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ABSTRACT Background Venous thromboembolism (VTE) may jeopardise excellent treatment results of germ cell tumours (GCT). We previously constructed a VTE risk score for GCT patients qualified for first‐line chemotherapy (CTH), including vein compression, clinical stage (CS) and haemoglobin concentration. Aim Validating our score in a separate cohort and establishing the cut‐off point for the score. Re‐assessing the numerical score in the training cohort. Materials and Methods We retrospectively analysed a new cohort of GCT patients staged IS–IIIC. Area under the curve of receiver‐operating characteristic (AUC‐ROC) was calculated for the developed score, Khorana Risk Score (KRS) and Padua Prediction Score (PPS). AUC‐ROC of the integer score was calculated for the training cohort. Cut‐off point was established by Youden's and Liu's indices. Results Among 336 eligible patients in the validation cohort, VTE occurred in 41 (12.2%). AUC‐ROC for our score, KRS and PPS were 0.818 (95% confidence interval (CI): 0.746–0.891), 0.608 (0.529–0.688) and 0.634 (0.547–0.720), respectively, p

Abstract Background Germ cell tumours (GCT) are highly curable malignancies. Venous thromboembolism (VTE) is a serious complication, needing better risk assessment models (RAM). Aim Identification of VTE incidence and risk factors in metastatic GCT patients starting first‐line chemotherapy. Developing a RAM and comparing it to Khorana risk score (KRS) and Padua Prediction Score (PPS). Material and methods We retrospectively analysed GCT patients staged IS–IIIC. VTE risk factors were identified with logistic regression. Area under curve of receiver operating characteristic (AUC‐ROC), Akaike and Bayesian Information Criteria (AIC, BIC) were calculated for the developed RAM, KRS and PPS. Results Among 495 eligible patients, VTE occurred in 69 (13.9%), including 40 prior to chemotherapy. Vein compression (OR: 8.96; 95% CI: 2.85–28.13; p 5 (OR 8.05; 95% CI 3.79–17.13; p

Testicular germ cell tumours (GCT) represent about 1–2% of malignant in men. The essential therapeutic option for early-stage GCT is radical orchiectomy (RO), except in situ ations that require immediate chemotherapy in patients with a massive dissemination and unequivocally elevated levels of tumour markers. Postoperative radiotherapy (PORT) in patients with testicular seminoma in Clinical Stage I (CS I) is one of the treatment options next to active surveillance (AS) and chemotherapy (CHTH). Regardless of the procedure, five-year survival in this group of patients ranges between 97% and 100%. In the article, we present the literature review pertinent to therapeutic options, with a focus on radiotherapy. We have searched MEDLINE (PubMed) for all studies on patients with GCT treated with radiation therapy during the last 20 years, and the current therapeutic recommendations. We used the following keywords: germ cell tumours, testis, seminoma, non-seminoma, radiotherapy, outcome.

Retinoic acid is a promising tool in adjuvant cancer therapies, including refractory thyroid cancer, and its biological role is mediated by the retinoic acid receptor beta (RARβ). However, expression of RARβ is lowered in papillary thyroid carcinoma (PTC), contributing to promotion of tumor growth and inefficiency of retinoic acid and radioactive iodine treatment. The causes of aberrant RARB expression are largely unknown. We hypothesized that the culpable mechanisms include the action of microRNAs from the miR-146 family, previously identified as significantly upregulated in PTC tumors. To test this hypothesis, we assessed the expression of RARB as well as miR-146a-5p and miR-146b-5p in 48 PTC tumor/normal tissue pairs by Taqman assay to reveal that the expression of RARB was 3.28-fold decreased, and miR-146b-5p was 28.9-fold increased in PTC tumors. Direct interaction between miRs and RARB was determined in the luciferase assay and further confirmed in cell lines, where overexpression of miR-146a-5p and miR-146b-5p caused a 31% and 33% decrease in endogenous RARB mRNA levels. Inhibition of miR-146a and miR-146b resulted in 62.5% and 45.4% increase of RARB, respectively, and a concomitant decrease in proliferation rates of thyroid cancer cell lines, analyzed in xCELLigence system.We showed that two microRNAs of the miR-146 family directly regulate RARB. Inhibition of miRs resulted in restoration of RARB expression and decreased rates of proliferation of thyroid cancer cells. By restoring RARB levels, microRNA inhibitors may become part of an adjuvant therapy in thyroid cancer patients.

