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.

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.

Long Non-Coding RNA Expression Profile in Vascular Endothelial Cells before and after Infected by Dengue Virus Type Ι / 中山大学学报(医学科学版)

@#【Objective】 To use high- throughout sequencing technologies for examining differentially expressed long non-coding RNA（lncRNA）in human umbilical vein endothelial cell（HUVEC）infected by dengue virus type Ι（DENV-1）， to analyze and explore the potential molecular mechanisms of HUVEC dysfunction or damage.【Methods】After 24 hours of DENV-1 infection，RNA samples were extracted from control groups and viral groups. Sequencing and the differentially expressed lncRNAs were screened ，and then GO and KEGG enrichment analysis were conducted and a co- expression network map was constructed.【Results】In contrast to the control group，there were 2 623 lncRNA expressed differently， among which 1 441 were up-regulated，while 1 182 were down-regulated. It was found that the differentially expressed lncRNA and the predicted corresponding target genes were mainly distributed in the regions of biological processes of antigen presentation，interferon synthesis，apoptosis and cell adhesion. 【Conclusion】After HUVEC were infected with DENV-1，lncRNA expression profile changes significantly，which is closely related to the occurrence and development of dengue hemorrhagic fever/dengue shock syndrome（DHF/DSS）.

Advances in the treatment of malignant melanoma / 中国肿瘤临床

Absdract Melanoma is characterized by high mortality and poor prognosis. The novel immunotherapy has offered a breakthrough in antitumor activity in melanoma and has offered incremental improvements over standard care. The ASCO annual meeting held on June 1, 2018 in Chicago, was conducted to present the progress of current treatment and promise of those still in clinical development. The academic event showed results of clinical trials in patients with lymph node dissection, adjuvant therapy, immunotherapy, and targeted therapy. Melanoma drugs introduced at the meeting included NIVO, Pembro, T-VEC, Encorafenib, Binimetinib, and CDk4/6i. The development of therapy is retrospected in this paper in order to provide a basis and give hope for melanoma treantment in China.

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.

Advances in treatment of melanoma with immunotherapy / 肿瘤

Immunotherapy, primarily headed by immune checkpoint inhibitors, has become a standard, first-line therapeutic methodin treatment for patients with melanoma. Combination immunotherapy, that is the combination of programmed cell death-1 (PD-1) inhibitor and cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) inhibitor, further enhanced the anti-tumor efficacy, improved the objective response rate, and extended both the overall and progressionfree survival of patients in the past years. Therefore, combination immunotherapy has also become a new direction for the treatment of melanoma. Meanwhile, the anti-tumor effects and clinical outcomes of combination immunotherapy in other types of tumors are also encouraging. Combination immunotherapy offers a new treatment option for patients, but there are still many issues that need to be further discussed. In order to maximize the benefit of patients, more large-scale clinical researches are needed to answer the questions which may strongly affect the clinical decisions, such as, how to optimize the regimens of combination therapy, how to identify the appropriate treatment population, and how to balance the risk-benefit ratio of patients.

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>

Coumarins from Leonurus japonicus and their anti-platelet aggregative activity / 中国中药杂志

Chemical constituents of Leonurus japonicus were isolated and purified by a combination of various chromatographic techniques including column chromatography over silica gel, Sephadex LH-20, MCI, and Rp C18. Structures of the isolates were determined by spectroscopic analysis as 10 coumarins: bergapten (1), xanthotoxin (2), isopimpinellin (3), isogosferal (4), imperatorin (5), meransin hydrate(6), isomeranzin(7), murrayone(8) , auraptenol(9), and osthol(10). In addition to compound 9, the others were isolated from the genus Leonurus for the first time. In the in vitro assay, compounds 4 and 8 significantly inhibited the abnormal increase of platelet aggregation induced by ADP.

