Effect of different HER2 expression on the efficacy of immunotherapy for advanced urothelial carcinoma who failed the previous chemotherapy / 中华泌尿外科杂志

Objective:To explore the effect of different HER2 expression levels and gene amplification on the efficacy of immunotherapy in metastatic urothelial carcinoma (UC).Methods:The clinical data of 77 patients with metastatic UC who received immunotherapy from June 2017 to April 2021 after failure to the previous chemotherapy were analyzed retrospectively, including 49 males and 28 females with the median age of 62 years. The primary tumors located in bladder in 28 cases (36.4%), renal pelvis in 25 cases (32.5%) and ureter in 24 cases (31.2%). The common metastatic sites included: lymph nodes (n = 45, 58.4%), lung (n = 40, 51.9%), bone (n = 20, 26.0%) and liver (n = 16, 20.8%). 27 patients with bladder UC received surgery on the primary tumors including radical cystectomy (n = 18), partial cystectomy (n = 4) and transurethral resection (n = 5). 43 patients with renal pelvis or ureteral UC received surgery on the primary tumors including radical nephroureterectomy (n = 38), local resection (n = 3) and palliative resection (n = 2). Postoperative intravesical chemotherapy was performed in 15 cases, adjuvant radiotherapy was performed in 6 cases. 3 patients who emerged postoperative bladder recurrence received local radiotherapy. 7 patients received radiotherapy and 1 case received microwave ablation to their metastatic sites. All patients had received first-line chemotherapy and 30 patients (40.0%) had received at least second-line treatment including 70 cases (90.9%) with platinum containing chemotherapy. All 77 patients received anti-PD-1 treatment. 38 patients received sequential regimen after failed to the anti-PD-1 therapy, including antibody-drug conjugate (n = 17), chemotherapy (n = 18) and chemotherapy combined with anti-angiogenesis drugs (n = 12). Immunohistochemical (IHC) staining was used to detect the expression level of HER2 protein in the tumor tissues (74 cases from primary tumors and 3 cases from metastatic tumors) obtained from the initial diagnosis. For patients with HER2 IHC (+ + ), the copy number (CN) of HER2 gene was detected by next-generation sequencing (NGS). HER2 copy number amplification [CN (+ )] was defined as CN ≥ 4, and HER2 copy number non-amplification [CN(-)] was defined as CN < 4. HER2 IHC (0) was defined as HER2 negative, IHC (+ ) or IHC (+ + ) / CN (-)was defined as HER2 low expression, while IHC (+ + ) / CN(+ ) and IHC (+ + + ) were defined as HER2 high expression. Chi-square test or Fisher exact test were used to evaluate the correlation between HER2 expression and objective response rate (ORR) after anti-PD-1 treatment. Kaplan-Meier method and log-rank test were used to compare the differences of median progression free survival (PFS) and overall survival (OS) under different HER2 expression status.Results:All the 77 patients received a median of 11 (range: 2 - 45) doses of anti-PD-1 treatment with a median duration of treatment of 6.4 (range: 1.5 - 47.8) months and the ORR was 33.8% (26/77). The median follow-up time was 30.9 months. The overall median PFS time was 5.8 (95% CI: 3.0 - 8.6) months and the median OS time was 23.6 (95% CI: 8.5 - 38.7) months. HER2 IHC tests were performed in 77 patients. HER2 IHC levels of (0), (+ ), (+ + ) and (+ + + ) were found in 33 (42.9%), 19 (24.7%), 20 (26.0%) and 5 (6.5%) patients, respectively. HER2 copy number was detected in 20 patients with IHC (+ + ), while 1 CN(+ ) and 19 CN(-) were found. The ORR of HER2 negative, low expression and high expression patients were 42.4% (14/33) vs. 31.6% (12/38) vs. 0 (0/6) ( P = 0.08), respectively. The median PFS of the three groups were 11.0 months, 3.7 months and 1.8 months, respectively, with significant differences in overall and pairwise comparison( P=0.001). The median OS of patients with HER2 negative and low expression after anti-PD-1 treatment were 23.6 months and 22.7 months, respectively, while the median OS of patients with HER2 high expression had not been reached, with no significant difference in the overall comparison ( P=0.623). Conclusions:For patients with metastatic UC received anti-PD-1 treatment, the PFS of patients with high HER2 expression was significantly worse than that of patients with low or negative HER2 expression. HER2 expression may have potential value in predicting the efficacy of immunotherapy for metastatic UC who failed the previous chemotherapy, which needs further research.

