans. RESULTS: In both humans and mice, community composition differed between individuals with and without prostate cancer. Odoribacter spp. and Desulfovibrio spp. were taxa associated with prostate cancer in mice and humans. Metabolic pathways associated with cofactor and vitamin synthesis were common in mouse and human prostate cancer, including bacterial synthesis of folate (vitamin B9), ubiquinone (CoQ10), phylloquinone (vitamin K1), menaquinone (vitamin K2), and tocopherol (vitamin E). CONCLUSIONS: Our study provides valuable data that can help bridge the gap between human and mouse microbiomes. Our findings provide evidence to support the notion that certain bacterial-derived metabolites may promote prostate cancer, as well as a preclinical model that can be used to characterize biological mechanisms and develop preventive interventions.

Prognostic model for second progression-free survival and overall survival in patients with high-risk metastatic hormone-sensitive prostate cancer treated with abiraterone acetate and androgen deprivation therapy.

BACKGROUND: To develop and validate a prognostic risk model for high-risk metastatic hormone-sensitive prostate cancer (mHSPC) patients treated with upfront abiraterone acetate (ABI). METHODS: This retrospective multicenter study involved 233 high-risk mHSPC patients who received upfront ABI, developed by three academic centers. The model was externally validated with an independent cohort of 282 patients. To identify independent prognostic factors for second progression-free survival (PFS2) and develop the best-fitted model, Cox proportional hazards regression, followed by the Akaike information criterion, was used. Patients were categorized into three groups based on their risk scores. PFS2 and overall survival (OS) were evaluated according to the risk groups in the discovery and validation cohorts. RESULTS: The median age was 72 (range 51-89) years, with a median follow-up duration of 27 months. Independent factors linked to PFS2 included an Eastern Cooperative Oncology Group performance status ≥2, a primary Gleason score of 5, an extent of disease score of ≥3 or liver metastasis, and lactate dehydrogenase >220 U/L. Median PFS2 for favorable-, intermediate-, and poor-risk groups were not reached, 43 months, and 16 months, respectively. The median OS was 29 months in the poor-risk group, whereas it was not reached in the favorable- and intermediate-risk groups. The 2-year OS rates in the favorable-, intermediate- and poor-risk groups were 94.5%, 80.1%, and 60.3%, respectively. The validation cohort confirmed the risk model's relationship with PFS2 and OS. The median PFS2 and OS in the high-risk group were 21 months and 32 months, respectively. CONCLUSIONS: Our prognostic model, including five clinical factors, is useful for patient care and treatment selection in high-risk mHSPC patients treated with ADT plus ABI. The developed model could provide more accurate information, guide treatment decisions, or classify patients in future clinical trials.

The efficacy of second-line tyrosine kinase inhibitor for patients with metastatic non-clear cell renal cell carcinoma following first-line immune-oncology combination therapy.

PURPOSE: Metastatic non-clear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with a poor prognosis and is treated with immunotherapy (IO)-based combinations according to the clear cell renal cell carcinoma. Tyrosine-kinase inhibitors (TKIs), such as cabozantinib and axitinib, are commonly used as the 2nd line therapy after 1st line IO combination therapy, but their efficacy as 2nd line TKI therapy for nccRCC is unknown. In this study, we performed a retrospective multicenter analysis of nccRCC patients who were previously treated with IO combination therapy and received 2nd line TKIs. METHODS: Among 254 patients enrolled in the Japanese multicenter retrospective study, 52 patients with nccRCC histology who received second-line TKIs were included in this study. Progression-free survival and overall survival (OS) from 2nd line TKIs were analyzed by log-rank test and Cox-proportional hazard model. Objective response rate (ORR) of 2nd line TKIs were analyzed. RESULTS: The 1-year PFS and OS rates were 25.0% (95% CI = 13.1-36.8) and 63.8% (95% CI, 48.0-75.9), respectively. No patients had a complete response, 11 had a partial response, and 18 had stable disease. ORR was 21.1%. IMDC poor risk and sunitinib as the 2nd line therapy were significantly associated with poor PFS. CONCLUSION: The 2nd-line TKI was effective for a small group of nccRCC patients previously treated with IO combination therapy, although this study was retrospectively analyzed with a small number of cases.

