Identification and validation of CRLF1 and NRG1 as immune-related signatures in hypertrophic scar.

BACKGROUND: Hypertrophic scar (HTS) is a prevalent chronic inflammatory skin disorder characterized by abnormal proliferation and extracellular matrix deposition and the precise mechanisms underlying HTS remain elusive. This study aimed to identify and validate potential immune-related genes associated with hypertrophic scar formation. METHODS: Skin samples from normal (n = 12) and hypertrophic scar tissues (n = 12) were subjected to RNA-seq analysis. Differentially expressed genes (DEGs) and significant modular genes in Weighted gene Co-expression Network Analysis (WGCNA) were identified. Subsequently, functional enrichment analysis was performed on the intersecting genes. Additionally, eight immune-related genes were matched from the ImmPort database. Validation of NRG1 and CRLF1 was carried out using an external cohort (GSE136906). Furthermore, the association between these two genes and immune cells was assessed by Spearman correlation analysis. Finally, RNA was extracted from normal and hypertrophic scar samples, and RT-qPCR, Immunohistochemistry staining and Western Blot were employed to validate the expression of characteristic genes. RESULTS: A total of 940 DEGs were identified between HTS and normal samples, and 288 key module genes were uncovered via WGCNA. Enrichment analysis in key module revealed involvement in many immune-related pathways, such as Th17 cell differentiation, antigen processing and presentation and B cell receptor signaling pathway. The eight immune-related genes (IFI30, NR2F2, NRG1, ESM1, NFATC2, CRLF1, COLEC12 and IL6) were identified by matching from the ImmPort database. Notably, we observed that activated mast cell positively correlated with CRLF1 expression, while CD8 T cells exhibited a positive correlation with NRG1. The expression of NRG1 and CRLF1 was further validated in clinical samples. CONCLUSION: In this study, two key immune-related genes (CRLF1 and NRG1) were identified as characteristic genes associated with HTS. These findings provide valuable insights into the immune-related mechanisms underlying hypertrophic scar formation.

Rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy in patients with high-volume, metastatic, hormone-sensitive prostate cancer (CHART): a randomised, open-label, phase 3 trial.

BACKGROUND: Rezvilutamide, a novel androgen-receptor inhibitor with low blood-brain barrier penetration, has shown potent antitumour activity against metastatic castration-resistant prostate cancer. In this study, we aimed to evaluate the efficacy and safety of rezvilutamide versus bicalutamide in combination with androgen-deprivation therapy (ADT) for high-volume, metastatic, hormone-sensitive prostate cancer. METHODS: CHART is a randomised, open-label, phase 3 study done at 72 hospitals in China, Poland, Czech Republic, and Bulgaria. Eligible patients were aged 18 years or older, had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and had high-volume metastatic, hormone-sensitive prostate cancer. Previous chemotherapy or other localised treatment for prostate cancer were not allowed. Patients were randomly assigned (1:1) to receive ADT plus either rezvilutamide (240 mg) or bicalutamide (50 mg) orally once daily. Randomisation was done via an interactive response technology system (block size of four) and stratified according to ECOG performance status and presence of visceral metastasis (excluding lymph nodes). Herein, we present the results of the preplanned interim analyses for the two co-primary endpoints of radiographic progression-free survival assessed by a blinded independent review committee and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study medication. This study is ongoing, but is closed to recruitment. This trial is registered with ClinicalTrials.gov, NCT03520478. FINDINGS: Between June 28, 2018, and Aug 6, 2020, 792 patients were screened and 654 patients were randomly assigned to receive rezvilutamide plus ADT (n=326) or bicalutamide plus ADT (n=328). At the preplanned interim analysis for radiographic progression-free survival (data cutoff May 16, 2021), the median follow-up duration was 21·2 months (IQR 16·6-25·8). Rezvilutamide significantly improved radiographic progression-free survival compared with bicalutamide (median radiographic progression-free survival not reached [95% CI not reached-not reached] vs 25·1 months [95% CI 15·7-not reached]; hazard ratio [HR] 0·44 [95% CI 0·33-0·58]; p<0·0001). At the preplanned interim analysis for overall survival (data cutoff Feb 28, 2022), the median follow-up duration was 29·3 months (IQR 21·0-33·3). Rezvilutamide significantly improved overall survival compared with bicalutamide (HR 0·58 [95% CI 0·44-0·77]; p=0·0001; median overall survival was not reached [95% CI not reached-not reached] vs not reached [36·2-not reached]). The most common grade 3 or worse adverse events of any cause in the safety population were hypertension (26 [8%] of 323 patients in the rezvilutamide group vs 24 [7%] of 324 patients in the bicalutamide group), hypertriglyceridaemia (24 [7%] vs seven [2%]), increased weight (20 [6%] vs 12 [4%]), anaemia (12 [4%] vs 16 [5%]), and hypokalaemia (11 [3%] vs four [1%]). Serious adverse events were reported in 90 (28%) of 323 patients in the rezvilutamide group and 69 (21%) of 324 patients in the bicalutamide group. No treatment-related deaths occurred in patients in the rezvilutamide group; one treatment-related death of unknown specific cause (<1%) occurred in the bicalutamide group. INTERPRETATION: In the two interim analyses, rezvilutamide plus ADT significantly improved radiographic progression-free survival and overall survival compared with bicalutamide plus ADT in patients with high-volume, metastatic, hormone-sensitive prostate cancer, with a tolerable safety profile. FUNDING: Jiangsu Hengrui Pharmaceuticals.

