Advances in basic research, clinical diagnosis and treatment of bladder cancer in 2022

Bladder cancer (BCa) is a common malignant tumor of the urinary tract. Significant progress has been made in both basic and clinical research on BCa, which has further elucidated the drivers of BCa development at the gene and protein levels, and explored the structure and interactions of the tumor microenvironment. The early diagnostic index nuclear matrix protein 22 (NMP22) of BCa has great clinical limitations, and new biomarkers are constantly being developed to make early diagnosis more accurate. A breakthrough has been made in the comprehensive treatment of BCa, including the combination of immune checkpoint inhibitor therapy on cisplatin-based first-line chemotherapy, the application of antibody-drug conjugate (ADC), and the combination of these drugs in different stages of BCa. In order to better describe the recently achieved research results, a review of the research progress of BCa in 2022 was presented

Advances in basic research, clinical diagnosis and treatment of prostate cancer in 2022

About 40%-70% of newly diagnosed prostate cancer patients in China are in the stage of metastatic disease, and the spatio-temporal heterogeneity of the occurrence and development of prostate cancer and the unique metastasis pattern make it difficult to analyze immune markers based on biopsy tissue. With the advancement of many basic and clinical studies, new advances have been made in the pathogenesis, diagnostic methods, perioperative management, radiotherapy techniques and systematic treatment of advanced diseases of prostate cancer. These results continuously enrich the means of diagnosis and treatment of prostate cancer patients and improve their prognosis. Here was a review of the major advances in prostate cancer research in 2022

Two-dose-level confirmatory study of the pharmacokinetics and tolerability of everolimus in Chinese patients with advanced solid tumors

<p>Abstract</p> <p>Background</p> <p>This phase I, randomized, multicenter, open-label study investigated the pharmacokinetics, safety, and efficacy of the oral mammalian target of rapamycin inhibitor everolimus in Chinese patients with advanced solid tumors.</p> <p>Methods</p> <p>A total of 24 patients with advanced breast cancer (n = 6), gastric cancer (n = 6), non-small cell lung cancer (n = 6), or renal cell carcinoma (n = 6) who were refractory to/unsuitable for standard therapy were randomized 1:1 to oral everolimus 5 or 10 mg/day. Primary end points were pharmacokinetic parameters and safety and tolerability. Pharmacokinetic 24-h profiles were measured on day 15; trough level was measured on days 2, 8, 15, 16, and 22. Tolerability was assessed continuously. This final analysis was performed after all patients had received 6 months of study drug or had discontinued.</p> <p>Results</p> <p>Everolimus was absorbed rapidly; median T_maxwas 3 h (range, 1-4) and 2 h (range, 0.9-6) in the 5 and 10 mg/day groups, respectively. Pharmacokinetic parameters increased dose proportionally from the 5 and 10 mg/day doses. Steady-state levels were achieved by day 8 or earlier. The most common adverse events suspected to be related to everolimus therapy were increased blood glucose (16.7% and 41.7%) and fatigue (16.7% and 33.3%) in the everolimus 5 and 10 mg/day dose cohorts, respectively. Best tumor response was stable disease in 10 (83%) and 6 (50%) patients in the 5 and 10 mg/day groups, respectively.</p> <p>Conclusions</p> <p>Everolimus 5 or 10 mg/day was well tolerated in Chinese patients with advanced solid tumors. The observed safety and pharmacokinetic profile of everolimus from this study were consistent with previous studies.</p> <p>Trial registration</p> <p>Chinese Health Authorities 2008L09346</p

Multi-omics profiles refine L-dopa decarboxylase (DDC) as a reliable biomarker for prognosis and immune microenvironment of clear cell renal cell carcinoma

BackgroundIncreasing evidence indicates that L-dopa decarboxylase (DDC), which mediates aberrant amino acid metabolism, is significantly associated with tumor progression. However, the impacts of DDC are not elucidated clearly in clear cell renal cell carcinoma (ccRCC). This study aimed to evaluate DDC prognostic value and potential mechanisms for ccRCC patients.MethodsTranscriptomic and proteomic expressions of and clinical data including 532 patients with ccRCC (The Cancer Genome Atlas RNA-seq data), 226 ccRCC samples (Gene Expression Omnibus), 101 ccRCC patients from the E-MTAB-1980 cohort, and 232 patients with ccRCC with proteogenomic data (Fudan University Shanghai Cancer Center) were downloaded and analyzed to investigate the prognostic implications of DDC expression. Cox regression analyses were implemented to explore the effect of DDC expression on the prognosis of pan-cancer. The "limma" package identified the differentially expressed genes (DEGs) between high DDC subgroups and low DDC groups. Functional enrichments were performed based DEGs between DDC subgroups. The differences of immune cell infiltrations and immune checkpoint genes between DDC subgroups were analyzed to identify potential influence on immune microenvironment.ResultsWe found significantly decreased DDC expression in ccRCC tissues compared with normal tissues from multiple independent cohorts based on multi-omics data. We also found that DDC expression was correlated with tumor grades and stages.The following findings revealed that lower DDC expression levels significantly correlated with shorter overall survival (P &lt;0.001) of patients with ccRCC. Moreover, we found that DDC expression significantly correlated with an immunosuppressive tumor microenvironment, higher intra-tumoral heterogeneity, elevated expression of immune checkpoint CD274, and possibly mediated malignant behaviors of ccRCC cells via the PI3k/Akt signaling pathway.ConclusionThe present study is the first to our knowledge to indicate that decreased DDC expression is significantly associated with poor survival and an immune-suppressive tumor microenvironment in ccRCC. These findings suggest that DDC could serve as a biomarker for guiding molecular diagnosis and facilitating the development of novel individual therapeutic strategies for patients with advanced ccRCC