Sex differences in lower urinary tract function in mice with or without spinal cord injury.

OBJECTIVES: We examined sex differences of lower urinary tract function and molecular mechanisms in mice with and without spinal cord injury (SCI). METHODS: SCI was induced by Th8-9 spinal cord transection in male and female mice. We evaluated cystometrograms (CMG) and electromyography (EMG) of external urethral sphincter (EUS) at 6 weeks after SCI in spinal intact (SI) and SCI mice. The mRNA levels of Piezo2 and TRPV1 were measured in L6-S1 dorsal root ganglia (DRG). Protein levels of nerve growth factor (NGF) in the bladder mucosa was evaluated using an enzyme-linked immunosorbent assay. RESULTS: Sex differences were found in the EUS behavior during voiding as voiding events in female mice with or without SCI occurred during EUS relaxation periods without EUS bursting activity whereas male mice with or without SCI urinated during EUS bursting activity in EMG recordings. In both sexes, SCI decreased voiding efficiency along with increased tonic EUS activities evident as reduced EUS relaxation time in females and longer active periods of EUS bursting activity in males. mRNA levels of Piezo2 and TRPV1 of DRG in male and female SCI mice were significantly upregulated compared with SI mice. NGF in the bladder mucosa showed a significant increase in male and female SCI mice compared with SI mice. However, there were no significant differences in Piezo2 or TRPV1 levels in DRG or NGF protein levels in the bladder mucosa between male and female SCI mice. CONCLUSIONS: We demonstrated that female and male mice voided during EUS relaxation and EUS bursting activity, respectively. Also, upregulation of TRPV1 and Piezo2 in L6-S1 DRG and NGF in the bladder could be involved in SCI-induced lower urinary tract dysfunction in both sexes of mice.

Association of lung immune prognostic index with survival outcomes in patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab.

OBJECTIVE: Lung immune prognostic index is based on derived neutrophil-to-lymphocyte ratio and lactate dehydrogenase level. Lung immune prognostic index has reported association with survival outcomes in patients with various malignancies undergoing treatment with immune checkpoint inhibitors. However, the prognostic impact of pre-treatment lung immune prognostic index in patients with metastatic renal cell carcinoma receiving nivolumab plus ipilimumab treatment remains unclear. This study examines the association between lung immune prognostic index and outcomes in this setting. METHODS: We retrospectively evaluated 156 patients with metastatic renal cell carcinoma treated with nivolumab plus ipilimumab at eight institutions. We assessed the associations between pre-treatment lung immune prognostic index and survival outcomes including progression-free survival, second progression-free survival (PFS2), cancer-specific survival and overall survival. RESULTS: Patients were classified into good (n = 84, 54%), intermediate (n = 52, 33%) and poor (n = 20, 13%) lung immune prognostic index groups. Progression-free survival did not significantly differ between lung immune prognostic index groups, but there was significant difference in PFS2, cancer-specific survival and overall survival. In multivariable Cox proportional hazard analyses, high pre-treatment lung immune prognostic index was a significant predictor of poor PFS2 (vs. good group, intermediate group: P = 0.01 and poor group: P = 0.04) and poor overall survival (vs. good group, intermediate group: P = 0.01 and poor group: P < 0.01). Moreover, the patients with poor lung immune prognostic index had significantly poorer cancer-specific survival than those with good LIPI (P < 0.01). CONCLUSIONS: High pre-treatment LIPI is suggested by our results to be a significant independent predictor of poor prognosis in patients receiving nivolumab plus ipilimumab for metastatic renal cell carcinoma.

Clinical outcomes and prognostic factors in metastatic nonclear cell renal cell carcinoma treated with immuno-oncology combination therapy.

