Explore the vast range of titles available.

Checkpoint immunotherapy (CPI) has increased survival for some patients with advanced-stage bladder cancer (BCa). However, most patients do not respond. Here, we characterized the tumor and immune microenvironment in pre- and post-treatment tumors from the PURE01 neoadjuvant pembrolizumab immunotherapy trial, using a consolidative approach that combined transcriptional and genetic profiling with digital spatial profiling. We identify five distinctive genetic and transcriptomic programs and validate these in an independent neoadjuvant CPI trial to identify the features of response or resistance to CPI. By modeling the regulatory network, we identify the histone demethylase KDM5B as a repressor of tumor immune signaling pathways in one resistant subtype (S1, Luminal-excluded) and demonstrate that inhibition of KDM5B enhances immunogenicity in FGFR3-mutated BCa cells. Our study identifies signatures associated with response to CPI that can be used to molecularly stratify patients and suggests therapeutic alternatives for subtypes with poor response to neoadjuvant immunotherapy. The response to checkpoint immunotherapy within bladder cancer patients is highly variable. Here, the authors use RNA-seq, ATAC-seq and digital spatial profiling of pre- and post-treatment samples from the PURE01 trial to identify subtypes associated with treatment response.

PurposeThe prognostic significance of lactate dehydrogenase (LDH) in patients with metastatic seminoma is not defined. We investigated the prognostic impact of LDH levels prior to first-line systemic treatment and other clinical characteristics in this subset of patients.MethodsFiles from two registry studies and one single-institution database were analyzed retrospectively. Uni- and multivariate analyses were conducted to identify patient characteristics associated with recurrence free survival (RFS), overall survival (OS), and complete response rate (CRR).ResultsThe dataset included 351 metastatic seminoma patients with a median follow-up of 5.36 years. Five-year RFS, OS and CRR were 82%, 89% and 52%, respectively. Explorative analysis revealed a cut-off LDH level of < 2.5 upper limit of normal (ULN) (n = 228) vs. ≥ 2.5 ULN (n = 123) to be associated with a significant difference concerning OS associated with 5-years OS rates of 93% vs. 83% (p = 0.001) which was confirmed in multivariate analysis (HR 2.87; p = 0.004). Furthermore, the cut-off LDH < 2.5 ULN vs. ≥ 2.5 ULN correlated with RFS and CRR associated with a 5-years RFS rate and CRR of 76% vs. 86% (p = 0.012) and 32% vs. 59% (p  ≤  0.001), respectively.ConclusionsLDH levels correlate with treatment response and survival in metastatic seminoma patients and should be considered for their prognostic stratification.

Background: Immune checkpoint inhibitors (ICIs) are currently the standard of care for metastatic urothelial cancer (mUC) after the failure of previous platinum-based chemotherapy. The choice of further therapy after ICI progression is a new challenge, and scarce data support it. We aimed to examine the outcomes of mUC patients after progression to ICI, especially when receiving chemotherapy. Methods: Data were retrospectively collected from clinical records of mUC patients whose disease progressed to anti-programmed death 1 (PD-1)or programmed death ligand 1 (PD-L1) therapy at 14 Italian centers. Patients were grouped according to ICI therapy setting into SALVAGE (ie, ICI delivered ⩾ second-line therapy after platinum-based chemotherapy) and NAÏVE (ie, first-line therapy) groups. Progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan-Meier method and compared among subgroups. Cox regression assessed the effect of treatments after progression to ICI on OS. Objective response rate (ORR) was calculated as the sum of partial and complete radiologic responses. Results: The study population consisted of 201 mUC patients who progressed after ICI: 59 in the NAÏVE cohort and 142 in the SALVAGE cohort. Overall, 52 patients received chemotherapy after ICI progression (25.9%), 20 (9.9%) received ICI beyond progression, 115 (57.2%) received best supportive care only, and 14 (7.0%) received investigational drugs. Objective response rate to chemotherapy in the post-ICI setting was 23.1% (28.0% in the NAÏVE group and 18.5% in the SALVAGE group). Median PFS and OS to chemotherapy after ICI-PD was 5 months (95% confidence interval [CI]: 3-11) and 13 months (95% CI: 7-NA) for the NAÏVE group; 3 months (95% CI: 2-NA) and 9 months (95% CI: 6-NA) for the SALVAGE group, respectively. Overall survival from ICI initiation was 17 months for patients receiving chemotherapy (hazard ratio [HR] = 0.09, p < 0.001), versus 8 months for patients receiving ICI beyond progression (HR = 0.13, p < 0.001), and 2 months for patients who did not receive further active treatment (p < 0.001). Conclusions: Chemotherapy administered after ICI progression for mUC patients is advisable irrespective of the treatment line.

Temsirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) kinase, a protein that has been shown to be particularly active in metastatic renal cell carcinoma (mRCC) with poor prognosis. Therefore, temsirolimus should be considered as the first-line treatment indicated in mRCC patients classified as poor risk. The benefits of temsirolimus are not limited to an increased survival but are also related to a better quality of life, which is certainly one of the most important aspects in the clinical management of these frail patients. Temsirolimus is a well-tolerated treatment, and the most frequent adverse events are manageable with supportive care. To this end, the identification of predictive factors of response to temsirolimus could help us to better select patients and obtain a more tailored clinical management of mRCC.

Nivolumab is a fully human monoclonal antibody blocking PD-1 with demonstrated effectiveness against metastatic urothelial carcinoma. In this review, we describe the pharmacological properties of nivolumab and the treatment of metastatic urothelial carcinoma with this checkpoint inhibitor after the failure of first-line platinum-based chemotherapy. Cancer immunotherapy by checkpoint inhibition offers potential to prolong patient survival with well manageable toxicity although serious immune-related adverse events may occur. The overall response rate to nivolumab after first-line chemotherapy is about 20%. Patients unfit for cisplatin may benefit from first-line cancer immunotherapy. It remains unclear which patient will respond and PD-1/PD-L1 expression alone is not a sufficiently reliable predictive biomarker.

Purpose To investigate clinical and radiological differences between kidney metastases to the lung (RCCM +) and metachronous lung cancer (LC) detected during follow-up in patients surgically treated for Renal Cell Carcinoma (RCC). Methods cM0 surgically-treated RCC who harbored a pulmonary mass during follow-up were retrospectively scrutinized. Univariate logistic regression assessed predictive features for differentiating between LC and RCCM + . Multivariable analyses (MVA) were fitted to predict factors that could influence time between detection and histological diagnosis of the pulmonary mass, and how this interval could impact on survivals. Results 87% had RCCM + and 13% had LC. LC were more likely to have smoking history (75% vs. 29%, p  < 0.001) and less aggressive RCC features (cT1-2: 94% vs. 65%, p  = 0.01; pT1-2: 88% vs. 41%, p  = 0.02; G1-2: 88% vs. 37%, p  < 0.001). The median interval between RCC surgery and lung mass detection was longer between LC (55 months [32.8–107.2] vs. 20 months [9.0–45.0], p  = 0.01). RCCM + had a higher likelihood of multiple (3[1–4] vs. 1[1–1], p  < 0.001) and bilateral (51% vs. 6%, p  = 0.002) pulmonary nodules, whereas LC usually presented with a solitary pulmonary nodule, less than 20 mm. Univariate analyses revealed that smoking history (OR:0.79; 95% CI 0.70–0.89; p  < 0.001) and interval between RCC surgery and lung mass detection (OR:0.99; 95% CI 0.97–1.00; p  = 0.002) predicted a higher risk of LC. Conversely, size (OR:1.02; 95% CI 1.01–1.04; p  = 0.003), clinical stage (OR:1.14; 95% CI 1.06–1.23; p  < 0.001), pathological stage (OR:1.14; 95% CI 1.07–1.22; p  < 0.001), grade (OR:1.15; 95% CI 1.07–1.23; p  < 0.001), presence of necrosis (OR:1.17; 95% CI 1.04–1.32; p  = 0.01), and lymphovascular invasion (OR:1.18; 95% CI 1.01–1.37; p  = 0.03) of primary RCC predicted a higher risk of RCCM + . Furthermore, number (OR:1.08; 95% CI 1.04–1.12; p  < 0.001) and bilaterality (OR:1.23; 95% CI 1.09–1.38; p  < 0.001) of pulmonary lesions predicted a higher risk of RCCM + . Survival analysis showed a median second PFS of 10.9 years (95% CI 3.3-not reached) for LC and a 3.8 years (95% CI 3.2–8.4) for RCCM + . The median OS time was 6.5 years (95% CI 4.4-not reached) for LC and 6 years (95% CI 4.3–11.6) for RCCM + . Conclusions Smoking history, primary grade and stage of RCC, interval between RCC surgery and lung mass detection, and number of pulmonary lesions appear to be the most valuable predictors for differentiating new primary lung cancer from RCC progression.