BACKGROUND: Neoadjuvant chemotherapy followed by radical cystectomy is the standard treat-dement for cisplatin-eligible patients with muscle-invasive bladder cancer. Adding perioperative immunotherapy may improve outcomes. METHODS: In this phase 3, open-label, randomized trial, we assigned, in a 1:1 ratio, cisplatin eligible patients with muscle-invasive bladder cancer to receive neoadjuvant dur-valumab plus gemcitabine-cisplatin every 3 weeks for four cycles, followed by radical cystectomy and adjuvant durvalumab every 4 weeks for eight cycles (durvalumab group), or to receive neoadjuvant gemcitabine-cisplatin followed by radical cystectonly alone (comparison group). Event-free survival was one of two primary end points. Overall survival was the key secondary end point. RESULTS: In total, 533 patients were assigned to the durvalumab group and 530 to the comparison group. The estimated event-free survival at 24 months was 67.8% (95% confidence interval [CI], 63.6 to 71.7) in the durvalumab group and 59.8°/0 (95°/0 CI, 55.4 to 64.0) in the comparison group (hazard ratio for progression, recurrence, not undergoing radical cystectomy, or death from any cause, 0.68; 95% CI, 0.56 to 0.82; P<0.001 by stratified log-rank test). The estimated overall survival at 24 months was 82.2% (95% CI, 78.7 to 85.2) in the durvalumab group and 75.2°/o (95% CI, 71.3 to 78.8) in the comparison group (hazard ratio for death, 0.75; 95% CI, 0.59 to 0.93; P=0.01 by stratified log-rank test). Treatment-related adverse events of grade 3 or 4 in severity occurred in 40.6% of the patients in the durvalumab group and in 40.9% of those in the comparison group; treatment-related adverse events leading to death occurred in 0.6°/0 in each group. Radical cystectomy was performed in 88.0% of the patients in the durvalumab group and in 83.2% of those in the comparison group. CONCLUSIONS: Perioperative durvalumab plus neoadjuvant chemotherapy led to significant improvements in event-free survival and overall survival as compared with neoadjuvant chemotherapy alone. [ABSTRACT FROM AUTHOR]

Background: Venous thromboembolism (VTE) may jeopardise excellent treatment results of germ cell tumours (GCT). We previously constructed a VTE risk score for GCT patients qualified for first-line chemotherapy (CTH), including vein compression, clinical stage (CS) and haemoglobin concentration., Aim: Validating our score in a separate cohort and establishing the cut-off point for the score. Re-assessing the numerical score in the training cohort., Materials and Methods: We retrospectively analysed a new cohort of GCT patients staged IS-IIIC. Area under the curve of receiver-operating characteristic (AUC-ROC) was calculated for the developed score, Khorana Risk Score (KRS) and Padua Prediction Score (PPS). AUC-ROC of the integer score was calculated for the training cohort. Cut-off point was established by Youden's and Liu's indices., Results: Among 336 eligible patients in the validation cohort, VTE occurred in 41 (12.2%). AUC-ROC for our score, KRS and PPS were 0.818 (95% confidence interval (CI): 0.746-0.891), 0.608 (0.529-0.688) and 0.634 (0.547-0.720), respectively, p < 0.001. The optimal cut-off point for a low/high risk was 6 (≤ 6 vs. ≥ 7). In the training cohort, 369 patients had complete data on vein compression. AUC-ROC for our score, KRS and PPS were 0.819 (95% CI: 0.758-0.879), 0.710 (0.637-0.782) and 0.725 (0.651-0.800), p ≤ 0.001 and 0.015, respectively. Positive and negative predictive values were 30.8% and 96.5%, respectively., Conclusions: Our VTE risk score is a handy tool for GCT patients before first-line CTH for metastatic disease. Outperforming KRS and PPS, it has a good discriminatory value, especially for identifying low-risk patients., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Study Aim: ModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450-3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone., Methods: 103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1.1 and PCWG3 guidelines were randomized 1:1 into two cohorts. In Cohort 1, 49 patients received docetaxel 75 mg/m 2 i.v. every 3 weeks (Q3W). In Cohort 2, 52 patients received ModraDoc006/r; 21 patients with a starting dose of ModraDoc006 30 mg with ritonavir 200 mg in the morning and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/200-100 mg) bi-daily-once-weekly (BIDW) on Days 1, 8, and 15 of a 21-day cycle. To alleviate tolerability, the starting dose was amended to ModraDoc006/r 20-20/200-100 mg in another 31 patients. All patients received prednisone 10 mg daily. Primary endpoint was rPFS., Results: There was no significant difference in rPFS between the 2 arms (p = 0.1465). Median rPFS was 9.5 months and 11.1 months (95% CI) for ModraDoc006/r and i.v. docetaxel, respectively. Partial response was noted in 44.1% and 38.7% measurable disease patients, and 50% decline of PSA was seen in 23 (50%) and 26 (56.5%) evaluable cases treated with ModraDoc006/r and i.v. docetaxel, respectively. The safety profile of