BACKGROUND: Metastatic nonclear cell renal cell carcinoma (nccRCC) is a heterogeneous disease with poor prognosis. The clinical characteristics and prognostic factors of immuno-oncology (IO) combination therapy for nccRCC are not well known. This study analyzed patients with metastatic nccRCC treated with IO combination therapy. METHODS: We retrospectively collected data from 447 patients with metastatic RCC treated with IO-based combination therapy as first-line treatment between September 2018 and July 2023 in a Japanese multicenter study. The primary endpoints were objective response rate, progression-free survival (PFS), and overall survival (OS), comparing groups treated with IO-IO and IO-tyrosine kinase inhibitor (TKI) therapies. RESULTS: Seventy-five patients with metastatic nccRCC were eligible for analysis: 39 were classified into the IO-IO group and 36 into the IO-TKI group. Median PFS was 5.4 months (95% CI: 1.6-9.1) for the IO-IO group and 5.6 (95% CI: 3.4-12.0) for the IO + TKI group. Median OS was 24.2 months (95% CI: 7.5-NA) for the IO-IO group and 23.4 (95% CI: 18.8-NA) for the IO + TKI group, with no significant difference. In univariate analysis, International Metastatic Renal Cell Carcinoma Database Consortium scores, Karnofsky performance status, neutrophil-to-lymphocyte ratio, and the presence of liver metastases were significantly associated with OS, whereas in multivariate analysis, only the presence of liver metastases was significantly associated with OS (P = .035). CONCLUSIONS: There was no significant difference in OS or PFS between IO-IO and IO-TKI combination therapy as first-line treatment for patients with nccRCC. Liver metastasis is a poor prognostic factor for such patients.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Real-world outcomes in patients with metastatic castration-resistant prostate cancer beyond progression after upfront androgen receptor signaling inhibitor.

BACKGROUND: Upfront androgen receptor signaling inhibitor (ARSI) along with androgen deprivation therapy is the current standard of care for metastatic castration-sensitive prostate cancer. However, evidence on second-line therapy after upfront ARSI is scarce. We aimed to evaluate the oncological outcome of ARSI versus docetaxel (DOC) after upfront ARSI therapy in a real-world clinical practice. METHODS: Subjects were metastatic castration-resistant prostate cancer (mCRPC) patients who had progressed within 2 years of upfront ARSI therapy and received ARSI (ARSI group) or DOC (DOC group) as a second-line therapy. Second-line progression-free survival (second-line PFS), and second-line overall survival (second-line OS) were assessed. Propensity score matching (PSM) was used to adjust the clinicopathological features and treatment patterns. RESULTS: A total of 101 mCRPC patients, 68 in the ARSI group, and 33 in the DOC group, were included in this analysis. Median second-line PFS was 6.3 months in the ARSI group and 4.9 months in the DOC group (p = 0.21). Median second-line OS was 25.0 months in the ARSI group and 14.2 months in the DOC group (p = 0.06). Prostate-specific antigen nadir ≤ 0.2 ng/ml during upfront ARSI therapy was significantly associated with improved second-line PFS. After PSM, no significant difference in second-line PFS and second-line OS were observed between the two groups. CONCLUSION: ARSI or DOC has comparable oncologic outcomes in terms of second-line PFS and second-line OS. Further prospective research with longer follow-ups will be needed to identify the optimal treatment after upfront ARSI therapy.

Clinical outcomes of first-line combination therapy with immune checkpoint inhibitor for metastatic non-clear cell renal cell carcinoma: a multi-institutional retrospective study in Japan.

BACKGROUND: In metastatic clear cell renal cell carcinoma (ccRCC), recent studies have shown promising efficacy of immune checkpoint inhibitor (ICI) combination therapy. However, there are insufficient evidences about clinical efficacy and safety of ICI combination therapy in metastatic non-ccRCC (nccRCC). METHODS: We retrospectively investigated 44 patients treated with nivolumab plus ipilimumab (ICI + ICI group) or anti-PD-1/PD-L1 inhibitor plus tyrosine kinase inhibitors (TKI) (ICI + TKI group), and assessed clinical efficacy in both groups. RESULTS: Of all patients, overall response rate and disease control rate for ICI combination treatments were 36.3% and 75%, respectively. The median progression-free survival (PFS) and overall survival (OS) was 8.8 and 23.9 months, respectively. Multivariate analysis revealed that the presence of liver metastasis significantly affected worse PFS and OS (p = 0.035 and p = 0.049). Importantly, PFS and OS seemed similar in ICI + ICI group and ICI + TKI group (p = 0.778 and p = 0.559). Although the discontinuation rate of the combination therapy due to adverse effects in patients aged ≥ 75 years was significantly higher compared to that in patients aged < 75 years (45% versus 12%, p = 0.017), there were no significant differences in PFS and OS between two groups (p = 0.290 and p = 0.257, respectively). CONCLUSION: This study confirms clinical benefit of ICI combination therapy for metastatic nccRCC patients in real-world settings. Furthermore, the effectiveness of combination therapy was comparable between patients aged < 75 and those ≥75 years with respect to clinical prognosis.