Correlation between tumor cell proliferation and prognosis of primary cutaneous malignant melanoma in 127 patients / 中华病理学杂志

<p><b>OBJECTIVE</b>To investigate the correlations among Ki-67 expression, mitosis and other clinicopathological parameters of primary cutaneous malignant melanoma, and search for prognostic factors of malignant melanoma.</p><p><b>METHODS</b>Totally 127 cases of primary cutaneous malignant melanoma were collected from Beijing Cancer Hospital. Immunohistochemical study for Ki-67 was performed, and the mitosis was calculated referring to "hot spot" method recommended by the seventh edition of the American Joint Committee on Cancer (AJCC) melanoma staging system. The correlations of Ki-67 expression, mitosis and other clinicopathological parameters were analyzed, and the survival analysis of all these risk factors including TNM and Clark level was conducted based on follow up data.</p><p><b>RESULTS</b>The expression level of Ki-67 was associated with necrosis and Breslow thickness (P < 0.05). Mitosis was correlated with Clark level and Ki-67 expression (P < 0.05). Univariate analysis indicated Ki-67 expression level (P = 0.043), mitosis (P = 0.030) and TNM stage (P < 0.001) might influence the survival of patients. However, multivariate analysis showed that the TNM staging was the only independent prognostic factor affecting survival.</p><p><b>CONCLUSIONS</b>The prognosis of patients with primary cutaneous malignant melanoma was closely related to the TNM staging at the fist examination. Ki-67 expression and mitosis are two important clinicopathological parameters of primary cutaneous malignant melanoma.</p>

Expression and prognostic significance of galectin-1 and galectin-3 in benign nevi and melanomas / 中华病理学杂志

<p><b>OBJECTIVE</b>To study the expression and prognostic significance of galectin-1 and galectin-3 in different melanocytic lesions.</p><p><b>METHODS</b>The expression of galectin-1 and galectin-3 in 39 cases of benign nevus, 58 cases of primary cutaneous melanoma, 24 cases of primary mucosal melanoma, 69 cases of melanoma with lymph node metastasis and 8 cases of melanoma with distant metastasis were studied by immunohistochemistry and tissue microarray.</p><p><b>RESULTS</b>The expression of galectin-1 and galectin-3 was higher in benign nevi than in melanomas (P < 0.01). The nuclear expression of galectin-3 was higher in primary cutaneous melanomas than in primary mucosal melanomas or melanomas with metastases (P < 0.01, respectively). The expression correlated with age of patients (P < 0.05), necrosis (P < 0.05) and survival time (P < 0.01). Clark's level also correlated with survival time in patients with cutaneous melanomas (P = 0.037). TNM staging was the only independent prognostic factor for melanomas (P < 0.01).</p><p><b>CONCLUSIONS</b>The expression of galectin-1 and galectin-3 is decreased in melanomas. The decrease in nuclear expression of galectin-3 may represent a poor prognostic factor for melanomas. TNM staging is an independent prognostic factor which influences the survival time.</p>

Role of C6ORF120, an N-glycosylated protein, is implicated in apoptosis of CD4⁺ T lymphocytes / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Although CD4(+) T cell apoptosis and CD8(+) T cell responses have been extensively studied during HIV infection, how apoptosis signals being initiated in CD4(+) T cells still need to be elucidated. The present study was designed to characterize the function-unknown gene, C6orf120, and elucidates its primary role in tunicamycin-induced CD4(+) T apoptosis.</p><p><b>METHODS</b>The C6orf120 coding sequence was amplified from peripheral blood mononuclear cells (PBMCs) total RNA of AIDS patients. The DNA fragment was inserted into the pET-32a expression system, transformed into Escherichia coli, and preparation of C6ORF120 recombinant protein. The magnetic cell separation technology was used to prepare primary CD4(+) T cells and CD8(+) T cells. The primary T cells were cultured at 1 × 10(6) cells/ml, treated with 0, 0.1, 1, 10, 100, and 200 ng/ml of C6orf120 recombinant protein for 48 hours, then harvested for cell cycle and apoptosis analysis. Tunicamycin (0.5 µmol/L) was used to induce endoplasmic reticulum stress in Jurkat cells. The biomarker 78 KDa glucose-regulated protein (GRp78) and growth arrest and DNA damage (GADD) were used to evaluate endoplasmic reticulum stress of Jurkat cells.</p><p><b>RESULTS</b>We prepared C6ORF120 recombinant protein and its polyclonal antibody. Immunohistochemical analysis showed that C6orf120 mainly expressed in hepatocytes and cells in germinal center of lymph node. At concentration of 0.1, 1, 10, 100, and 200 ng/ml, C6orf120 recombinant protein could induce apoptosis of Jurkat cells and primary CD4(+) T cells, and promoting G2 phase of its cell cycle. Western blotting analysis showed that C6ORF120 recombinant protein increased the expression of GRp78 and GADD in Jurkat cells in vitro.</p><p><b>CONCLUSION</b>Our results suggested that C6ORF120 could induce apoptosis of CD4(+) T cells, at least in part, mediated with endoplasmic reticulum stress.</p>