Activity and safety of SHR3680, a novel antiandrogen, in patients with metastatic castration-resistant prostate cancer: a phase I/II trial.

BACKGROUND: Antagonizing the androgen-receptor (AR) pathway is an effective treatment strategy for patients with metastatic castration-resistant prostate cancer (CRPC). Here, we report the results of a first-in-human phase 1/2 study which assessed the safety, pharmacokinetics, and activity of SHR3680 (a novel AR antagonist) in patients with metastatic CRPC. METHODS: This phase 1/2 study enrolled patients with progressive metastatic CRPC who had not been previously treated with novel AR-targeted agents. In the phase 1 dose-escalation portion, patients received oral SHR3680 at a starting daily dose of 40 mg, which was subsequently escalated to 80 mg, 160 mg, 240 mg, 360 mg, and 480 mg per day. In phase 2 dose-expansion portion, patients were randomized to receive daily dose of 80 mg, 160 mg, or 240 mg of SHR3680. The primary endpoint in phase 1 was safety and tolerability and in phase 2 was the proportion of patients with a prostate-specific antigen (PSA) response (≥ 50% decrease of PSA level) at week 12. RESULTS: A total of 197 eligible patients were enrolled and received SHR3680 treatment, including 18 patients in phase 1 and 179 patients in phase 2. No dose-limiting toxicities were reported and the maximum tolerated dose was not reached. Treatment-related adverse events (TRAEs) occurred in 116 (58.9%) patients, with the most common one being proteinuria (13.7%). TRAEs of grade ≥ 3 occurred in only 23 (11.7%) patients, and no treatment-related deaths occurred. Antitumor activities were evident at all doses, including PSA response at week 12 in 134 (68.0%; 95% CI, 61.0-74.5) patients, stabilized bone disease at week 12 in 174 (88.3%; 95% CI, 87.2-95.5) patients, and responses in soft tissue lesions in 21 (34.4%, 95% CI, 22.7-47.7) of 61 patients. CONCLUSION: SHR3680 was well tolerated and safe, with promising anti-tumor activity across all doses tested in patients with metastatic CRPC. The dose of 240 mg daily was recommended for further phase 3 study. TRIAL REGISTRATION: Clinical trials.gov NCT02691975; registered February 25, 2016.

Prevalence of comprehensive DNA damage repair gene germline mutations in Chinese prostate cancer patients.

Germline DNA damage repair (DDR) deficiency has been associated with increased cancer risk, poor prognosis and therapeutic opportunity for prostate cancer (PCa) patients. However, the landscape of germline mutations in PCa covering comprehensive DDR genes has not been reported. We performed whole-exome sequencing in 246 patients who meet the National Cancer Center Network guidelines for genetic testing and analyzed variants in 276 DDR genes, which was from the Cancer Genome Atlas. A total of 79 deleterious germline alterations in 60 DDR genes were identified in 31% (76/246) patients. Mutations were found in nine DDR pathways, including 11.8% men in homologous recombination repair (HR) pathways, 2.4% men in mismatch repair (MMR) pathway and 16.7% (41/246) patients in non-HR/MMR pathways. In HRR and MMR pathways, mutations were mostly identified in BRCA2 (5.3%), HFM1 (0.8%), ZSWIM7 (0.8%), MSH2 (0.8%) and MSH3 (0.8%). When compared with the cancer-free cohort, POLN and POLG conferred high risk to PCa with odds ratio 6.9 and 20.5, respectively. We provided a comprehensive view of germline DDR gene mutations in PCa patients. We also identified two potential PCa predisposition genes: POLN and POLG, which have not been reported in the Western population, confirming the necessity of customizing a multigene panel for Chinese PCa patients.