Iodine-125 low-dose rate prostate brachytherapy.

Robotic-assisted laparoscopic radical prostatectomy and intensity-modulated radiation therapy are the most common radical treatments for localized prostate cancer, and brachytherapy (BT) also plays a role in this field. Iodine-125 (I-125) low-dose rate (LDR) prostate BT is an established treatment. However, it remains controversial. Specifically, there are a variety of issues, such as indications for combined treatment with external beam radiotherapy and androgen deprivation therapy, prostate-specific antigen follow-up, the significance of postimplant biopsy, the usefulness of salvage BT and focal therapy, reduction of toxicities, and bladder cancer after BT. In this review, we summarize the recent developments in I-125 LDR BT.

Urinary markers for bladder cancer diagnosis: A review of current status and future challenges.

Bladder cancer is a common urological cancer with a high recurrence rate that requires long-term follow-up, and early detection positively affects prognosis. To date, the initial diagnosis and follow-up for bladder cancer rely on cystoscopy, which is an invasive and expensive procedure. Therefore, urinary markers for the detection of bladder cancer have attracted research attention for decades to reduce unnecessary cystoscopies. Urine, which is in continuous contact with bladder cancer, is considered a suitable fluid for providing tumor information. Urinary cytology is the only widely used urinary marker in clinical practice; however, it has poor sensitivity for low-grade tumors; indicating the need for novel urinary markers. Considerable research has been conducted on this topic over the years, resulting in a complex landscape with a wide range of urinary markers, including protein-, exfoliated cell-, RNA-, DNA-, and extracellular vesicle-based markers. Although some of these markers have been approved by the U.S. Food and Drug Administration and are commercially available, their use in clinical practice is limited. To facilitate clinical application, potential urinary markers must withstand prospective clinical trials and be easy for patients and clinicians to understand and utilize in a clinical context. This review provides a comprehensive overview of currently available and recently reported promising urinary markers for bladder cancer. Additionally, the challenges and the prospects of these urinary markers for clinical implementation in bladder cancer treatment were discussed.

Moving toward improved immune checkpoint immunotherapy for advanced prostate cancer.

Human prostate cancer is a heterogenous malignancy that responds poorly to immunotherapy targeting immune checkpoints. The immunosuppressive tumor microenvironment that is typical of human prostate cancer has been the main obstacle to these treatments. The effectiveness of these therapies is also hindered by acquired resistance, leading to slow progress in prostate cancer immunotherapy. Results from the highly anticipated late-stage clinical trials of PD-1/PD-L1 immune checkpoint blockade in patients with advanced prostate cancer have highlighted some of the obstacles to immunotherapy. Despite the setbacks, there is much that has been learned about the mechanisms that drive resistance, and new strategies are being developed and tested. Here, we review the status of immune checkpoint blockade and the immunosuppressive tumor microenvironment and discuss factors contributing to innate and adaptive resistance to immune checkpoint blockade within the context of prostate cancer. We then examine current strategies aiming to overcome these challenges as well as prospects.

Real world evidence of enfortumab vedotin in patients with advanced urothelial cancer: A multicenter observational study.

OBJECTIVES: To explore the characteristics of patients and assess the effectiveness of enfortumab vedotin (EV) in those with treatment-resistant advanced urothelial cancer in a real-world setting. PATIENTS AND METHODS: A multicenter observational study was conducted on 103 evaluable patients with advanced urothelial cancer who received EV. Outcomes were assessed by radiographic response, progression-free survival (PFS), and overall survival (OS), with treatment-related adverse events (trAEs). Radiographic response was assessed using Response Evaluation Criteria in Solid Tumors version 1.1, while trAEs were studied in line with Common Terminology Criteria for Adverse Events version 5.0. RESULTS: The median follow-up was 8.9 months (range, 0.1-16.4). The observed objective response rate was 50.5%. The median PFS was 6.0 months (95% CI: 4.7-9.8), and the median OS was 14.5 months (95% CI: 12.4-not reached). Out of the 103 patients, 19 (18.4%) had an Eastern Cooperative Oncology Group performance status of 2 or more, 14 (14.7%) had an non-urothelial carcinoma histology, and 40 (38.3%) had at least one pre-existing comorbidity. There were 26 (25.2%) patients who reported 49 trAEs, with 9 (18.3%) being grade 3 or higher. The most common trAEs included rash, occurring in 18.4%. CONCLUSIONS: This study describes the characteristics and outcomes of patients with previously treated advanced urothelial cancer receiving EV. The findings demonstrate that EV showed robust anti-tumor activity and had manageable safety profiles outside the clinical trial setting.