Summary Background and purpose Salvage therapies for urothelial carcinoma are needed. A single-arm trial in patients with advanced or metastatic urothelial carcinoma refractive to other therapies found that alisertib, a selective inhibitor of aurora kinase A, maintained stable disease in a few cases, despite a low objective response rate. To better understand why some patients benefited from alisertib, we genotyped the 22 patients of this pilot trial for two single nucleotide polymorphisms (rs2273535 and rs1047972) in AURKA , the gene encoding aurora kinase A, and looked for associations with survival and treatment response. Results Carrier status for the minor allele of rs2273535 (T91A, p. F31I) was a favorable prognostic factor for progression-free survival (HR = 0.18; 95% CI, 0.039–0.81; P  = 0.026) but not for overall survival (HR = 0.88; 95% CI, 0.26–2.9; P  = 0.83). These results were confirmed in multivariable analyses, adjusting for sex, age and hemoglobin, for both progression-free survival (HR = 0.11; 95% CI, 0.018–0.69; P  = 0.018) and overall survival. No association was found between rs1047972 and survival. Moreover, neither SNP was associated with treatment response. Conclusion In patients who received alisertib for advanced or metastatic urothelial carcinoma, longer progression-free survival was observed in carriers of the minor allele A of rs2273535 in AURKA than in patients who were homozygous for the major allele T. This finding, based on a small pilot trial, warrants further investigation.

Background Up to 15% of patients with locally advanced renal cell carcinoma (RCC) harbors tumor thrombus (TT). In those cases, radical nephrectomy (RN) and thrombectomy represents the standard of care. We assessed the impact of TT on long-term functional and oncological outcomes in a large contemporary cohort. Methods Within a prospective maintained database, 1207 patients undergoing RN for non-metastatic RCC between 2000 and 2021 at a single tertiary centre were identified. Of these, 172 (14%) harbored TT. Multivariable logistic regression analyses evaluated the impact of TT on the risk of postoperative acute kidney injury (AKI). Multivariable Poisson regression analyses estimated the risk of long-term chronic kidney disease (CKD). Kaplan Meier plots estimated disease-free survival and cancer specific survival. Multivariable Cox regression models assessed the main predictors of clinical progression (CP) and cancer specific mortality (CSM). Results Patients with TT showed lower BMI (24 vs. 26 kg/m 2 ) and preoperative Hb (11 vs. 14 g/mL; all— p  < 0.05). Clinical tumor size was higher in patients with TT (9.6 vs. 6.5 cm; p  < 0.001). After adjusting for potential confounders, the presence of TT was significantly associated with a higher risk of postoperative AKI (OR 2.03, 95% CI 1.49–3.6; p  < 0.001) and long-term CKD (OR: 1.32, 95% CI 1.10–1.58; p  < 0.01). Notably, patients with TT showed worse long-term oncological outcomes and TT was a predictor for CP (2.02, CI 95% 1.49–2.73, p  < 0.001) and CSM (HR 1.61, CI 95% 1.04–2.49, p  < 0.03). Conclusions The presence of TT in RCC patients represents a key risk factor for worse perioperative, as well as long-term renal function. Specifically, patients with TT harbor a significant and early estimated glomerular filtration rate (eGFR) decrease. However, despite TT patients show a greater eGFR decline after surgery, they retain acceptable renal function, which remains stable over time.