Identification of a methylation panel aid in risk stratification in node-positive penile squamous cell carcinoma.

Molecular prognostic factors for individualized treatment of squamous cell carcinoma (SCC) are poorly defined. Our study developed and validated a novel molecular tools aid in preinguinal and postinguinal lymphadenectomy risk stratification in node-positive penile SCC. Patients with node-positive penile SCC who underwent inguinal or ilioinguinal lymphadenectomy were divided into three cohorts: a discovery set, a development set and a validation set. The local ethics committee approved the study. The primary endpoint was cancer-specific survival (CSS). At the discovery stage, 17 CpG sites were significantly associated with CSS. In the development set, we constructed a 3-CpG-based prognostic score for survival prediction. The hazard ratio (HR) of the panel (dichotomized using the optimal cutoff) was 5.8 in the multivariate analyses (P < .001). The addition of the methylation score significantly improved the pN-stage C-index from 0.70 to 0.79 (incremental C = 0.09, P < .001). In the validation set, the methylation panel showed a HR of 9.9 in the multivariate analyses. The addition of the molecular marker improved the pN-stage C-index from 0.69 to 0.78 (incremental C = 0.09, P < .001). The methylation score remarkably separated survival curves in different pN stages, which indicate that the tool can be applied to tailor the treatment in both preinguinal and postinguinal lymphadenectomy settings. We developed and validated a prognostic methylation panel for node-positive penile SCC. The tool may aid in the risk stratification of the population with heterogeneous outcomes and needs prospective validation. Patients in high-risk group may benefit from more aggressive therapy or clinical trials.

Drug Discovery of Nucleos(t)ide Antiviral Agents: Dedicated to Prof. Dr. Erik De Clercq on Occasion of His 80th Birthday.

Nucleoside and nucleotide analogues are essential antivirals in the treatment of infectious diseases such as human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus (HSV), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). To celebrate the 80th birthday of Prof. Dr. Erik De Clercq on 28 March 2021, this review provides an overview of his contributions to eight approved nucleos(t)ide drugs: (i) three adenosine nucleotide analogues, namely tenofovir disoproxil fumarate (Viread®) and tenofovir alafenamide (Vemlidy®) against HIV and HBV infections and adefovir dipivoxil (Hepsera®) against HBV infections; (ii) two thymidine nucleoside analogues, namely brivudine (Zostex®) against HSV-1 and VZV infections and stavudine (Zerit®) against HIV infections; (iii) two guanosine analogues, namely valacyclovir (Valtrex®, Zelitrex®) against HSV and VZV and rabacfosadine (Tanovea®-CA1) for the treatment of lymphoma in dogs; and (iv) one cytidine nucleotide analogue, namely cidofovir (Vistide®) for the treatment of HCMV retinitis in AIDS patients. Although adefovir dipivoxil, stavudine, and cidofovir are virtually discontinued for clinical use, tenofovir disoproxil fumarate and tenofovir alafenamide remain the most important antivirals against HIV and HBV infections worldwide. Overall, the broad-spectrum antiviral potential of nucleos(t)ide analogues supports their development to treat or prevent current and emerging infectious diseases worldwide.

Prostate Cancer Screening Using Prostate-Specific Antigen Tests in a High-Risk Population in China: A Cost-Utility Analysis.