J-AVENUE: A retrospective, real-world study evaluating patient characteristics and outcomes in patients with advanced urothelial carcinoma treated with avelumab first-line maintenance therapy in Japan.

OBJECTIVES: The JAVELIN Bladder 100 phase 3 trial showed that avelumab first-line maintenance + best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with advanced urothelial carcinoma who were progression-free following first-line platinum-based chemotherapy. We report findings from J-AVENUE (NCT05431777), a real-world study of avelumab first-line maintenance therapy in Japan. METHODS: Medical charts of patients with advanced urothelial carcinoma without disease progression following first-line platinum-based chemotherapy, who received avelumab maintenance between February and November 2021, were reviewed. Patients were followed until June 2022. The primary endpoint was patient characteristics; secondary endpoints included time to treatment failure and progression-free survival. RESULTS: In 79 patients analyzed, median age was 72 years (range, 44-86). Primary tumor site was upper tract in 45.6% and bladder in 54.4%. The most common first-line chemotherapy regimen was cisplatin + gemcitabine (63.3%). Median number of chemotherapy cycles received was four. Best response to chemotherapy was complete response in 10.1%, partial response in 58.2%, and stable disease in 31.6%. Median treatment-free interval before avelumab was 4.9 weeks. With avelumab first-line maintenance therapy, the disease control rate was 58.2%, median time to treatment failure was 4.6 months (95% CI, 3.3-6.4), and median progression-free survival was 6.1 months (95% CI, 3.6-9.7). CONCLUSIONS: Findings from J-AVENUE show the effectiveness of avelumab first-line maintenance in patients with advanced urothelial carcinoma in Japan in clinical practice, with similar progression-free survival to JAVELIN Bladder 100 and previous real-world studies, supporting its use as a standard of care.

Prognostic outcomes in patients with metastatic renal cell carcinoma receiving second-line treatment with tyrosine kinase inhibitor following first-line immune-oncology combination therapy.

OBJECTIVES: This study aimed to assess the prognostic outcomes in mRCC patients receiving second-line TKI following first-line IO combination therapy. METHODS: This study retrospectively included 243 mRCC patients receiving second-line TKI after first-line IO combination therapy: nivolumab plus ipilimumab (n = 189, IO-IO group) and either pembrolizumab plus axitinib or avelumab plus axitinib (n = 54, IO-TKI group). Oncological outcomes between the two groups were compared, and prognostication systems were developed for these patients. RESULTS: In the IO-IO and IO-TKI groups, the objective response rates to second-line TKI were 34.4% and 25.9% (p = 0.26), the median PFS periods were 9.7 and 7.1 months (p = 0.79), and the median OS periods after the introduction of second-line TKI were 23.1 and 33.5 months (p = 0.93), respectively. Among the several factors examined, non-CCRCC, high CRP, and low albumin levels were identified as independent predictors of both poor PFS and OS by multivariate analyses. It was possible to precisely classify the patients into 3 risk groups regarding both PFS and OS according to the positive numbers of the independent prognostic factors. Furthermore, the c-indices of this study were superior to those of previous systems as follows: 0.75, 0.64, and 0.61 for PFS prediction and 0.76, 0.70, and 0.65 for OS prediction by the present, IMDC, and MSKCC systems, respectively. CONCLUSIONS: There were no significant differences in the prognostic outcomes after introducing second-line TKI between the IO-IO and IO-TKI groups, and the histopathology, CRP and albumin levels had independent impacts on the prognosis in mRCC patients receiving second-line TKI, irrespective of first-line IO combination therapies.