Coronavirus GenBrowser for monitoring adaptive evolution and transmission of SARS-CoV-2

Genomic epidemiology is important to study the COVID-19 pandemic and more than two million SARS-CoV-2 genomic sequences were deposited into public databases. However, the exponential increase of sequences invokes unprecedented bioinformatic challenges. Here, we present the Coronavirus GenBrowser (CGB) based on a highly efficient analysis framework and a movie maker strategy. In total, 1,002,739 high quality genomic sequences with the transmission-related metadata were analyzed and visualized. The size of the core data file is only 12.20 MB, efficient for clean data sharing. Quick visualization modules and rich interactive operations are provided to explore the annotated SARS-CoV-2 evolutionary tree. CGB binary nomenclature is proposed to name each internal lineage. The pre-analyzed data can be filtered out according to the user-defined criteria to explore the transmission of SARS-CoV-2. Different evolutionary analyses can also be easily performed, such as the detection of accelerated evolution and on-going positive selection. Moreover, the 75 genomic spots conserved in SARS-CoV-2 but non-conserved in other coronaviruses were identified, which may indicate the functional elements specifically important for SARS-CoV-2. The CGB not only enables users who have no programming skills to analyze millions of genomic sequences, but also offers a panoramic vision of the transmission and evolution of SARS-CoV-2.

Prognostic value of PD-L1 expression level in metastatic renal cell carcinoma / 中华泌尿外科杂志

Objective:To explore the prognostic value of PD-L1 expression level in patients with metastatic renal cell carcinoma (mRCC).Methods:The clinicopathological and survival data of patients with mRCC in our hospital from Jan 2014 to Apr 2016 were retrospectively analyzed including 46 males and 15 females. The median age of these patients was 56 years(range: 29-75 years), with 41 patients ≤60 years and 20 patients >60 years. The baseline data before the systemic therapy showed 36 patients(59.0%)had 1 metastatic organ and 25 patients (41.0%) had equal or more than 2 organs to be metastasized. Among them, 17 patients(27.9%)had lung metastasis and 54 patients(88.5%)had liver metastasis. Abnormal baseline LDH occurred in 4 patients and 52 patients had normal LDH. Favorite and intermediate risk patients categorized by MSKCC risk stratification accounted for 59.6%(34 patients)and 40.4%(23 patients), respectively. Six patients(9.8%)experienced distant metastasis at initial diagnosis, with 4 of them undergoing primary site resection, and the other 55 patients undergoing radical nephrectomy. PD-L1 expression was detected by the immunohistochemical staining method. PD-L1 staining rate ≥1% detected on the tumor cell membrane was defined as positive expression. The correlation between PD-L1 expression and clinicopathological characteristics were compared. Kaplan-Meier method and log-rank test were used to compare the differences about DFS and OS under different factors. Cox proportional hazards regression model is used for multivariable analysis of survival data.Results:The detailed pathological types of the 61 patients with renal cell carcinoma were classified as 53 clear cell carcinomas, 3 papillary carcinomas, 1 collecting duct carcinoma, 2 translocation renal cell carcinomas and 2 being unclassified. There were 4, 20, 19 and 9 patients categorized as WHO/ISUP nuclear grade 1, 2, 3 and 4, and 26, 12, 20 and 2 patients were categorized as T 1, T 2, T 3 and T 4 stage, respectively. Five patients had regional lymph node metastasis(N+), and the other 56 patients had no regional lymph node metastasis(N-). The numbers of patients categorized as stage Ⅰ, Ⅱ, Ⅲ and Ⅳ diseases according to TNM staging system were 20, 11, 21 and 8, respectively. The total PD-L1 positive rate was 24.6%(15/61). The corresponding PD-L1 expression rate of patients with WHO/ISUP nuclear grade 1-4 were 0(0 patient), 5.0%(1 patient), 31.6%(6 patients)and 44.4%(4 patients), respectively; With the increasing WHO/ISUP nuclear grade, the positive rate of PD-L1 gradually escalated with a linear correlation ( P=0.006). The PD-L1 expression of the normal and abnormal LDH group were 19.2%(10 patients)and 75.0%(3 patients), respectively, with significant difference( P=0.035). Univariate analysis of disease-free survival time(DFS)showed that the prognostic factors include PD-L1( P=0.045), age group( P=0.014), WHO/ISUP nuclear grade( P<0.001), T stage( P=0.015), N stage( P=0.026)and TNM stage( P=0.005). However multivariate analysis only suggested WHO/ISUP nuclear grade as the independent prognostic factors for DFS( HR=1.8, 95% CI 1.1-2.9, P=0.018). Either in univariate or multivariate analysis, PD-L1 was not a prognostic factor for overall survival (OS)of mRCC patients(univariate analysis: P=0.154; multivariate analysis: P=0.902). The independent prognostic factors of OS include WHO/ISUP nuclear grade( HR=3.0, 95% CI 1.1-8.0, P=0.033)and MSKCC risk stratification( HR=5.9, 95% CI 1.2-29.7, P=0.03). Conclusions:This study showed that the higher the WHO/ISUP nuclear grade of patients with mRCC, the higher the positive rate of PD-L1. PD-L1 expression was not the independent prognostic factor for DFS or OS of mRCC.