BACKGROUND: Both National Comprehensive Cancer Network and Chinese guidelines recommend beginning prostate-specific antigen (PSA) screening for men aged 50 years or 45 years with a family history because they were at a higher risk of developing prostate cancer. Several model-based economic evaluations of PSA screening studies have been conducted, but with little evidence from China. OBJECTIVE: The aim of this study was to conduct an economic evaluation of the cost-utility of PSA-based prostate cancer screening in Chinese men. METHODS: We developed a decision-tree and Markov model in Excel (Microsoft Corp, Redmond, Washington) to compare 2 strategies that can be used to detect prostate cancer: PSA-based screening followed by a biopsy, and non-PSA screening. We assumed that the patients would repeat screening in subsequent years if their first-year PSA value was higher than 4.0 ng/mL. The model adopted health care system perspective and lifetime horizon. Screening efficacy, cost, utility, and long-term survival of prostate cancer were retrieved from published literature and physician surveys. Both quality-adjusted life year and costs were discounted at an annual rate of 3.5%. Uncertainty was assessed by 1-way and probabilistic sensitivity analyses. Our model also calculated the risk-to-benefit ratio as the ratio of overdiagnosis (biopsy without diagnosed) to prostate cancer-related deaths prevented in different age groups. RESULTS: The results suggested that PSA-based screening was cost-effective compared with no PSA screening, with an incremental cost-utility ratio of ¥11,381 ($1821/€1480) per quality-adjusted life year. This value was less than the threshold of 1-time gross domestic product per capita in China (ie, ¥70,892 [$11,343/€9216]). Sensitivity analyses confirmed the robustness of the results. The risk-to-benefit ratios of the 50 to 65 years and the 65 to 80 years age groups were 1.3 and 2.8, respectively. CONCLUSIONS: PSA-based prostate cancer screening appears to be cost-effective in some high-risk Chinese men. PSA screening (PSA testing followed by magnetic resonance imaging and biopsy if positive) can be recommended for Chinese men aged 50 to 65 years because this approach had the lowest risk-to-benefit ratio. The approach should be further adapted based on future updated data. (Curr Ther Res Clin Exp. 2022; 83:XXX-XXX)© 2022 Elsevier HS Journals, Inc.

Prognostic Value of Germline DNA Repair Gene Mutations in De Novo Metastatic and Castration-Sensitive Prostate Cancer.

BACKGROUND: Germline DNA damage repair gene mutations (gDDRm) have been found in approximately 12% of patients with metastatic prostate cancer (mPCa). Previous studies of the clinical impact of gDDRm have mainly been in the setting of metastatic castration-resistant prostate cancer (mCRPC). This study aimed to determine the prognostic value of gDDRm in de novo metastatic and castration-sensitive prostate cancer (mCSPC). MATERIALS AND METHODS: We retrospectively collected the records of 139 consecutive men with de novo mCSPC who initially received systemic therapies following guidelines. This included 128 patients who underwent genetic testing at our center and 11 patients referred to our center after being identified as gDDRm carriers. Time to mCRPC was collected. Kaplan-Meier and log-rank analysis were used to analyze the association between gDDRm and clinical outcomes. Survival outcomes were adjusted using multivariable Cox regression models. RESULTS: Of the 139 patients with de novo mCSPC, 28 gDDRm carriers were identified. Median time progressing to mCRPC was significantly shorter in patients carrying gDDRm than in those without mutations (8.3 vs 13.2 months; hazard ratio [HR], 2.37; p < .001). Moreover, median progression time was almost halved in BRCA2 carriers (6.3 vs. 13.2 months; HR, 3.73; p < .001). Subgroup analysis revealed that the presence of gDDRm indicated poor therapy response regardless of disease volume and prostate-specific antigen nadir within the first 7 months. Presence of gDDRm remained independently associated with increased risk of progression to mCRPC in multivariate analysis (adjusted HR, 1.98; p = .006). CONCLUSION: Our study suggested that positive gDDRm status predicted rapid progression to castration resistance in patients with de novo mCSPC. We propose identifying gDDRm status at the time of diagnosis for mCSPC patients, considering it is the first step of tailoring individualized treatment. In addition, DNA repair genes were a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and our results call for more frontline targeted therapy trials in gDDRm carriers to prolong the progression time. IMPLICATIONS FOR PRACTICE: Results of this study suggested that positive germline DNA damage repair gene mutation (gDDRm) status predicted earlier progression to castration resistance in patients with de novo metastatic and castration-sensitive prostate cancer (mCSPC). These findings indicated the importance of intense therapy for some subgroups of mCSPC, especially for mCSPC harboring gDDRm with low-volume disease. Moreover, gDDRm was a good therapeutic target for poly (ADP-ribose) polymerase inhibitors, and these findings call for more molecular marker driven trials moving to the mTNPC setting.

