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Abstract: Adrenocortical carcinoma (ACC) is an extremely rare and aggressive endocrine malignancy with a poor prognosis. The most common symptom of ACC is hypercortisolism (Cushing''s syndrome), which has the highest mortality. Mitotane is used as a steroidogenesis inhibitor for Cushing''s syndrome or as a chemical adrenalectomy drug for ACC. Mitotane induces adrenal cortex necrosis, mitochondrial membrane impairment, and irreversible binding to CYP proteins. In this study, we explored the molecular effect of mitotane on steroidogenesis in human adrenocortical cancer NCI-H295 cells. Mitotane (10–40μM) inhibited basal and cAMP-induced cortisol secretion but did not cause cell death. Mitotane exhibited an inhibitory effect on the basal expression of StAR and P450scc protein. Furthermore, 40μM of mitotane significantly diminished StAR, CYP11A1 and CYP21 mRNA expression. HSD3B2 and CYP17 seem to be insensitive to mitotane. The stimulatory effects of mitotane on CYP11B1 were more remarkable than its inhibitory effects. In contrast, the activation of cAMP signaling strongly elevated the expression of all these genes. Mitotane (40μM) almost completely neutralized this positive effect and returned 8-Br-cAMP-induced StAR, CYP11A1, CYP17 and CYP21 mRNA to control levels. After cAMP activation, mitotane did not change the levels of CYP11B1 mRNA. The present study demonstrates that mitotane can inhibit cortisol biosynthesis due to a non-specific interference with the gene transcription of steroidogenic enzymes under both basal and 8-Br-cAMP-activated conditions in NCI-H295 cells. We also identified that StAR and CYP11A1 key enzymes that participate in the rate-limiting step of steroidogenesis, were more sensitive to mitotane. In addition, the biphasic effect of mitotane on CYP11B1 was also elucidated. [Copyright &y& Elsevier]

Background: The first interim analysis of the KEYNOTE-564 study showed improved disease-free survival with adjuvant pembrolizumab compared with placebo after surgery in patients with clear cell renal cell carcinoma at an increased risk of recurrence. The analysis reported here, with an additional 6 months of follow-up, was designed to assess longer-term efficacy and safety of pembrolizumab versus placebo, as well as additional secondary and exploratory endpoints.Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 KEYNOTE-564 trial, adults aged 18 years or older with clear cell renal cell carcinoma with an increased risk of recurrence were enrolled at 213 hospitals and cancer centres in North America, South America, Europe, Asia, and Australia. Eligible participants had an Eastern Cooperative Oncology Group performance status of 0 or 1, had undergone nephrectomy 12 weeks or less before randomisation, and had not received previous systemic therapy for advanced renal cell carcinoma. Participants were randomly assigned (1:1) via central permuted block randomisation (block size of four) to receive pembrolizumab 200 mg or placebo intravenously every 3 weeks for up to 17 cycles. Randomisation was stratified by metastatic disease status (M0 vs M1), and the M0 group was further stratified by ECOG performance status and geographical region. All participants and investigators involved in study treatment administration were masked to the treatment group assignment. The primary endpoint was disease-free survival by investigator assessment in the intention-to-treat population (all participants randomly assigned to a treatment). Safety was assessed in the safety population, comprising all participants who received at least one dose of pembrolizumab or placebo. As the primary endpoint was met at the first interim analysis, updated data are reported without p values. This study is ongoing, but no longer recruiting, and is registered with ClinicalTrials.gov, NCT03142334.Findings: Between June 30, 2017, and Sept 20, 2019, 994 participants were assigned to receive pembrolizumab (n=496) or placebo (n=498). Median follow-up, defined as the time from randomisation to data cutoff (June 14, 2021), was 30·1 months (IQR 25·7-36·7). Disease-free survival was better with pembrolizumab compared with placebo (HR 0·63 [95% CI 0·50-0·80]). Median disease-free survival was not reached in either group. The most common all-cause grade 3-4 adverse events were hypertension (in 14 [3%] of 496 participants) and increased alanine aminotransferase (in 11 [2%]) in the pembrolizumab group, and hypertension (in 13 [3%] of 498 participants) in the placebo group. Serious adverse events attributed to study treatment occurred in 59 (12%) participants in the pembrolizumab group and one (<1%) participant in the placebo group. No deaths were attributed to pembrolizumab.Interpretation: Updated results from KEYNOTE-564 support the use of adjuvant pembrolizumab monotherapy as a standard of care for participants with renal cell carcinoma with an increased risk of recurrence after nephrectomy.Funding: Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA. [ABSTRACT FROM AUTHOR]