ModraDoc006/r 20-20/200-100 mg dose was significantly better than i.v. docetaxel, with mild (mostly Grade 1) gastrointestinal toxicities, no hematologic adverse events, and neuropathy and alopecia incidence of 11.5% and 25%, respectively., Conclusions: ModraDoc006/r potentially represents a widely applicable, convenient, effective, and better tolerated oral taxane therapy option for mCRPC. Further investigation of ModraDoc006/r in a large randomized trial is warranted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Modra Pharmaceuticals BV was founded as a spin-off company of the Netherlands Cancer Institute, enabling the further clinical development of novel oral taxane formulations, after their pharmaceutical and preclinical development in the Netherlands Cancer Institute. Marianne Keessen is a full-time employee of Modra Pharmaceuticals BV. The other authors declare no relevant conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Germ cell tumours (GCT) are highly curable malignancies. Venous thromboembolism (VTE) is a serious complication, needing better risk assessment models (RAM)., Aim: Identification of VTE incidence and risk factors in metastatic GCT patients starting first-line chemotherapy. Developing a RAM and comparing it to Khorana risk score (KRS) and Padua Prediction Score (PPS)., Material and Methods: We retrospectively analysed GCT patients staged IS-IIIC. VTE risk factors were identified with logistic regression. Area under curve of receiver operating characteristic (AUC-ROC), Akaike and Bayesian Information Criteria (AIC, BIC) were calculated for the developed RAM, KRS and PPS., Results: Among 495 eligible patients, VTE occurred in 69 (13.9%), including 40 prior to chemotherapy. Vein compression (OR: 8.96; 95% CI: 2.85-28.13; p < 0.001), clinical stage IIIB-IIIC (OR: 5.68; 95% CI: 1.82-17.70; p = 0.003) and haemoglobin concentration (OR for 1 g/dL decrease: 1.32; 95% CI: 1.03-1.67; p = 0.026) were significant in our RAM. KRS ≥ 3 (OR: 3.31; 95% CI: 1.77-6.20; p < 0.001), PPS 4-5 (OR: 3.06; 95% CI: 1.49-6.29; p = 0.002) and PPS > 5 (OR 8.05; 95% CI 3.79-17.13; p < 0.001) correlated with VTE risk. Diagnostic criteria (AUC-ROC, AIC, BIC) for the developed RAM, KRS and PPS were (0.885; 0.567; -1641), (0.588; 0.839; -1576) and (0.700; 0.799; -1585), respectively. In the numerical score, the optimal cut-off point for high-risk was ≥9, with sensitivity, specificity, positive and negative predictive value of 0.78, 0.77, 0.35 and 0.96, respectively., Conclusions: Our RAM, based on vein compression, clinical stage and haemoglobin concentration proved superior to both KRS and PPS. VTE is frequent in GCT patients., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Immunotherapy-based combinations including pembrolizumab plus lenvatinib are the standard of care for patients with first-line clear-cell renal cell carcinoma, but these combinations are not well characterised in non-clear-cell renal cell carcinoma. We aimed to assess the activity and safety of pembrolizumab plus lenvatinib as a first-line treatment for patients with advanced non-clear-cell renal cell carcinoma., Methods: KEYNOTE-B61 is a single-arm, phase 2 trial being conducted at 48 sites (hospitals and cancer centres) in 14 countries (Australia, Canada, France, Hungary, Ireland, Italy, Poland, South Korea, Russia, Spain, Türkiye, Ukraine, the UK, and the USA). Adult patients (aged ≥18 years) with previously untreated stage IV non-clear-cell renal cell carcinoma and a Karnofsky performance status of 70% or higher were eligible for enrolment. All enrolled patients received pembrolizumab 400 mg intravenously every 6 weeks for up to 18 cycles (2 years) plus lenvatinib 20 mg orally once daily or until disease progression, unacceptable toxicity, or withdrawal; lenvatinib could be continued beyond 2 years. The primary endpoint was the proportion of patients with a confirmed objective response as per adjusted Response Evaluation Criteria in Solid Tumours (version 1.1) assessed by independent central review. Activity and safety were analysed in all patients who received at least one dose of study treatment (the as-treated population). This trial is registered with ClinicalTrials.gov (NCT04704219) and is no longer recruiting participants but is ongoing., Findings: Between Feb 23, 2021, and Jan 21, 2022, 215 patients were screened; 158 were enrolled and received treatment. Median age at baseline was 60 years (IQR 52-69), 112 (71%) of 158 patients were male, 46 (29%) were female, 128 (81%) were White, 12 (8%) were Asian, three (2%) were Black or African American, and 15 (9%) were missing data on race. As of data cutoff (Nov 7, 2022), median study follow-up was 14·9 months (IQR 11·1-17·4). 