Efficacy of sorafenib on metastatic renal cell carcinoma in Asian patients: Results from a multicenter study

<p>Abstract</p> <p>Background</p> <p>The effects of sorafenib in the treatment of advanced renal cell carcinoma (RCC) have been confirmed in an international collaborative phase III trial. This study aims to confirm similar efficacy and treatment-induced toxicities of sorafenib in the treatment of metastatic RCC in ethnic Chinese patients.</p> <p>Methods</p> <p>Ninety-eight consecutive and non-selected patients with pathologically confirmed metastatic RCC were treated according to an institutional treatment protocol. All patients were treated with 400 mg of sorafenib orally twice daily on a continuous basis until disease progression or intolerance to treatment occurred. Dose reduction to 400 mg once daily was required if grade 3 or 4 toxicities occurred. All patients except for 7 received nephrectomy in the course of their disease. All patients were assessed for tumor response, progression-free survival (PFS), overall survival (OS), and treatment-induced toxicities.</p> <p>Results</p> <p>The median follow-up time was 76 weeks (range 2–296 weeks) for the entire group of patients. Radiologically confirmed complete response (CR), partial response (PR), stable disease (SD) of more than 4 months, and disease progression as best objective responses were observed in 1 (1%), 23 (23.5%), 62 (63.3%), and 12 (12.2%) patients, respectively. The tumor control rate (CR+PR+SD of >4 months) was 87.8%. The 1-year estimated PFS and OS were 58.4% and 64.6%, respectively. The median progression-free survival (PFS) time was 60 weeks (95% CI 41–79); and the median overall survival (OS) time was not reached with a follow-up of 76 weeks. Reduction of sorafenib dose was required in 26 patients who developed grade 3 or 4 treatment-cause adverse-effects. An additional 9 patients discontinued sorafenib treatment due to severe adverse-effects. No grade 5 toxicity occurred.</p> <p>Multivariate analysis revealed that independent predictive factors for tumor response to sorafenib treatment included ECOG status, presence of lymph node metastasis, and nephrectomy prior to the development of metastasis.</p> <p>Conclusion</p> <p>Sorafenib produced an 87.8% disease control rate for metastatic renal cell carcinoma in Chinese patients, with acceptable rates of toxicity. The medication dosed at 400 mg twice daily is both efficacious and safe in the treatment of metastatic renal cell carcinoma in Chinese patients.</p

Advances in the research, diagnosis and treatment of renal cell carcinoma in 2022

Renal cell carcinoma (RCC) is one of the three major urinary system tumors. With the changes of lifestyle and the rise of obesity, hypertension and other diseases, the incidence of RCC is increasing. The onset of RCC is hidden, and RCC has strong heterogeneity. Most RCC patients are found accidentally by imaging examination, so many patients were diagnosed in the advanced stage. Although the emergence of targeted therapy and immunotherapy has greatly prolonged the survival time of patients with advanced RCC, due to many pathological types of RCC, it is still difficult for many patients to benefit from the systematic treatment. Many basic and clinical studies are devoted to the development of new targets or drugs to prolong the survival time of patients. This article reviewed the advances in the research, diagnosis and treatment of RCC in 2022

Five Inhibitory Receptors Display Distinct Vesicular Distributions in Murine T Cells.

T cells can express multiple inhibitory receptors. Upon induction of T cell exhaustion in response to a persistent antigen, prominently in the anti-tumor immune response, many are expressed simultaneously. Key inhibitory receptors are CTLA-4, PD-1, LAG3, TIM3, and TIGIT, as investigated here. These receptors are important as central therapeutic targets in cancer immunotherapy. Inhibitory receptors are not constitutively expressed on the cell surface, but substantial fractions reside in intracellular vesicular structures. It remains unresolved to which extent the subcellular localization of different inhibitory receptors is distinct. Using quantitative imaging of subcellular distributions and plasma membrane insertion as complemented by proximity proteomics and biochemical analysis of the association of the inhibitory receptors with trafficking adaptors, the subcellular distributions of the five inhibitory receptors were discrete. The distribution of CTLA-4 was most distinct, with preferential association with lysosomal-derived vesicles and the sorting nexin 1/2/5/6 transport machinery. With a lack of evidence for the existence of specific vesicle subtypes to explain divergent inhibitory receptor distributions, we suggest that such distributions are driven by divergent trafficking through an overlapping joint set of vesicular structures. This extensive characterization of the subcellular localization of five inhibitory receptors in relation to each other lays the foundation for the molecular investigation of their trafficking and its therapeutic exploitation