In the phase 3 KEYNOTE-564 study (NCT03142334), adjuvant pembrolizumab prolonged disease-free survival (DFS) in patients with clear cell renal cell carcinoma (ccRCC) at increased risk of recurrence after nephrectomy compared with placebo (DFS at 24 months: 77.3% vs 68.1%; hazard ratio [HR] for recurrence or death, 0.68; 95% CI, 0.53-0.87; P=0.002).;Continued DFS improvement with adjuvant pembrolizumab was observed after 30 months of follow-up. Results of a post hoc exploratory analysis of DFS in patient subgroups based on UCLA Integrated Staging System (UISS) risk groups and disease stage are reported. Patients with histologically confirmed ccRCC (pT2, grade 4 or sarcomatoid, N0, M0; pT3 or pT4, any grade, N0, M0; any pT, any grade, N+, M0; or M1 with no evidence of disease [NED]) were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg or placebo every 3 weeks for up to 17 cycles (∼1 year). DFS was assessed by investigator. UISS risk groups were derived retrospectively from TNM stage, Fuhrman nuclear grade, and Eastern Cooperative Oncology Group performance status (ECOG PS). UISS groups were intermediate risk (pT2, grade 4, N0, M0; pT3, grade 1, N0, M0; or pT3, grades 2-4, N0, M0, ECOG PS of 0), high risk (pT3, grades 2-4, N0, M0, ECOG PS 1; pT4, any grade, N0, M0; or N1, M0), or M1 NED. Other subgroups based on disease stage were also evaluated. Baseline characteristics were generally balanced within subgroups. Median follow-up was 30.1 months (range, 20.8-47.5). Of 994 enrolled patients, most had UISS intermediate risk (n = 732 [73.6%]; pembrolizumab, n = 359; placebo, n = 373); 195 patients (19.6%; pembrolizumab, n = 100; placebo, n = 95) had UISS high risk, and 58 patients (5.8%; pembrolizumab, n = 29; placebo, n = 29) had M1 NED. DFS favored pembrolizumab versus placebo in the UISS intermediate-risk group (HR, 0.65 [95% CI, 0.48-0.88]; 24-month rate: 81.5% vs 72.4%), UISS high-risk group (HR, 0.77 [95%;CI, 0.49-1.20]; 24-month rate: 65.0% vs 55.9%), and M1 NED group (HR, 0.28 [95% CI, 0.12-0.66]; 24-month rate: 78.4% vs 37.9%). DFS favored pembrolizumab versus placebo across all patient subgroups based on disease stage (Table). Consistent with the results of the intention-to-treat (ITT) population, adjuvant pembrolizumab prolonged DFS compared with placebo for all patient subgroups based on UISS risk groups and disease stage. Taken together with results in the ITT population, these results further support the use of adjuvant pembrolizumab as standard of care for patients with RCC at increased risk of recurrence after nephrectomy. ©2023 American Society of Clinical Oncology, Inc. Reused with permission. This abstract was accepted and previously presented at the 2023 Genitourinary Cancers Symposium. All rights reserved. [ABSTRACT FROM AUTHOR]

Objectives: To determine the association of a common variant, rs1447295, at the 8q24 region with prostate cancer (PCa) risk in Taiwanese men. Common variants at the 8q24 region have been shown to be associated with PCa risk. The variant rs1447295 has shown the strongest association. Most of the studies have been performed in European and American populations. Methods: This case-control study comprised 340 PCa patients and 337 controls. Genotyping was performed for rs14417295 to test for the association between its risk allele and PCa. Its association with disease stage, Gleason score, PSA level, and disease aggressiveness was also determined. Results: The A allele of rs1447295 was significantly associated with increased PCa risk (odds ratio = 1.49, 95% CI = 1.12-1.99). When compared with controls, the risk allele A was more frequent in PCa patients of both stages I+II (P = .028) and stages III+IV (P = .023), in patients of all Gleason scores (P < .05 in all subgroups), in patients with PSA levels >20 ng/mL (P = .001), and in patients with aggressive disease (P = .005). Conclusions: This study confirmed that the A allele of rs1447295 is associated with a high risk of PCa in Taiwanese men. [Copyright &y& Elsevier]

Objectives: Prostate cancer incidence varies significantly among different ethnic groups. However, little is known about the survival outcome among groups. We sought to compare the survival outcome in patients with metastatic prostate cancer among different ethnic groups and to identify independent prognostic factors affecting overall survival in Taiwanese patients. Methods: From January 1996 to February 2005, 482 men with newly diagnosed metastatic prostate adenocarcinoma were enrolled from five major medical centers in Taiwan. The cohort accounted for about 11.5% of all patients with metastatic disease during the period in Taiwan. The demographics, tumor characteristics, and survival outcome were compared with several published Western and Japanese series. Five series were selected from MEDLINE: the Southwest Oncology Group; Detroit Metropolitan Surveillance, Epidemiology, and End Results Program Registry; American College of Surgeons; National Cancer Registry in Sweden; and Gurma and Nagasaki University Group in Japan. Results: The Taiwanese patients were the oldest among the selected series. The median overall survival of our patients was 38.4 months (95% confidence interval 33 to 45 months), which was longer than that in the Western series (median 25 to 32 months) and similar to those in the Japanese series (median 36 months). In a multivariate analysis with age adjustment, bone pain, Gleason score 8 or greater, and visceral metastases independently predicted a reduced overall survival in our series compared with each favorable strata (hazard ratio 2.22, 1.96, and 1.51, respectively; all P <0.05). Conclusions: Taiwanese men with metastatic prostate cancer might have a better survival compared with Western men. [Copyright &y& Elsevier]