Deep Learning-Based Differential Diagnosis of Follicular Thyroid Tumors Using Histopathological Images.

Deep learning systems (DLSs) have been developed for the histopathological assessment of various types of tumors, but none are suitable for differential diagnosis between follicular thyroid carcinoma (FTC) and follicular adenoma (FA). Furthermore, whether DLSs can identify the malignant characteristics of thyroid tumors based only on random views of tumor tissue histology has not been evaluated. In this study, we developed DLSs able to differentiate between FTC and FA based on 3 types of convolutional neural network architecture: EfficientNet, VGG16, and ResNet50. The performance of all 3 DLSs was excellent (area under the receiver operating characteristic curve = 0.91 ± 0.04; F1 score = 0.82 ± 0.06). Visual explanations using gradient-weighted class activation mapping suggested that the diagnosis of both FTC and FA was largely dependent on nuclear features. The DLSs were then trained with FTC images and linked information (presence or absence of recurrence within 10 years, vascular invasion, and wide capsular invasion). The ability of the DLSs to diagnose these characteristics was then determined. The results showed that, based on the random views of histology, the DLSs could predict the risk of FTC recurrence, vascular invasion, and wide capsular invasion with a certain level of accuracy (area under the receiver operating characteristic curve = 0.67 ± 0.13, 0.62 ± 0.11, and 0.65 ± 0.09, respectively). Further improvement of our DLSs could lead to the establishment of automated differential diagnosis systems requiring only biopsy specimens.

Diagnostic Accuracy of Clinical Lymph Node Staging for Upper Tract Urothelial Cancer Patients: A Multicenter, Retrospective, Observational Study.

PURPOSE: Treatment options for the management of upper tract urothelial cancer are based on accurate staging. However, the performance of conventional cross-sectional imaging for clinical lymph node staging (N-staging) remains poorly investigated. This study aims to evaluate the diagnostic accuracy of conventional cross-sectional imaging for upper tract urothelial cancer N-staging. MATERIALS AND METHODS: This study was a multicenter, retrospective, observational study. We included 865 nonmetastatic (M0) upper tract urothelial cancer patients treated with curative intended surgery and lymph node dissection who had been staged with conventional cross-sectional imaging before surgery. We compared clinical (c) and pathological (p) N-staging results to evaluate the concordance of node-positive (N+) and node-negative (N0) disease and calculate cN-staging's diagnostic accuracy. RESULTS: Conventional cross-sectional imaging categorized 750 patients cN0 and 115 cN+. Lymph node dissection categorized 641 patients pN0 and 224 pN+. The cN-stage was pathologically downstaged in 6.8% of patients, upstaged in 19%, and found concordant in 74%. The sensitivity and specificity of cN-staging were 25% (95% CI 20; 31) and 91% (95% CI 88; 93). Positive and negative likelihood ratios were 2.7 (95% CI 2.0; 3.8) and 0.83 (95% CI 0.76; 0.89). The area under the receiver operating characteristics curve (0.58, 95% CI 0.55; 0.61) revealed low diagnostic accuracy. CONCLUSIONS: Conventional cross-sectional imaging had low sensitivity in detecting upper tract urothelial cancer pN+ disease. However, cN+ increased the likelihood of pN+ by almost threefold. Thus, conventional cross-sectional imaging is a rule-in but not a rule-out test. Lymph node dissection should remain the standard during extirpative upper tract urothelial cancer surgery to obtain accurate N-staging. cN+ could be a strong argument for early systemic treatment.

Current status and future perspectives of the managements of metastatic hormone-sensitive prostate cancer.

PURPOSE: The therapeutic landscape for metastatic hormone-sensitive prostate cancer (mHSPC) has changed dramatically. Here, we provide the current status and future prospective of the management of mHSPC. METHODS: We reviewed recent literature of landmark studies on the managements of mHSPC. RESULTS: Upfront docetaxel or androgen receptor signaling inhibitor (ARSi) in addition to ADT has improved survival in mHSPC patients and has become the new standard of care. Triplet therapy with docetaxel, ARSi and ADT also improved survival. In the future, triplet therapy may become the standard of care. Oligometastatic mHSPC patients could benefit from local therapy. The inclusion of risk factors or the genetic biomarkers will provide the best treatment for individual mHSPC patients. CONCLUSION: Strong systemic therapy in the first-line treatment of mHSPC has been shown to improve survival and quality of life. Currently, several clinical trials are evaluating novel compounds such as PARP inhibitor, AKT inhibitor, and immune checkpoint inhibitor. The therapeutic landscape of mHSPC management will change dramatically.

