[Effects of VEGF on Proliferation, Apoptosis and Insulin Secretion in Rat Pancreatic Islet Cells].

OBJECTIVE: To investigate the effect of vascular endothelial growth factor (VEGF) on proliferation, apoptosis, insulin secretion and related gene expression in rat pancreatic islet cell (INS-1). METHODS: INS-1 cells were treated with different concentrations of VEGF. CCK-8 kit was used to detect the proliferation of INS-1 cells and the cell apoptosis were evaluated by using Annexin V and propidium iodide (PI) double staining kit. INS-1 cells were treated with VEGF and the standard glucose stimulated insulin secretion test with ELISA was conducted. The expression of related genes in pancreatic islets was detected by real-time quantitative PCR. The effect of VEGF on isulin protein expression was evaluated with Western blot. RESULTS: No significant changes (P > 0.05) in INS-1 cells were observed after treated with different concentrations of VEGF at 24 h, 48 h and 72 h. But when VEGF concentration were 80 ng/mL and 160 ng/mL, an inhibitory effect on cell apoptosis were noticed (P < 0.01). The addition of VEGF to the high-glucose media significantly reduced the release of insulin at the concentration of 40 ng/mL. A decreasing trends of the expression level of sulfonylurea receptor gene (Sur), inwardly rectifying potassium channel gene 6. 2 (Kir6. 2) as well as the release of insulin were noticed as the increasing of VEGF concentrations. The expression of glucokinase gene (GCK) first decreased and then increased, but the expression of glucose transporter gene 2 (Glut 2) were increased first and then decreased. CONCLUSION; VEGF inhibited the secretion of insulin from INS-1 cells in the high-glucose condition. Our study provides new clues to the function of VEGF on the glucose metabolism.

[Prognostic determinants of adrenocortical carcinoma in adults].

OBJECTIVE: To investigate the clinical features and prognostic determinants of adrenocortical carcinoma (ACC) in adult patients. METHODS: All adult patients (aged > or =18 years old) who were admitted to West China Hospital, Sichuan University from 1st Jan., 2000 to 31st Jan., 2013 with a pathologically diagnosed ACC were included in this study. Data about the demographics, clinical characteristics, laboratory examinations and outcomes of those patients were extracted and analyzed. RESULTS: A total of 52 cases were identified, with a median follow-up of 26 months (3-159 months). The patients had a median survival time of 29 months (1-156 months), with a 1-year, 3-year; and 5-year survival rate of 71.0%, 47.0%, and 42.7%, respectively. In the univariate analysis, aged >45 years old at diagnosis (P = 0.017), advanced stage (III-IV stage, P<0.001), incomplete resection (P = 0.011), symptomatic (P = 0.017), hypoalbuminemia (P = 0.003), and elevated lactate dehydrogenase (LDH) (P = 0.017) were associated with poor prognosis of ACC. The multivariate analysis confirmed that hypoalbuminemia Chazard ratio (HR) = 5.306; 95% confidence interval (95% CI: 1.975, 14.258; P = 0.001), female (HR = 4.020; 95% CI: 1.610, 10.038; P = 0.003), advanced stage (HR = 7.405; 95% CI: 2.561, 21.410; P < 0.001), and older age (HR = 4.628; 95% CI: 1.791, 11.959; P = 0.002) were predictors of poor prognosis of ACC. CONCLUSION: Hypoalbuminemia, female, older age, and advanced stage are independent risk factors associated with poor prognosis of ACC.in adult patients.

Upregulation of the antiapoptotic factor Livin contributes to cisplatin resistance in colon cancer cells.