Objectives: The CYP19 gene encodes aromatase—a key enzyme involved in the conversion of androstenedione/testosterone to estrone/estradiol. In this study, we analyzed the association between the TCT insertion (Ins)/deletion (Del) and TTTA repeat polymorphisms of CYP19 and prostate cancer (PCa). Methods: Automated sequencer with GeneScan software was used to determine the CYP19 gene polymorphisms in peripheral blood mononuclear cell DNA from 244 patients with PCa and 261 age-matched healthy male controls. The distribution of Stage I to IV was 3.4%, 23.8%, 19.6%, and 53.2%, respectively. The Gleason score was 2 to 5 in 22.9%, 6 to 7 in 53.2%, and 8 to 10 in 23.8%. Results: The frequency of the TCT Del/Del genotype in the Taiwanese patients with PCa (12.3%) was significantly greater than that in the controls (5.4%; P = 0.015, odds ratio [OR] 2.43, 95% confidence interval [CI] 1.23 to 4.80). Individuals with a homozygous A1 (seven TTTA repeats) genotype had a significantly greater risk of developing PCa (OR 1.59, 95% CI 1.04 to 2.44, P = 0.044). The frequency of the Ins-A6 (12 TTTA repeats) haplotype was significantly greater in the control group than in the patient group (9.8% versus 6.1%, OR 0.61, 95% CI 0.38 to 0.97). The OR of developing PCa for men with the homozygous Del-A1 diplotype was 2.31 (95% CI 1.10 to 4.83). Conclusions: The results of our study have shown that the CYP19 TCT Del/Del genotype might be a susceptibility marker for PCa. Men with the Ins-A6 haplotype had a lower risk of developing PCa. [Copyright &y& Elsevier]

Objectives. Unusually high incidences of upper urinary tract urothelial carcinoma (UUT-UC) have been reported from the endemic area for “blackfoot disease” of southern Taiwan, and the arsenic-contaminated water was considered to be the reason for this prevalence. In this study, we determined the ratio of UC in different locations, the difference in clinical profiles for UUT-UC and urinary-bladder urothelial carcinoma (UB-UC), and the influence of tumor location on survival in a medical center of northern Taiwan.Methods. A total of 535 patients with pathologically proven UC were reviewed retrospectively in this study, and clinical data were recorded from pathologic and chart reviews. Statistical analyses to determine the association between tumor location and clinical variables, and stratified survival analyses to determine the effect of tumor location on survival were performed.Results. The incidence of UUT-UC was relatively high (the ratio of renal pelvis/ureter/urinary bladder was 1:2.08:6.72), even though most of the patients did not reside in the endemic “blackfoot disease” area. Young age, female sex, higher T stage, and elevated pretreatment serum lactate dehydrogenase and creatinine level were significantly associated with UUT-UC after multivariate logistic regression analysis. Tumor location influenced survival in patients with early-stage disease or favorable prognostic factors.Conclusions. Factors other than arsenic water contamination may contribute to the unusually high incidence of UUT-UC in the non-“blackfoot disease” area in Taiwan. UUT-UC carried a more aggressively clinical behavior than UB-UC; tumor location influences patient survival markedly in patients with early-stage disease or favorable prognostic factors. [Copyright &y& Elsevier]

Objectives. To develop a prognostic-factors-based predictive model for invasive urothelial carcinoma of the urinary bladder derived from statistical comparison of clinical characteristics.Methods. The medical records for patients with invasive urinary bladder urothelial carcinoma were reviewed. Clinical data for age, sex, serum lactate dehydrogenase, creatinine, albumin, alkaline phosphatase, alanine aminotransferase, total bilirubin and hemoglobin levels, white blood cell and platelet counts, positive urine cytology, Eastern Cooperative Oncology Group performance status score, tumor size, histologic grading, T stage, presence of lymph node metastases, squamous differentiation, hydronephrosis, prostatic involvement, Charlson comorbidity index, surgical procedures, and adjuvant chemotherapy status were recorded. Univariate and multivariate analyses were performed to test independent factors for prediction of survival and disease recurrence.Results. After univariate and multivariate analyses, six independent prognostic factors were found: T stage, grading, prostatic involvement, Eastern Cooperative Oncology Group performance status score, and pretreatment serum creatinine and albumin levels. A scoring system was developed on the basis the relative risk associated with the proposed prognostic factors and patients were stratified into three groups according to their scores, with statistically significant prognostic differences revealed for each of the between-group comparisons. Independent factors affecting recurrence-free survival and best predicted disease recurrence were pretreatment serum creatinine, T stage, and surgical procedure.Conclusions. This prognostic-factors-based risk-stratification model for invasive urothelial carcinoma of the urinary bladder may help clinicians predict outcome and select the most appropriate therapeutic modalities. The incidence of recurrent disease is significantly higher for patients with poor renal function before treatment or advanced T stage and those undergoing transurethral tumor resection instead of radical cystectomy. [Copyright &y& Elsevier]