External beam radiotherapy combination is a risk factor for bladder cancer in patients with prostate cancer treated with brachytherapy.

PURPOSE: To investigate the risk of bladder cancer (BCa) in patients treated with brachytherapy for prostate cancer (PCa). METHODS: We retrospectively analyzed 583 patients with PCa who underwent brachytherapy with or without external beam radiotherapy (EBRT). We analyzed the disease-free survival (DFS) of BCa in patients with PCa who underwent brachytherapy with or without EBRT. We performed multivariate Cox regression analyses of DFS using age, EBRT, and Brinkman index (BI) score (number of cigarettes smoked per day × number of years smoking) ≥ 200 as variables for BCa after brachytherapy. RESULTS: Fourteen patients (2.4%) developed BCa after brachytherapy with or without EBRT. The percentage of high-grade urothelial carcinoma (UC) was 63.6%. A total of 85.7% of patients had non-muscle invasive BCa, and 14.3% of patients had muscle invasive BCa. DFS was longer in brachytherapy monotherapy than in combination therapy (brachytherapy + EBRT). Multivariate Cox regression analysis showed that a BI score ≥ 200 (Hazard Ratio (HR 8.61; 95% Confidence Interval (CI) 1.12-65.98) and EBRT combination (HR 3.29; 95% CI 1.03-10.52) were significantly associated with BCa development in patients with PCa treated with brachytherapy. Furthermore, patients with BI score ≥ 200 and EBRT combination had a significantly higher risk of BCa compared with patients with BI score < 200 (HR Log-rank test P = 0.010). CONCLUSION: Most cases of BCa after brachytherapy with or without EBRT are high grade and invasive. We hypothesized that the EBRT combination might be a risk factor for BCa in patients with PCa who underwent brachytherapy.

Increased toxicities associated with dose escalation of stereotactic body radiation therapy in prostate cancer: results from a phase I/II study.

BACKGROUND: This dose-escalation study evaluated the toxicity and efficacy of different stereotactic body radiation therapy (SBRT) doses for selecting an optimal dose for prostatic adenocarcinoma (PCa). MATERIALS AND METHODS: This clinical trial was registered at UMIN (UMIN000014328). Patients with low- or intermediate-risk PCa were equally assigned to 3 SBRT dose levels: 35, 37.5, and 40 Gy per 5 fractions. The primary endpoint was the occurrence rate of late grade ≥2 genitourinary (GU) and gastrointestinal (GI) adverse events at 2 years, while the secondary endpoint was the 2-year biochemical relapse-free (bRF) rate. Adverse events were evaluated using the Common Terminology Criteria for Adverse Events version 4.0. RESULTS: Seventy-five patients (median age, 70 years) were enrolled from March 2014 to January 2018, of whom 10 (15%) and 65 (85%) had low- and intermediate-risk PCa, respectively. The median follow-up time was 48 months. Twelve (16%) patients received neoadjuvant androgen deprivation therapy. The 2-year occurrence rates of grade 2 late GU and GI toxicities were 34 and 7% in all cohorts, respectively (35 Gy: 21 and 4%; 37.5 Gy: 40 and 14%; 40 Gy: 42 and 5%). The occurrence risk of GU toxicities significantly increased with dose escalation (p = 0.0256). Grades 2 and 3 acute GU toxicities were observed in 19 (25%) and 1 (1%), respectively. Grade 2 acute GI toxicity was observed in 8 (11%) patients. No grade ≥3 GI or ≥4 GU acute toxicity or grade ≥3 late toxicity was observed. Clinical recurrence was detected in 2 patients. CONCLUSIONS: An SBRT dose of 35 Gy per 5 fractions is less likely to cause adverse events in patients with PCa than 375- and 40-Gy SBRT doses. Higher doses of SBRT should be applied with caution.