Preliminary report of sunitinib as first line treatment in patients with metastatic renal cell carcinoma / 中华泌尿外科杂志

Objective To evaluate the efficacy and safety of sunitinib as first line treatment in patients with metastatic renal cell carcinoma (RCC). Methods This study included 46 Chinese patients who were diagnosed with metastatic RCC after radical nephrectomy. The patients received oral sunitinib (50 mg once daily on a 4 weeks on, 2 weeks off) on a 6 weeks cycle dose schedule until disease progression or intolerable toxicities occurred. Results The overall objective response rate was 32.6% (95% confidence interval [CI, 19.1% to 46. 1%]), and the disease control rate was 86.9%,with complete response (CR) 0 (0%), partial responses (PRs) 15 (32.6%), stable disease (SD) 25(54.3 %), and progression disease (PD) 6 ( 13. 1%). The median progression-free survival was 11 months, and the 1-year survival rate was 65.2%, while the median overall survival (mOS) has not been reached. The main adverse events included fatigue 33 (71.7%), skin discoloration 29 (63.0 %),anorexia 28 (60.9%), hand-foot syndrome 26 (56.5%), oral mucositis 25 (54.3%), hypertension 19 (41.3%), facial edema 18 (39.1%), diarrhea 17 (37.0%), hemorrhage 17 (37.0%), nausea 15 (32.6%), and hematological toxicity: leukopenia 32 (69.6%), neutropenia 30 (65.2%), thrombocytopenia 28 (60.9%), anemia 21 (45.7%). Most of grade 3/4 serious adverse events were thrombocytopenia in 15 (32. 6%) patients. Conclusions Sunitinib has a prominent effect in metastatic renal cell cancer in a Chinese population with mostly mild to moderate adverse reactions. More attention should be paid to grade 3/4 adverse reaction of thrombocytopenia.

The succession of sarcophagus beetles on carrion and its application in forensic medicine / 法医学杂志

Sarcophagus beetles, which can not be replaced by Diptera, play a pivotal role not only in estimating PMI of dry human skeletal remains in the later stages decomposition of carcasses, but also the corruption, destruction, decomposition and posture changes of carcasses. This article explicates the succession of sarcophagus beetles on carrion and its influencing factors, and introduces the application and prospects of sarcophagus beetles in forensic entomology. Although few researches focus on sarcophagus beetles at present, it is believed that more and more forensic scientists will pay attention to sarcophagus beetles' application in forensic identification.

Predictive factors of sorafenib in the treatment of metastatic renal cell carcinoma / 中华泌尿外科杂志

Objective To analyze the effect and related factors of sorafenib in the treatment of metastatic renal cell carcinoma(MRCC), and identify the potential predictive factors of sorafenib re-sponse. Methods The data of 51 MRCC patients who received sorafenib therapy, with or without combination with interferon or chemotherapy were retrospectively reviewed. After two cycles of treat-ment, patients were evaluated for progression or response. Pearson Chi-square test and Logistic re-gression test were performed respectively as univariate and multivariate analyses of sorafenib response. Results The overall objective response rate was 29.4%(95% confidence interval 16.9% to 41.9%, with 1(2.0%) complete response and 14(27.4%) partial responses. Twenty-nine(56.9%) had stable disease, and 7 (13.7%) had progression disease (PD). Significant independent predictive factors asso-ciated with good response in multivariate analysis were lung metastasis only(P=0.021, HR=5.127). Conclusions Sorafenib is effective in MRCC patients. Lung metastasis only is predictive factor in mul-tivariate analysis for sorafenib response.