Prognosis of the 8th TNM Staging System for Penile Cancer and Refinement of Prognostication by Incorporating High Risk Human Papillomavirus Status.

PURPOSE: We evaluated the prognostic value of the 8th TNM staging system and assessed a modified N stage incorporating high risk human papillomavirus status in a multicenter cohort. MATERIALS AND METHODS: Included in analysis were 292 patients with M0 penile squamous cell carcinoma from a total of 6 referral centers. High risk human papillomavirus status was examined. The Chinese multicenter cohort of 230 patients was used to validate the 8th TNM staging system and propose a modified N classification. The modified classification was further validated in an independent cohort of 62 patients at Moffitt Cancer Center. RESULTS: Median followup was 48.9 months. Of the patients 42% had node positive disease. In the primary cohort the 8th TNM staging system achieved better discriminative ability compared with the 7th edition (C-index 0.769 vs 0.751, p=0.029). The 8th N category better stratified survival between pN1 and pN2 (p <0.001) and reclassified 15% of node positive cases into pN1 with 64% 5-year overall survival. High risk human papillomavirus status further stratified pN2-3 disease (p=0.040) and pN2-3 high risk human papillomavirus negative status was associated with 32% 5-year survival. The newly proposed 3-tier classification (1-pN1, 2-pN2-3 high risk human papillomavirus positive and 3-pN2-3 high risk human papillomavirus negative) significantly increased the C-index from 0.620 to 0.666 compared with the 8th N classification of pN1 and pN2-3 (p=0.04). In the external validation cohort significantly improved results were observed using the modified N classification (C-index 0.567-0.641, p=0.027). CONCLUSIONS: The 8th edition of the AJCC (American Joint Committee on Cancer) Staging System for penile cancer showed better discriminative ability for prognostic stratification. Adding high risk human papillomavirus status further improved the prognostic stratification in patients with node positive disease.

42 °C heat stress pretreatment protects human melanocytes against 308-nm laser-induced DNA damage in vitro.

Vitiligo is a common depigment of skin disorder due to loss of functional melanocytes. Recently, the phototherapy with a 308-nm xenon-chloride excimer laser (UVB laser) is wildly used in vitiligo treatment. However, excessive UVB will induce photo-damage and photo-carcinogenesis in melanocytes. Previous studies revealed a protective effect of heat on UVB-induced melanocyte damage. In this study, we combined heat stress pretreatment with UVB to evaluate whether heat stress pretreatment has an ameliorative effect on UVB-induced damage. Human primary melanocytes (HMCs) were cultured and irradiated with a 308-nm laser with/without heat treatment. MTT assay, apoptosis analysis, and comet assay were conducted to monitor the damage of HMCs. Western blot and immunofluorescence staining were performed to assess the expression and subcellular localization of HSP70. HMCs heated at 42 °C for 1 h exhibit no cytotoxicity. Furthermore, preheat treatment attenuated the UVB laser-induced injury, reduced the DNA damage, and attenuated the cell apoptosis. The level and the localization of HSP70 determined the protective effects against UVB-induced DNA damage. Combining preheat treatment with a 308-nm xenon-chloride excimer laser would be a potential therapeutic method not only promotes the repigment of vitiligo but also reduces the UVB-induced photo-damage.

Important Therapeutic Considerations in T1b Penile Cancer: Prognostic Significance and Adherence to Treatment Guidelines.

BACKGROUND: The clinical implications and contemporary management of T1b penile cancer are unknown. National treatment guidelines advocate surgical lymph node examination (SLNE) for T1b disease. OBJECTIVE: The aim of this study was to evaluate the prognosis of T1b disease and adherence to corresponding treatment guidelines. METHODS: We analyzed 296 patients from two academic centers, and 1263 patients from the Surveillance, Epidemiology, and End Results (SEER) registry (median follow-up 48.3 and 21 months, respectively). Multivariate Cox and Fine-Gray regressions were applied for penile cancer-specific survival (PCSS) analyses. RESULTS: In the academic center cohort, 28.3% of T1 patients had T1b disease, all of whom underwent SLNE. Nodal metastases were detected in 86.7% of T1b patients and 13.2% of T1a patients (p < 0.001). Using T1a as a reference, PCSS was significantly poorer in the T1b patients, with an adjusted hazard ratio (aHR) of 4.10 (p = 0.03). In the SEER cohort, 16.8% of T1 patients were classified as T1b. SLNE was performed in 21.7% of the T1b patients versus 38.2% of the T2 patients (p = 0.002). The probability of nodal metastases was 2.23-fold higher in T1b patients than in T1a patients (p < 0.001). In clinical N0M0 patients without SLNE, compared with T1a disease, T1b was associated with an aHR of 4.40 and a subdistribution HR of 4.53 for PCSS (both p = 0.003). CONCLUSIONS: T1b penile cancer is strongly associated with nodal metastases and adverse PCSS, and is poorly managed according to guidelines recommended in the nationwide registry.