78 of 158 patients had a confirmed objective response (49%; 95% CI 41-57), including nine (6%) patients with a confirmed complete response and 69 (44%) with a confirmed partial response. Grade 3-4 treatment-related adverse events occurred in 81 (51%) of 158 patients, the most common of which were hypertension (37 [23%] of 158), proteinuria (seven [4%]), and stomatitis (six [4%]). Serious treatment-related adverse events occurred in 31 (20%) of 158 patients. Eight (5%) patients died due to adverse events, none of which was considered related to the treatment by the investigators (one each of cardiac failure, peritonitis, pneumonia, sepsis, cerebrovascular accident, suicide, pneumothorax, and pulmonary embolism)., Interpretation: Pembrolizumab plus lenvatinib has durable antitumour activity in patients with previously untreated advanced non-clear-cell renal cell carcinoma, with a safety profile consistent with that of previous studies. Results from KEYNOTE-B61 support the use of pembrolizumab plus lenvatinib as a first-line treatment option for these patients., Funding: Merck Sharp & Dohme (a subsidiary of Merck & Co, NJ, USA), and Eisai., Competing Interests: Declaration of interests LA reports consulting fees (paid to their institution) from Astellas, Bristol Myers Squibb, Ipsen, Janssen, Merck, MSD, Pfizer, Eisai, and Roche; and travel expenses from Bristol Myers Squibb, MSD, and Ipsen. HG has received honoraria from Pfizer and MSD; and participated on advisory boards for Pfizer, Merck Serono, MSD, Ipsen, Bristol Myers Squibb, and Astellas. CS has received research support from Ipsen; honoraria from Bristol Myers Squibb, Pfizer, Roche, Astellas, Ipsen, Sanofi, Bayer, and MSD; and travel support from Bristol Myers Squibb, Pfizer, Roche, Astellas, Ipsen, Sanofi, Bayer, and MSD. MAC has received honoraria from Bristol Myers Squibb, Roche, MSD, Ipsen, EUSA, AstraZeneca, Merck, Pfizer, Astellas, Janssen, and Bayer; and travel support from Astellas, Janssen, Bayer, Roche, MSD, Merck, and Pfizer. DP has received honoraria from Bayer and Merck/Pfizer; travel support from Merck/Pfizer and Janssen, and participated in advisory boards for Merck/Pfizer, Bristol Myers Squibb, and MSD. PB has received research support from MSD, Bristol Myers Squibb, Ipsen, Pfizer, Merck, AstraZeneca, and Janssen; consulting fees from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Amgen, Gilead, Eisai, and AstraZeneca; honoraria from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, Astellas, Bayer, Novartis, Eisai, and AstraZeneca; travel support from Bristol Myers Squibb, Ipsen, MSD, Merck, Pfizer, Janssen-Cilag, and Astellas; and participated on a data safety monitoring board or advisory board for Orion. JLL has received research support (paid to their institution) from Pfizer, Ipsen, Bristol Myers Squibb, MSD, Merck, Roche, Genentech, AstraZeneca, Amgen, SeaGen, and GI Innovation; participated on a data safety monitoring board or advisory board for Pfizer Korea, Astellas Korea, Bristol Myers Squibb, Merck, MSD, AstraZeneca, Amgen, and GI Innovation; and has stocks in Amgen, Johnson and Johnson, and Merck. VS has received research support from Merck Sharp & Dohme (a subsidiary of Merck & Co, Rahway, NJ, USA); honoraria from Pfizer Export BV, Stada-Ukraine, Kyiv Vitamin Plant, Astellas Pharma, PrJSC Pharmaceutical firm Darnytsia, and Pharma Personal Group Bionorica. TF has received research support from MSD; and travel support from Bayer and MSD. PW has received consulting fees and honoraria from Astellas Pharma and MSD, Bayer, Janssen Cilag, Ipsen, Pfizer, and Merck; travel support from Pfizer; and has participated on advisory boards for Astellas Pharma, MSD, Bayer, Janssen Cilag, Ipsen, Pfizer, and Merck. EG has received honoraria from Eli Lilly, Roche, Pfizer, Novartis, Janssen Oncology, Astellas Pharma, Amgen, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Sandoz-Novartis, Abdi Ibrahim, MSD Oncology, and Genekor; travel support from Roche, Pfizer, Novartis, Janssen Oncology, Astellas Pharma, AstraZeneca, Bristol Myers Squibb, Sciences, and Abdi Ibrahim; participated on advisory boards for Eli Lilly, Roche, Pfizer, Novartis, AstraZeneca, Bristol Myers Squibb, Gilead Sciences, Sandoz-Novartis, and MSD Oncology; and owns stock in ImmunoGen and MacroGenics. CG has received consulting fees from Cadex Genomics and BCAL Diagnostics, participated on a data safety monitoring board or advisory board for Alloplex Biotherapeutics, and was a member of a scientific advisory committee for Brain Cancer Biobanking Australia, Cooperative Trials Group for Neuro-Oncology, Australian and New Zealand Urogenital and Prostate Cancer Trials Group, Mark Hughes Foundation, and International Kidney Cancer Coalition. RFP, MS, and XP are employees of Merck & Co (Rahway, NJ, USA). C-HL has received research support (paid to institution) from Merck, Eisai, AstraZeneca, Bristol Myers Squibb, Calithera Biosciences, and Exelixis; consulting fees from Aveo, Bristol Myers Squibb, Exelixis, Eisai, Merck, Pfizer, EMD Serono, and Cardinal; honoraria from AiCME, IDEOlogy Health, Intellisphere, MJH Life Sciences, Medscape, and Research to Practice; and is on the medical steering committee for the Kidney Cancer Association. PT, LL, and VA declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Results of this double-blind, phase 2 trial