Relationship between sorafenib's side effects and efficacy in treatment of advanced renal cell carcinoma patients / 中华泌尿外科杂志

Objective To identify the relationship between sorafenib's efficacy and its side effects in treatment of advanced renal cell carcinoma patients. Methods Fifty-one patients having measurable diseases were diagnosed with advanced renal cell carcinoma. Of whom, 26 patients were in stage T1Nx,0,1M1, 12 patients in stage T2Nx,0 M1, 8 patients in stage T3NxM1, 5 patients in stage T4NxM1. These 46 patients of T1 -T3 had their primary diseases removed, but the 5 T~ patients didn"t have their primary diseases removed. These 51 patients received oral sorafenib 400 mg Bid continual-ly and they had CT scan every two months to evaluate the progression. The dosage of sorafenib wasmodified according to efficacy and toxicity. Two patients changed the dosage to 200 mg Bid due to se-vere side effects. Sixteen patients increased the dosage to 600 mg Bid or 800 mg Bid. The response ofSorafenib and toxicities as well as their severity were recorded. The toxicity severity was graded ac-cording to National Cancer Institute Common Toxicity Criteria version 3.0. The efficacy was deter-mined by RECIST criteria. The efficacy and progression free survival (PFS) were recorded. The sta-tistics analysis was conducted between sorafenib's side effects and efficacy as well as their severity by multi-faetor Logistic regression. Results The rates of adverse events in the patients receiving oral sorafenib were hand-foot skin reaetion 68. 6% (35/51), diarrhea 39. 2% (20/51), rash 25. 5% (13/ 51), mucositis 23.5% (12/51), hypertension 17.6% (9/51), and myelosuppression 13. 7%(7/51). The response rate in the patients who had toxicity of grade 3-4 was 33.3%(12/36), and that in the patients who had slight toxicity was 12.0%(3/25). The rate of hand-foot skin reaction was higher than that of diarrhea, rash, mucositis, hypertension and bone marrow suppression (P<0.01). Sor-afenib's efficacy was eorrelated to rash and mueositis (P=0.048, 0.045 respectively). More grade 3 4 side effects occurred in the patients who would have better response to sorafenib (P=0.008). The median PFS was 15.0 months and PFS was not related to the toxicity and its severity. Conclusions It may help to predict the response for sorafenib's side effects and efficacy in the treatment of the patients with advaneed renal cell earcinoma.

Preliminary report of dosage-escalated sorafenib in patients with metastatic renal cell carcinoma / 中华泌尿外科杂志

Objective To evaluate the safety and efficacy of dosage-escalated sorafenib in pa-tients with metastatic renal cell carcinoma. Methods Twelve male patients and 4 female patients with median age of 53 (37-71 years) were included in this study. They were with refractory meta-static renal-clear-cell carcinoma and received sorafenib from 800 mg/d to 1200mg/d or 1800 mg/d gradually until intolerable or disease progression occurred. Overall response rate, toxicity and progres-sion free survival (PFS) were recorded and analyzed. Results The median follow-up was 11 months (9-16 months). The overall rate of objective response and disease control rate were 44%(7/16)and 81%(13/16), respectively. Serious adverse effects (≥Grade Ⅲ) included hand-foot skin reaction (25%, 4/16), mucositis (19%, 3/16), diarrhea (19%, 3/16), hypertension (12%, 2/16) and my-elosuppression (12%, 2/16). PFS for high risk patient was 9.2 months at the end of this study. Conclusions The dosage-escalated sorafenib could obtain a high response rate and prolong PFS of high-risk patients. The toxicities are tolerable for metastatic renal cell carcinoma patients treated with sorafenib.