Clinical characteristics and prognosis of metastatic papillary renal cell carcinoma / 中国肿瘤临床

Objective: To investigate the clinical characteristics, treatment methods, and prognosis of metastatic papillary renal cell car-cinoma (pRCC). Methods: The clinical data of metastatic pRCC patients treated at the Department of Kidney Cancer and Melanoma, Pe-king University Cancer Hospital, were retrospectively analyzed. The prognosis of these patients was stratified through international metastatic renal cell carcinoma database consortium (IMDC) model. Survival and influencing factors were further analyzed using the Kaplan-Meier method and Cox proportional risk regression model. Results: From January 2003 to March 2018, 93 patients (median age, 50.0 years) were diagnosed with metastatic pRCC: 89 (95.7%) typeⅡcases and 4 (4.3%) typeⅠcases. The median follow-up dura-tion was 23.1 months, with 90, 44, and 14 patients having received first-line, second-line, and third-line treatments, respectively. The median overall survival (OS) of the 93 patients was (31.5±5.9) months [95% confidence interval (CI): 19.9-43.1], while the median OS of patients with low-, intermediate-, and high-risk (classified as per the International Metastatic Renal Cell Carcinoma Database Con-sortium [IMDC]) were (100.0±32.8), (38.3±8.2), and (16.4±1.2) months, respectively (high-risk vs. low/intermediate-risk, P<0.001; low-risk vs. intermediate-risk, P=0.015). The median progression free survival (PFS) with first-line treatment was (6.6±0.5) months. And the median PFS of the corresponding three groups stratified by IMDC score were (17.5±5.7), (7.1±2.3), and (5.2±1.5) months, respectively (high-risk vs . low-risk, P=0.002; high-risk vs . intermediate-risk, P=0.01). Conclusions: Metastatic pRCC is noted to have unique biologi-cal characteristics. The IMDC model can be used to predict the efficacy of first-line treatment using tyrosine kinase inhibitors as well as the prognosis of metastatic papillary renal cell carcinoma in such patients.

Advances of toripalimab for the treatment of melanoma / 中国肿瘤临床

On December 27, 2018, the first domestic anti-PD-1 antibody, toripalimab, was approved by the State Food and Drug Ad-ministration for the treatment of advanced melanoma after the failure of standard treatment. This represented a major breakthrough in the field of biopharmaceuticals in China and laid the foundations for pharmaceutical research and development in the field of tu-mor immunotherapy. In this article, we summarize the clinical research of the treatment of melanoma, the application of toripalimab in this field, and the global development of other anti-PD-1 antibodies, to provide guidance for the research and treatment of melano-ma in China.