showed patients with metastatic castration-resistant prostate cancer given olaparib plus abiraterone versus placebo plus abiraterone had significantly improved progression-free survival. Here, we present an exploratory analysis of pain and health-related quality of life (HRQOL)., Methods: This double-blind, randomised, placebo-controlled, phase 2 trial was conducted across 41 urological oncology sites in 11 countries in Europe and North America. Eligible patients were aged 18 years or older, had metastatic castration-resistant prostate cancer, and had previously received docetaxel and up to one additional line of previous chemotherapy. Metastatic castration-resistant prostate cancer was defined as increasing prostate-specific antigen (PSA) concentration or other signs of disease progression despite androgen-deprivation therapy and serum testosterone concentrations at castrate levels (≤50 ng/dL), and with at least one metastatic lesion on bone scan, CT, or MRI. Eligible patients were randomly assigned (1:1) to receive oral olaparib (300 mg twice per day) plus oral abiraterone (1000 mg once a day) and oral prednisone or prednisolone (5 mg twice a day) or placebo plus abiraterone (1000 mg once a day) and prednisone or prednisolone (5 mg twice a day). Randomisation was done without stratification and by use of an interactive voice or web response system. A randomised treatment kit ID number was assigned sequentially to each patient as they became eligible. The primary endpoint (radiographic progression-free survival) has previously been reported. HRQOL was a prespecified exploratory patient-reported outcome. Patients were asked to complete the Brief Pain Inventory-Short Form (BPI-SF), single-item worst bone pain, Functional Assessment of Cancer Therapy-Prostate (FACT-P) questionnaire, and EuroQol-5 five-dimension five level (EQ-5D-5L) assessment at baseline, at weeks 4, 8, and 12, then every 12 weeks until treatment discontinuation. Prespecified outcomes were change from baseline in BPI-SF worst pain, single-item worst bone pain and FACT-P Total Outcome Index (TOI) scale scores, time to deterioration in BPI-SF worst pain and worst bone pain, and assessment of the EQ-5D-5L pain and discomfort domain. All analyses were exploratory and done in the full analysis set (all randomly assigned patients, including patients who were randomly assigned but did not subsequently go on to receive study treatment), with the exception of mean baseline and total change from baseline analyses, for which we used the population who had a valid baseline and at least one post-baseline assessment. This trial is registered with Clinicaltrials.gov, NCT01972217, and is no longer recruiting patients., Findings: Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. 29 patients were excluded, and 142 were enrolled and randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). Data cutoff was Sept 22, 2017. Median follow-up was 15·9 months (IQR 8·1-25·5) in the olaparib plus abiraterone group and 24·5 months (8·1-27·6) in the placebo plus abiraterone group. Questionnaire compliance was generally high (43-100%). Least-squares mean changes from baseline in BPI-SF worst pain, single-item worst bone pain, and FACT-P TOI remained stable across all visits for patients in both treatment groups. Adjusted mean change in FACT-P TOI from baseline across all visits was -0·10 (95% CI -2·50 to 2·71) in the olaparib plus abiraterone group and -1·20 (-4·15 to 1·74) in the placebo plus abiraterone group (difference 1·30, 95% CI -2·70 to 5·30; p=0·52). Time to deterioration in pain was similar in both groups (BPI-SF worst pain HR 0·90 [95% CI 0·62-1·32], p=0·30; worst bone pain HR 0·85 [0·59-1·22], p=0·18). Improvement rates in the pain and discomfort domain of the EQ-5D-5L were similar in both groups from baseline to week 48, beyond which a higher proportion of patients in the olaparib plus abiraterone arm reported an improvement compared to the placebo plus abiraterone group., Interpretation: In these prespecified exploratory analyses, there was no significant difference in pain or HRQOL when olaparib was added to abiraterone. In this phase 2 trial, a statistically significant radiographic progression-free survival benefit was observed with the olaparib plus abiraterone combination. These results suggest that the improved survival benefits observed when combining olaparib with abiraterone does not result in different HRQOL compared with placebo plus abiraterone. Phase 3 studies are required to validate these results., Funding: AstraZeneca and Merck Sharp & Dohme, a subsidiary of Merck & Co, Rahway, NJ, USA., Competing Interests: Declaration of interests FS reports fees to his institution from AstraZeneca and Merck and Co during the conduct of the study, and institutional and personal fees from Astellas, Bayer, Janssen, Novartis, Sanofi, Myovant, Bristol Myers Squibb (BMS), and Pfizer outside the submitted work. AT-V reports grants from Pfizer, Ipsen, and Bayer; and personal fees from AstraZeneca, Roche, Merck Sharpe & Dohme (MSD), JNJ, BMS, Astellas, Ipsen, and Novartis outside of the submitted work. PW reports personal fees from AstraZeneca, Bayer, Ipsen, Pfizer, Merck and Co, Astellas, and MSD outside the submitted work. BA reports support from Eisai for the submitted work and fees from AstraZeneca, Astellas, Bayer, BMS, Eisai, Ferring, Ipsen, Janssen, Merck and Co, MSD, Pfizer, Roche, and Sanofi outside the submitted work. NS reports receiving personal fees from Astellas Pharma, Bristol-Myers Squibb, and Janssen outside the submitted work. RJ reports personal fees from Roche and support for attending meetings or travel from Bayer outside the submitted work. VEC reports personal fees from Janssen and Ipsen outside the submitted work. JJ reports personal fees from AstraZeneca, Exact Sciences, and MSD; and support from Boehringer outside the submitted work. AF reports personal fees from AstraZeneca, Janssen, Astellas, Pfizer, Novartis, and AAA Pharmaceutical outside the submitted work. CR reports Pfizer stock ownership. JK reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. JB reports full-time employment and stock ownership with Merck, and past employment with AstraZeneca. CG reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. AD reports full-time employment with AstraZeneca during the conduct of the study and AstraZeneca stock ownership. NWC reports receiving consulting fees, honoraria for lectures, and support for trial-related work from AstraZeneca. IK declares no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

About 40% of clear cell renal cell carcinoma (ccRCC) cases carry the pbrm1 mutation inactivating BAF180 subunit of the SWI/SNF chromatin remodeling complex (CRC). Here we show that the majority of transcriptomic changes appear at the stage I of ccRCC development. By contrast, the stage II ccRCC exhibits hyperactivation of DNA replication demonstrated by the overexpression of several genes, e.g., RRM1 and RRM2 genes encoding subunits of ribonucleotide reductase (RNR) complex. We found that the degree of RRM1 and RRM2 upregulation in ccRCC patients depends on pbrm1 mutation. We show that the BAF180 protein product of the PBRM1 gene directly binds to RRM1 and RRM2 loci . The BAF180 binding regions are targeted by regulatory proteins previously reported as SWI/SNF CRC interacting partners. BAF180 binding to RRMs loci correlates with enrichment of H3K27me3 in case of RRM1 and H3K14Ac on RRM2 , indicating the existence of differential regulatory mechanism controlling expression of these genes. We found that the strong overexpression of RRM2 in ccRCC patient samples correlates with T cell infiltration. Surprisingly, the majority of tumor infiltrating lymphocytes (TILs) consisted of CD4 + T cells. Furthermore, we show that exhausted CD4 + T cells induced the expression of the RRM2 gene in the primary ccRCC cell line. Collectively, our results provide the link between PBRM1 loss, RRM2 expression and T cell infiltration, which may lead to the establishment of new treatment of this disease., Competing Interests: None., (AJCR Copyright © 2021.)

Clinical practice shows significant differences in treatment outcomes across patients treated with cabozantinib for metastatic renal cell carcinoma (mRCC). It is not known whether cabozantinib-induced adverse events are predictive factors of survival as in case of drugs such as sunitinib or axitinib. The study participants were 30 adult patients with mRCC treated with cabozantinib as a second- or further line setting. All adverse events were evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Progression-free survival (PFS) values were calculated by taking the beginning of cabozantinib treatment as the start date and either disease progression or death as the end date. PFS were estimated using the Kaplan-Meier method, and compared using the log-rank test. We identified independent PFS predictors using multiple Cox proportional hazards models and reported hazard ratios (HR) with 95% confidence intervals. The median observation time cabozantinib treatment was 7.5 months, with a range of 2-15 months. During that time, 11 (37%) of the patients had mRCC progression. Median PFS on cabozantinib was not reached, and lower quartile was 6 months. All patients developed at least one adverse event in the course of cabozantinib therapy. Hypertension, hypothyroidism and HFS were observed most frequently, in about two-thirds of the patients. The co-incidence of multiple adverse events was common. Hypertension, hypothyroidism, diarrhea and liver toxicity were significantly associated with longer PFS values. Patients with three or more side effects had significantly longer PFS than those with two or fewer. Even though this study was conducted in a small patient sample and the observation time was relatively short our results confirm the predictive value of the incidence of adverse events during cabozantinib treatment in mRCC patients. To the best of our knowledge, this is the first study of this kind conducted in this group of patients.