Sorafenib in combination with interferon-α-2b for the treatment of metastatic renal cell carcinoma: pre-liminary results / 中华泌尿外科杂志

Objective To explore the efficacy and tolerability of sorafenib in combination with interferon-α-2b for Chinese patients with metastatic renal cell carcinoma. Methods Seventeen pa-tients with unreseetable metastatic renal cell carcinoma were enrolled and received sorafenib in combi-nation with interferon-α-2b. Sorafenib was continuously given at the dose of 400 mg twice per day, in-terferon-α-2b 300 MIU subscutaneously once per day for 5 d each week, until disease progression or intolerable toxieities occurred. Tumor responses were evaluated every two months by response evalua-tion criteria in solid tumor. Results The median treatment duration was 120(51-442)d. All 17 pa-tients were evaluable for efficacy and safety. Five patients achieved partial responses (PR), 1 uncon-firmed PR,9 stable diseases. Two patients had progressed diseases. The overall response rate was 29%(5/17)with the disease control rate of 88%(15/17). Due to short-time follow up, the median progression free and overall survival time were not yet available. The common side effects included: fever 82%(14/17), diarrhea 82%(14/17), hand-foot syndrome 71%(12/17), asthenia 65%(11/17), rash 53%(9/17), alopecia 41% (7/17), mucosities 41% (7/17), hypertension 29% (5/17), anorexia 24% (4/17), hoarseness 24% (4/17), myalgia 24 % (4/17), nausea/vomiting 12 % (2/17) and headach/ dizzle 12%(2/17). Eleven (65%) out of 17 patients developed neutropenia, 5(29%) thrombocytope-nia and 5 (29%)anemia. Four(24%) out of 17 patients had abnormally elevated ALT/AST. Conclu-sion Sorafenib in combination with interferon-α-2b for metastatic renal cell carcinoma improves re-sponse rate with manageable toxicity.

Phase II study of adoptive immunotherapy for advanced melanoma / 肿瘤

Objective: To observe the efficacy and safety of chemotherapy combined with cytokine-induced killer (CIK) cells in the treatment of metastatic melanoma (MM). Methods: Fifty three chemotherapy-naive MM patients were administered fotemustine at 100 mg/m2 on d 1-5; dacarbazine were given at 400 mg/d on d 2-6; CIK were infused on d 7, d 14, d 16. Twenty-eight days were regarded as one cycle. The clinical efficay was evaluated every 2 cycles. Results: Thirty-four out of 53 patients were eligible to be evaluated. The overall response rate (ORR) was 23.5% including 1 case with complete response (CR) (2.9%) and 7 cases with partial response (PR) (20.6%). Fourteen cases had stable disease (44%). The clinical benefit response was 67.5%. Median progression free survival (PFS) was 8 months. Median overall survival (OS) was 11 months. The patients with normal lactate dehydrogenase (LDH) had longer OS; those with stable disease had longer PFS and OS. Adverse reaction included grade III/IV thrombopenia (41%), decrease in the number of WBC (23.5%), and hyperreactivity (2 cases). No treatment-related death occurred. Conclusion: Chemotherapy followed by the infusion of CIK was tolerable. The response rate was higher than common chemotherapy. It could prolong the survival time of tumor patients with elevated LDH and non progression disease. Phase III study is needed to confirm the results.

Curcumin reduces A?generation of neurons by PPAR? activation and BACE1 inhibition / 重庆医科大学学报

Objective: To investigate the inhibitory effects of Curcumin on A? generation in vitro and explore its potential mechanisms involing BACE1 and PPAR?.Methods: Plasmids APPswe and BACE1-mychis were transiently co-transfected into SHSY5Y cells by LipofectaminTM2000,then treated with Curcumin at 0(control Group),1.25,5.0,20.0 ?mol/L for 24 hr,or with Curcumin at 5 ?mol/L for 0,12,24 and 48 hrs for the time course assay.RT-PCR was performed to measure the endogenous levels of BACE1 mRNA and PPAR?.Western blot were used to detect the protein expression of BACE1 and PPAR?.The major cleavage product——A?40 and A?42 was detected by ?-amyloid 1-40 or 42 Colorimetric ELISA assay.Results: The mRNA level and protein level of BACE1 were decreased obviously in a dose-and time-dependent manner after treated with Curcumin in the cell line(P