The antiapoptotic factor Livin has been considered critical for tumor progression and poor prognosis for variant types of tumors. However, there are only limited reports regarding its expression and biological functions in colon cancer. Here, we examined Livin expression in four colon cancer cell lines (HCT116, RKO, KM12C, and SW620) in the presence or absence of cisplatin that was used as a model reagent. We found the different response to cisplatin was related to endogenous Livin expression level. From among a panel of apoptosis-related factors (p53, Bcl-2, Bcl-XL, BAX, and survivin), the expression of Livin was upregulated after cisplatin treatment in a dose-dependent manner. Both immunocytochemistry and nuclear cytoplasmic fractionation indicated Livin remained in the cytoplasm after treatment with cisplatin. In an attempt to explore the mechanism, we found the elevated expression of Livin was not due to the decreased degradation by proteosome but was enhanced at the mRNA level. Besides, cisplatin treatment activated the mammalian target of rapamycin (mTOR) pathway as shown by increased phosphorylation of Akt1, mTOR, S6K, and 4E-BP1, together with the elevated Livin. The PI3K inhibitor LY294002 inhibited both the phosphorylation of mTOR and upregulation of Livin. The stable overexpression of Livin inhibited the activation of caspase-3 and led to resistance to cisplatin, while the knockdown of Livin by siRNA rendered colon cancer cells more sensitive to cisplatin. Our study, along with others, highlighted the potential of Livin for cancer therapy in colon cancer.

[Autologous cytokine-induced killer cells therapy on the quality of life of patients with breast cancer after adjuvant chemotherapy: a prospective study].

OBJECTIVE: To explore the effect of autologous cytokine-induced killer cells on the quality of life in patient with breast cancer who have already finished the adjuvant chemotherapy. METHODS: One hundred and twenty-eight postoperative patients with breast cancer who underwent anthracycline-based adjuvant chemotherapy were enrolled in this prospective study, and they were randomized into 2 groups, i.e., treatment group, which received the therapy of CIK cells transfusion, and control group, which was given regular follow-up. Meanwhile, patients with positive hormone receptor in the two groups were given endocrine therapy, and the patients with positive axillary lymph nodes were given radiotherapy to the chest wall and regional lymph nodes. The difference of quality of life between the two groups was analyzed according to the EORTC QLQ-BR53 quality of life questionnaire, and the adverse reactions were monitored. RESULTS: As regarding the functional evaluation, the physical function scores of patients of the treatment group were (83.43 ± 14.87) and (88.55 ± 11.62) at 3 and 6 months after the CIK cell therapy, respectively, significantly higher than the baseline value [(74.83 ± 13.82), P < 0.05)]. Global health status/QOL scores were (83.30 ± 19.09) and (89.68 ± 10.81), significantly higher than the baseline value [(77.72 ± 21.05), P < 0.05]. As regarding symptoms, the scores of fatigue, nausea, vomiting and loss of appetite of patients in the treatment group were higher than the baseline value, with significant differences (P < 0.05). The nausea and vomiting scores in the control group at 3 and 6 months of followed-up were (26.67 ± 22.56) and (21.47 ± 21.06), significantly lower than the baseline values [(33.31 ± 27.07), P < 0.05]. The scores of worrying about the future in the patients of treatment group were (47.56 ± 30.84) and (42.33 ± 26.95) after 3 and 6 months, significantly better than the baseline value [(57.41 ± 30.63), P < 0.05]. The systematic therapy side effects scores were (31.95 ± 27.52) and (23.72 ± 22.87), significantly better than the baseline value [(40.56 ± 26.28), P < 0.05]. The scores of arm edema were (45.26 ± 25.42) and (36.61 ± 20.51), significantly milder than the baseline value [(55.11 ± 22.82), P < 0.05]. In the control group, the scores of arm edema were (44.85 ± 28.94) and (38.64 ± 23.68), significantly lower than the baseline values [(53.26 ± 23.84) points, P < 0.05]. Alopecia scores were (29.93 ± 24.72) and (24.18 ± 22.66), significantly lower than the baseline values [(35.92 ± 22.08), P < 0.05]. In the treatment group, the patients' physical function, social function and global health status/QOL, fatigue, insomnia, and worrying about the future rates were significantly higher than that of the control group (P < 0.05 for all). Three patients after CIK reinfusion had transient fever, and 6 cases felt pain in the lower limb, but the symptoms were relieved after symptomatic treatment. CONCLUSIONS: Therapy of autologous CIK cells transfusion can significantly improve the quality of life of breast cancer patients, and the adverse reactions during the treatment can be alleviated by symptomatic treatment.