Prognostic significance of the dynamic changes of systemic inflammatory response in metastatic renal cell carcinoma.

PURPOSE: To elucidate the prognostic value of systemic inflammatory response in patients with metastatic renal cell carcinoma (mRCC) who are treated with sunitinib, we evaluated the prognostic role of C-reactive protein (CRP) kinetics. This study also compared prognostic models containing CRP kinetics and neutrophil-to-lymphocyte ratio (NLR) kinetics. MATERIALS AND METHODS: A consecutive cohort of 94 patients with mRCC who were treated with sunitinib was retrospectively included from Fudan University Shanghai Cancer Center. According to dynamic changes in CRP and the NLR, patients were divided into three groups for analysis of CRP and NLR kinetics. The associations between survival and potential prognostic factors were assessed. The incremental value of prognostication was evaluated. RESULTS: A significant difference (P<0.001) in overall survival (OS) was observed among the three groups of CRP kinetics. The median OS of the non-elevated group was nearly 1.3-fold longer than that of the normalized group (33.0 vs. 26.3 months), and two times longer than that of the non-normalized group (33.0 vs. 14.0 months). Multivariate analysis showed that CRP and NLR kinetics were independent prognostic indicators. The model containing CRP kinetics had a better predictive accuracy than that with NLR kinetics, which was supported by the C-index (0.731 vs. 0.684) and the likelihood ratio χ² test (79.9% vs. 44.9%). CONCLUSION: Our study suggests that dynamic changes in CRP can better predict survival in patients with mRCC who are treated with sunitinib. Routine assessment of CRP before and after targeted therapy would help identify patients at risk of a poor outcome.

Identification and validation of an eight-gene expression signature for predicting high Fuhrman grade renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a malignancy with heterogeneous outcomes. Currently, renal mass biopsies are commonly employed to extract disease characteristics and aid prognosis. Although the pathological diagnosis of malignant disease is accurate in contemporary reports, the classification of Fuhrman grade using biopsy specimens remains far from promising. To generate a gene signature to distinguish high-grade ccRCC, we used the cancer genome atlas (TCGA) database to develop a gene expression signature for distinguishing high-grade (G3/4) from low-grade (G1/2) disease. The expression profile was further validated for performance and clinical use in 283 frozen renal cancer samples and 127 ex vivo renal mass biopsy samples, respectively. The area under curve (AUC) was used to quantify discriminative ability and was compared using the De-long test. Using the discovery dataset, we identified a 24-gene signature for high-grade disease with an AUC of 0.884. After applied to the development dataset, an eight-gene profile was defined and achieved an AUC of 0.823. Accuracy of eight-gene panel was maintained in the renal mass biopsies (RMB) samples (AUC = 0.821). In summary, using three-stage design, we validated an eight-gene expression signature for predicting high Fuhrman grade of ccRCC. This tool may help to reveal the characteristics of ccRCC biopsy specimens.

Design, synthesis, and biological evaluation of thieno[2,3-d]pyrimidine derivatives as novel dual c-Met and VEGFR-2 kinase inhibitors.

Both c-Met and VEGFR-2 are important targets for cancer therapies. Here we report a series of potent dual c-Met and VEGFR-2 inhibitors bearing thieno[2,3-d]pyrimidine scaffold. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 12j and 12m. Based on the further enzyme assay in vitro, compound 12j was considered as the most potent one, the IC50 values of which were 25 nM and 48 nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 12j with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogues. All the results indicate that 12j is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.

Discovery of novel 2-substituted-4-(2-fluorophenoxy) pyridine derivatives possessing pyrazolone and triazole moieties as dual c-Met/VEGFR-2 receptor tyrosine kinase inhibitors.