The perception feature and influence factors in people with subjective memory complaints / 中华行为医学与脑科学杂志

Objective To study the memory disorder perception characteristics of subjective memo-ry complaints(SMCs)and to analyze the influencing factors. Methods 302 subjects conforming to the in-clusion criteria were selected.All the subjects completed the illness perception questionnaire-memory of Chi-nese version(IPQ-M). Results (1)There was no statistical difference between the score of social compari-son(2.95±0.78)and the middle value 3.The differences between the score of the remaining dimensions of memory impairment perception(timeline acute/chronic(3.57 ± 0.89),consequences(2.24 ± 0.77),timeline stability/decline(3.71±0.88),personal control(blame)(3.61±0.92),personal control(helplessness)(3.31± 0.73),emotional representation(2.29 ± 0.70),treatment control(2.78 ± 0.67),illness coherence(3.14 ± 0.64))and the middle value 3 were statistically significant(all P<0.05).(2)Gender,education level,living condition,marital status,economic condition,family history of dementia and knowledge education of dementia were the influencing factors of memory perception of SMCs. Conclusion The memory complaining people are less aware of the related knowledge of memory decline,and there are more errors and negative percep-tions.The factors that affect the perception of memory disorders are complex.

Efficacy and safety of transcatheter arterial chemoembolization combined with systemic chemotherapy in urothelial carcinoma patients with liver metastasis / 肿瘤

Objective: To investigate the efficacious and safe therapy for urothelial carcinoma patients with liver metastasis. Methods: A total of 42 urothelial carcinoma patients with liver metastasis from December 2006 to December 2016 at Department of Renal Carcinoma and Melanoma in Beijing Cancer Hospital were included in this retrospective study. All patients were divided into three groups, and treated with paclitaxel plus gemcitabine, paclitaxel plus gemcitabine and cisplatin, or paclitaxel plus gemcitabine combined with transcatheter arterial chemoembolization (TACE), respectively. The treatment continued until disease progression or intolerable adverse reactions occurred. The efficacy and treatment-related adverse reactions in different groups were analyzed specifically. Results: For the 42 patients, the median progression-free survival time (PFS) was 2.0±0.7 months [95% confidence interval (CI): 0.6-3.4], and the median overall survival time (OS) was 6.1±1.7 months (95% CI: 4.1-9.9). For the 12 patients receiving TACE combined with systemic chemotherapy, the median PFS was 7.1 ±0.7 months (95% CI: 5.7-8.5), the median OS was 14.1 ±3.0 months (95% CI: 8.3-19.9), which were statistically different from those in systemic chemotherapy group (both P < 0.01). The patients could tolerate TACE combined with systemic chemotherapy. The common adverse effects were gastrointestinal reaction at grade 1-2, upper abdominal pain and leukopenia. Conclusion: TACE combined with systemic chemotherapy is an efficacious and safe treatment regimen for urothelial carcinoma patients with liver metastasis.

The reliability and validity of Chinese version of the illness perception questionnaire-memory / 中华行为医学与脑科学杂志

Objective To introduce the illness perception questionnaire-memory (IPQ-M) and translate it into Chinese and to evaluate its reliability and validity.Methods The Chinese version of IPQ-M was translated from the original,back translated and adjusted for culture adaptation.A total of 152 community-dwelling people with subjective memory complaints (SMCs),who were aged 50 years or above,were investigated with the Chinese version of IPQ-M.40 participants among them were re-evaluated 2 weeks later.Results Exploratory factor analysis got 9 factors which could explain 70.757％ of the total variance.The factor loading of each item on the corresponding factors was higher than 0.4.The correlation between Chinese version of IPQ-M and GDS were-0.208 to 0.763 (P＜0.01).The Cronbach's α coefficient was 0.872,the testretest reliability was 0.894,and the Spearman-Brown split coefficient was 0.890.Conclusion The Chinese version of IPQ-M has good reliability and validity,and it can be used in Chinese elderly people with SMCs.