PurposeThe KEYNOTE-564 trial showed improved disease-free survival (DFS) for patients with high-risk renal cell carcinoma (RCC) receiving adjuvant pembrolizumab as compared to placebo. However, if systematically administered to all high-risk patients, it might lead to the overtreatment in a non-negligible proportion of patient. Therefore, we aimed to determine the optimal candidate for adjuvant pembrolizumab.MethodsWithin a prospectively maintained database we selected patients who fulfilled the inclusion criteria of the KEYNOTE-564. We compared baseline characteristics and oncologic outcomes in this cohort with those of the placebo arm of the KEYNOTE-564. Regression tree analyses was used to generate a risk stratification tool to predict 1-year DFS after surgery.ResultsIn the off-trial setting, patients had worse tumor characteristics then in the KEYNOTE-564 placebo arm, i.e. there were more pT4 (5.4 vs. 2.7%, p = 0.046) and pN1 (15 vs. 6.3%, p < 0.001) cases. Median DFS was 29 (95% CI 21–35) months as compared to value not reached in KEYNOTE-564 and 1-year DFS was 64.2% (95% CI 59.6–69.2) as compared to 76.2% (95% CI 72.2–79.7), respectively. Patients with pN1 were at the highest risk of 1-year recurrence (1-year DFS 28.6% [95% CI 20.2–40.3]); patients without LNI, but necrosis were at intermediate risk (1-year DFS 62.5% [95% CI 56.9–68.8]); those without LNI and necrosis were at the lowest risk (1-year DFS 83.8% [95% CI 79.1–88.9]). LVI substratification furtherly improved the accuracy in the prediction of early recurrence.ConclusionsPatients potentially eligible for adjuvant pembrolizumab have worse characteristics and DFS in the off-trial setting as compared to the placebo arm of the KEYNOTE-564. Patients with either LNI or necrosis were at the highest risk of early-recurrence, which make them the ideal candidate to adjuvant pembrolizumab.

Immunotherapy, and in particular immune-checkpoints blockade therapy (ICB), represents a new pillar in cancer therapy. Antibodies targeting Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) and Programmed Death 1 (PD-1)/Programmed Death Ligand-1 (PD-L1) demonstrated a relevant clinical value in a large number of solid tumors, leading to an improvement of progression free survival and overall survival in comparison to standard chemotherapy. However, across different solid malignancies, the immune-checkpoints inhibitors efficacy is limited to a relative small number of patients and, for this reason, the identification of positive or negative predictive biomarkers represents an urgent need. Despite the expression of PD-L1 was largely investigated in various malignancies, (i.e., melanoma, head and neck malignancies, urothelial and renal carcinoma, metastatic colorectal cancer, and pancreatic cancer) as a biomarker for ICB treatment-patients selection, it showed an important, but still imperfect, role as positive predictor of response only in nonsmall cell lung cancer (NSCLC). Importantly, other tumor and/or microenvironments related characteristics are currently under clinical evaluation, in combination or in substitution of PD–L1 expression. In particular, tumor-infiltrating immune cells, gene expression analysis, mismatch- repair deficiency, and tumor mutational landscape may play a central role in predicting clinical benefits of CTLA-4 and/or PD-1/PD-L1 checkpoint inhibitors. In this review, we will focus on the clinical evaluation of emerging biomarkers and how these may improve the naïve vision of a single- feature patients-based selection.