In our efforts to develop novel dual c-Met/VEGFR-2 inhibitors as potential anticancer agents, a series of 2-substituted-4-(2-fluorophenoxy) pyridine derivatives bearing pyrazolone scaffold were designed and synthesized. The cell proliferation assay in vitro demonstrated that most target compounds had inhibition potency on both c-Met and VEGFR-2, especially compound 9h, 12b and 12d. Based on the further enzyme assay in vitro, compound 12d was considered as the most promising one, the IC50 values of which were 0.11µM and 0.19µM for c-Met and VEGFR-2, respectively. Further molecular docking studies suggested a common mode of interaction at the ATP-binding site of c-Met and VEGFR-2, indicating that 12d was a potential compound for cancer therapy deserving further study.

Design, synthesis and biological evaluation of 4-aminopyrimidine-5-cabaldehyde oximes as dual inhibitors of c-Met and VEGFR-2.

The synergistically collaboration of c-Met/HGF and VEGFR-2/VEGF leads to development of tumor angiogenesis and progression of various human cancers. Therefore, inhibiting both HGF/c-Met and VEGF/VEGFR signaling may provide a novel and effective therapeutic approach for treating patients with abroad spectrum of tumors. Toward this goal, we designed and synthesized a series of derivatives bearing 4-aminopyrimidine-5-cabaldehyde oxime scaffold as potent dual inhibitors of c-Met and VEGFR-2. The cell proliferation assay in vitro demonstrated most target compounds have inhibition potency both on c-Met and VEGFR-2 with IC50 values in nanomolar range, especially compound 14i, 18a and 18b. Based on the further enzyme assay in vitro, compound 18a was considered as the most potent one, the IC50s of which were 210nM and 170nM for c-Met and VEGFR-2, respectively. Following that, we docked the compound 10 and 18a with the proteins c-Met and VEGFR-2, and interpreted the SAR of these analogs. All the results indicate that 18a is a dual inhibitors of c-Met and VEGFR-2 that holds promising potential.

Prognostic value of pathological features of primary lesion in metastatic renal cell carcinoma treated with sorafenib.

AIM: This study aimed to investigate whether the pathological features of primary lesions show additional prognostic value in patients with metastatic renal cell carcinoma who are treated with sorafenib. PATIENTS & METHODS: A consecutive cohort of 284 patients was included from Fudan University Shanghai Cancer Center between 2007 and 2013. The association between survival and pathological features of primary tumors was assessed using the Cox proportional hazards model. The incremental value of prognostication was evaluated. RESULTS: We found that the pathological features of primary lesions provided added prognostic value over the Memorial Sloan-Kettering Cancer Center model in patients with metastatic renal cell carcinoma who were treated with sorafenib. CONCLUSION: Addition of a pathological score in the clinical setting could better identify patients at risk of poor survival.

Pretreatment neutrophil-to-lymphocyte ratio predicts prognosis in patients with metastatic renal cell carcinoma receiving targeted therapy.

BACKGROUND: The neutrophil-to-lymphocyte ratio (NLR) is associated with clinical outcomes of various cancers. This study aimed to evaluate whether pretreatment NLR can be used as a prognostic factor in patients with metastatic renal cell carcinoma (mRCC) receiving targeted therapy. METHODS: In this single-center retrospective study, the Kaplan-Meier method was used to estimate progression-free survival (PFS) and overall survival (OS) of 373 mRCC patients receiving targeted therapy. The survival outcomes of patients with high (≥ 2.2) and low (< 2.2) pretreatment NLRs were compared by log-rank test, and Cox proportional hazard regression model was used to compare OS and PFS between groups. RESULTS: The overall median PFS and OS times for all 373 patients were 18.4 and 34.3 months, respectively. Patients with high NLRs had significantly shorter median OS (28.8 vs 410 months, P = 0.005) and PFS (15.4 vs 23.9 months, P = 0.001) than those with low NLRs. After adjusting for confounding variables, each unit increase of NLR was associated with a 40 % increase in mortality (hazard ratio [HR] 1.391; 95 % confidence interval [CI] 1.022-1.894; P = 0.036). High NLR was also an independent predictor of poor PFS (HR 1.544; 95 % CI 1.166-2.045; P = 0.002). CONCLUSION: Pretreatment NLR may be an independent prognostic factor for mRCC patients who are receiving targeted therapy.