Renal cell carcinoma (RCC) represents 2-3% of all malignancies. Most RCC-related deaths are caused by metastases of the disease. Studies suggest that inflammation-related parameters are of prognostic significance in metastatic renal cell carcinoma (mRCC) patients. Neutrophilia and thrombocytosis are markers of systemic inflammation that accompanies cancer, while lymphopenia is related to dysfunctions of the immune system. Neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) thus seem particularly interesting from a clinical perspective. The goal of this study was to determine if the response to therapy, consisting of reductions in radiologically assessed tumor burden and in inflammation-related parameters after 12 weeks of treatment with sunitinib, has a predictive value for outcome. One hundred thirty-one mRCC patients treated with the first-line sunitinib were evaluated. Inflammation-related parameters and radiologic response were correlated with treatment outcomes, progression-free, and overall survival. We found that the longest median progression-free survival of 37 months (Q1; Q3-15; not reached) and overall survival of 40 months (Q1; Q3-26; not reached) were achieved by patients who had either partial or complete response according to RECIST 1.1 and NLR lower than 1.64. In conclusion, the study confirmed that both objective response and lower grade of inflammation during treatment are predictive of better outcomes in mRCC patients treated with sunitinib.

Patients with metastatic clear cell renal cell carcinoma (mRCC) typically receive systemic treatment with tyrosine kinase inhibitors (TKI). Side effects include the hand-foot syndrome (HFS), tiredness, nausea, decreased appetite, diarrhea, myelosuppression, and hypertension. This study seeks to define the relationship between the incidence of HFS after the first cycle of treatment with sunitinib as the first-line treatment for mRCC (50 mg/day, 6-week schedule: 4 weeks on and 2 weeks off) and progression-free survival. We found that patients, treated with sunitinib for mRCC, who did not experience HFS had the median progression-free survival of 9.8 months. HFS symptoms appeared in 20% of patients after the first treatment cycle. The appearance of HFS was a predictor of a longer progression-free survival. In fact, progression-free survival was elongated in the HFS group over and beyond the observation period of 60 months, which rendered the median progression-free survival calculation impossible. These findings reaffirm the importance of monitoring skin toxicity during treatment with TKI. We conclude that the appearance of adverse skin symptoms presages better outcomes in patients treated with sunitinib for mRCC.

Background: Patients with metastatic castration-resistant prostate cancer and homologous recombination repair (HRR) mutations have a better response to treatment with the poly(ADP-ribose) polymerase inhibitor olaparib than patients without HRR mutations. Preclinical data suggest synergy between olaparib and androgen pathway inhibitors. We aimed to assess the efficacy of olaparib plus the androgen pathway inhibitor abiraterone in patients with metastatic castration-resistant prostate cancer regardless of HRR mutation status., Methods: We carried out this double-blind, randomised, placebo-controlled phase 2 trial at 41 urological oncology sites in 11 countries across Europe and North America. Eligible male patients were aged 18 years or older with metastatic castration-resistant prostate cancer who had previously received docetaxel and were candidates for abiraterone treatment. Patients were excluded if they had received more than two previous lines of chemotherapy, or had previous exposure to second-generation antihormonal drugs. Patients were randomly assigned (1:1) using an interactive voice or web response system, without stratification, to receive oral olaparib 300 mg twice daily or placebo. All patients received oral abiraterone 1000 mg once daily and prednisone or prednisolone 5 mg twice daily. Patients and investigators were masked to treatment allocation. The primary endpoint was investigator-assessed radiographic progression-free survival (rPFS; based on Response Evaluation Criteria in Solid Tumors version 1.1 and Prostate Cancer Clinical Trials Working Group 2 criteria). Efficacy analyses were done in the intention-to-treat population, which included all randomly assigned patients, and safety analyses included all patients who received at least one dose of olaparib or placebo. This trial is registered with ClinicalTrials.gov, number NCT01972217, and is no longer recruiting patients., Findings: Between Nov 25, 2014, and July 14, 2015, 171 patients were assessed for eligibility. Of those, 142 patients were randomly assigned to receive olaparib and abiraterone (n=71) or placebo and abiraterone (n=71). The clinical cutoff date for the final analysis was Sept 22, 2017. Median rPFS was 13·8 months (95% CI 10·8-20·4) with olaparib and abiraterone and 8·2 months (5·5-9·7) with placebo and abiraterone (hazard ratio [HR] 0·65, 95% CI 0·44-0·97, p=0·034). The most common grade 1-2 adverse events were nausea (26 [37%] patients in the olaparib group vs 13 [18%] patients in the placebo group), constipation (18 [25%] vs eight [11%]), and back pain (17 [24%] vs 13 [18%]). 