Analysis on the everyday memory characteristics and life quality of people with subjective memory complaints / 中华行为医学与脑科学杂志

Objective To investigate the characteristics of everyday memory of adults with subjective memory complaints (SMC),and probe into the correlation between everyday memory function and life quality.Methods Through convenience sampling,150 adults with SMC were face-to-face interviewed by an investigator,with demographic characteristics collected,and the cognition function,everyday memory function and life quality were also assessed during the interview.Results Among the 150 adults with SMC,the impairment rate of everyday memory function reached 96％,and the median score of RBMT-II was 16.00 (interquartile range 6.00),indicating a low level of everyday memory function,with the Name andDelayed recall Story items having lower scores.All participants were divided into two groups according to cognitive status,with 67 (44.70％) adults having normal cognitive function and 83 (55.30％) impaired cognitive function.After comparison,significant differences were found in the total score of RBMT-II and scores ofFaces recognition andDelayed recall Story between the two groups (P＜0.05).In all dimensions of SF-36,the median score of general health dimension for the 150 adults was 55.00 (inter-quartile range 31.25).The Spearman rank correlation analysis showed that the scores of several dimensions in RBMT-II were positively correlated with the scores of several dimensions in SF-36 (P＜0.05).Conclusion Everyday memory function of people with SMC was positively CorTelated with their life quality.

A pilot study of sunitinib as first-line therapy for metastatic renal cell carcinoma on a 2 weeks on/1 week off intermittent dosing schedule / 中华肿瘤杂志

<p><b>OBJECTIVE</b>To investigate the efficacy and safety of sunitinib as first-line therapy for metastatic renal cell carcinoma (mRCC) on a 2 weeks on/1 week off intermittent dosing schedule.</p><p><b>METHODS</b>A total of 11 mRCC patients were enrolled to receive sunitinib 50 mg/day in 2 weeks on/1 week off schedule per 6 weeks till disease progression or intolerable toxicity occurred. The primary end point was progression free survival (PFS), the secondary end points were overall survival (OS), incidence of adverse effects and objective response.</p><p><b>RESULTS</b>The objective response rate in the 11 cases was 45.5% and disease control rate 72.7% (partial response n = 5, stable disease n = 3). Till the last follow up on Dec 2013, the median PFS was 17.0 months (95% CI 7.3 to 26.7 months), and median OS 26.0 months (95% CI 2.2 to 49.8 months). The common adverse events included leucopenia, thrombocytopenia, diarrhea, mucositis and hand-foot skin reaction. Dose reduction to 37.5 mg was seen only in 2 patients without discontinuation.</p><p><b>CONCLUSIONS</b>Sunitinib on an intermittent dosing schedule 2 weeks on /1 week off as first-line therapy for mRCC patients shows a good efficacy and tolerance, with less grade 3-4 drug-related toxicities and a tendency of prolonged PFS in mRCC patients.</p>

The effect of p53 expression in fibrablast-like synaviocytes on CD4+ T lymphocytes in patients with rheumatoid arthritis / 中华风湿病学杂志

Objective To investigate that p53 expression in fibroblast-like synoviocytes (FLS) and its effects on CD4+ T lymphocytes from active rheumatoid arthritis (RA) patients. Methods Human FLS was transfected with p53siRNA and cocultured with CD4+ T lymphocytes from active RA patients. The expression of osteoprotegerin and IL-6 secretion was detected in the transfected FLS. In addition, the expressions of IFN-γ, IL-17, IL-4 and CD25 as well as mRNA levels of IFN-γ RORγt, IL-17 and Foxp3 in cocuhured CD4+ T lymphocytes were also measured. Results IL-6 secretion decreased in p53-inhibited FLS while osteopro-tegerin expression was not altered, p53-inhibited FLS could significantly increase IL-17 and IFN-γ expres-sions. It also upregulated Foxp3 expression though had no effect on CD4+CD25high T lymphocytes. Conclusion p53 expression in FLS regulates Th1 and Th17 cells of RA patients, and therefore participate in the pathogenesis of RA.

Relationship between IL-17 and autoimmune diseases / 基础医学与临床

IL-17 is the cytokine secreted by the subgroup of CD4+T cells named Th17.The differentiation,proliferation and cytokine secretion of Th17 are regulated by TGF-?,IL-6,IL-15 and IL-23.IL-17 modulates the production and secretion of proinflammative factors,CXCs,affecting the transfer of neutrophil,the activation and the absorption of bone.It suggests that IL-17 also plays an important role in the pathogenesis of autoimmune diseases.