38 (54%) of 71 patients in the olaparib and abiraterone group and 20 (28%) of 71 patients in the placebo and abiraterone group had grade 3 or worse adverse events, including anaemia (in 15 [21%] of 71 patients vs none of 71), pneumonia (four [6%] vs three [4%]), and myocardial infarction (four [6%] vs none). Serious adverse events were reported by 24 (34%) of 71 patients receiving olaparib and abiraterone (seven of which were related to treatment) and 13 (18%) of 71 patients receiving placebo and abiraterone (one of which was related to treatment). One treatment-related death (pneumonitis) occurred in the olaparib and abiraterone group., Interpretation: Olaparib in combination with abiraterone provided clinical efficacy benefit for patients with metastatic castration-resistant prostate cancer compared with abiraterone alone. More serious adverse events were observed in patients who received olaparib and abiraterone than abiraterone alone. Our data suggest that the combination of olaparib and abiraterone might provide an additional clinical benefit to a broad population of patients with metastatic castration-resistant prostate cancer., Funding: AstraZeneca., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: In Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial, radium-223 versus placebo prolonged overall survival with favorable safety in castration-resistant prostate cancer patients with symptomatic bone metastases. Long-term radium-223 monitoring underlies a comprehensive safety and risk/benefit assessment., Objective: To report updated ALSYMPCA safety, including long-term safety up to 3 yr after the first injection., Design, Setting, and Participants: Safety analyses from phase 3 randomized ALSYMPCA trial included patients receiving ≥1 study-drug injection (600 radium-223 and 301 placebo). Patients (405 radium-223 and 167 placebo) entered long-term safety follow-up starting 12 wk after the last study-drug injection, to 3 yr from the first injection. Forty-eight of 405 (12%) radium-223 and 12/167 (7%) placebo patients completed follow-up, with evaluations every 2 mo for 6 mo, then every 4 mo until 3 yr., Outcome Measurements and Statistical Analysis: All adverse events (AEs) were collected until 12 wk after the last injection; subsequently, only treatment-related AEs were collected. Additional long-term safety was assessed by development of acute myelogenous leukemia (AML), myelodysplastic syndrome (MDS), aplastic anemia, and secondary malignancies. Data analysis used descriptive statistics., Results and Limitations: During treatment to 12 wk following the last injection, 564/600 (94%) radium-223 and 292/301 (97%) placebo patients had treatment-emergent AEs (TEAEs). Myelosuppression incidence was low. Grade 3/4 hematologic TEAEs in radium-223 and placebo groups were anemia (13% vs 13%), neutropenia (2% vs 1%), and thrombocytopenia (7% vs 2%). Ninety-eight of 600 (16%) radium-223 and 68/301 (23%) placebo patients experienced grade 5 TEAEs. Long-term follow-up showed no AML, MDS, or new primary bone cancer; secondary non-treatment-related malignancies occurred in four radium-223 and three placebo patients. One radium-223 patient had aplastic anemia 16 mo after the last injection. No other cases were observed. Limitations include short (3-yr) follow-up., Conclusions: Final long-term safety ALSYMPCA analysis shows that radium-223 remained well tolerated, with low myelosuppression incidence and no new safety concerns., Patient Summary: Updated Alpharadin in Symptomatic Prostate Cancer (ALSYMPCA) trial findings show that radium-223 remained well tolerated during treatment and up to 3 yr after each patient's first injection., (Copyright © 2017 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Cardiovascular complications are a significant problem in systemically treated cancer patients. One such complication is Takotsubo cardiomyopathy, also known as Takotsubo syndrome. It is most frequently defined as a sudden and transient left or right ventricular systolic dysfunction; mimicking acute coronary syndrome, but without the associated changes in coronary arteries. Takotsubo syndrome is a relatively little known complication that appears in the course of oncological treatment, and its incidence has not yet been established. In this study, we reviewed Medline database according to case reports concerning takotsubo syndrome appearing after systemic treatment in oncological patients. We took into consideration all types of anticancer drugs. We reviewed the changes reported in the electrocardiography, echocardiography, and coronary angiography, and also the level of troponin, a marker of acute coronary syndrome elevation. In view of the increasing frequency of cardiac complications reported in patients receiving systemic oncological treatment, Takotsubo syndrome appears to be underdiagnosed. However, the syndrome may be linked to potentially fatal complications such as cardiogenic shock or cardiac arrest. Therefore, it seems essential to carry out appropriate diagnostic procedures for every patient experiencing clinical side effects of onco-pharmacotherapy. In patients with chest pain and dyspnea during or after treatment, Takotsubo syndrome should be considered, particularly that the syndrome requires a different therapy approach than that used in a coronary syndrome. Diagnostic procedures should include echocardiogram and the assessment of myocardial necrosis markers and natriuretic peptides.