[Comparison of platinum-containing doublet chemotherapy and liposome paclitaxel monotherapy for the treatment of elderly patients with advanced non-small cell lung cancer].

OBJECTIVE: Given controversy remains on monotherapy and combinatory chemotherapy in elderly patients (> or = 70 years) with advanced non-small cell lung cancer (NSCLC), we conducted this study to compare the safety and efficacy of liposome paclitaxel and platinum-containing doublets. METHODS: From January 2007 to March 2009, totally 65 patients (age > or = 70 years) with pathologically confirmed NSCLC were enrolled. 33 patients received liposome paclitaxel monotherapy (monotherapy group) and 32 patients received platinum-containing doublets chemotherapy (combinatory group). RESULTS: No CR was observed in all patients. Both groups had similar objective response rate (ORR) (6.1% vs. 15.6%, P = 0.399). However, a statistically significant higher disease control rate (DCR) (65. 6%) was observed in he combinatory group when compared with that of monotherapy group (39.4%, P = 0.034). The combinatory group had longer time-to-progression (TTP) (94 days, 95% CI: 60-127 days) than the monotherapy group (51 days, 95% CI: 22-79 days, P = 0.046). The median overall survival days in the combinatory group was 524 days (95% CI: 146-901 days) where as in the monotherapy group only 146 days (95% CI 32-259 days) (P = 0.001). The most common adverse reactions were myelosuppression, gastrointestinal reactions and elevated transaminase in the monotherapy group, while those were myelosuppression, gastrointestinal reactions and infection in the combinatory group. Generally there was no significant difference in the adverse reaction, except grade 3-4 thrombocytopenia (P = 0.004). It should be addressed that 1 patient (3.0%) in the monotherapy group had an onset of severe infection, while the number rose to 5 (15.6%) in the combinatory group (P = 0.079). CONCLUSION: Platinum-containing doublet chemotherapy achieved a higher response rate, longer time-to-progression and overall survival compared with liposome paclitaxel monotherapy in the treatment of elderly patients with advanced NSCLC. However thrombocytopenia and severe infection should be monitored for the combinatory chemotherapy.

Comparison of clinicopathological features and survival analysis between esophageal neuroendocrine carcinoma and esophageal squamous cell carcinoma based on the SEER database, alongside nomogram analysis for esophageal neuroendocrine carcinoma.

Background: Esophageal neuroendocrine carcinoma (ENEC) is a rare subtype of esophageal cancer (EC). It presents distinctive clinical and pathological features in comparison to esophageal squamous cell carcinoma (ESCC). To better elucidate the disparities between the two and establish a prognostic prediction model for ENEC, we conducted this study. Methods: Data of ENEC and ESCC patients (1975 to 2016) were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Patients with a confirmed pathological diagnosis of ENEC and ESCC were enrolled in the study. The Chi-square test was employed to compare categorical variables, and the median survival time was analyzed using the Kaplan-Meier curve. Training and validation groups were randomly assigned at a ratio of 7:3. Factors with a significance level of <0.05 in the multifactor regression model as well as age were integrated into the nomogram model. Concordance index (C-index), calibration curves, and decision curve analyses (DCA) were generated for model validation. Results: This study encompassed a total of 737 ENEC patients and 29,420 ESCC. Compared to ESCC, ENEC patients had higher probability of liver metastasis (13.8% vs. 1.9%, P<0.001), poor differentiation (68.0% vs. 37.1%, P<0.001), and late SEER stage (52.8% vs. 26.9%, P<0.001). Patients who received either surgery, radiotherapy (RT), or chemotherapy had a significantly longer disease-specific survival (DSS) and overall survival (OS) (all P<0.001). After propensity score matching (PSM), ENEC patients were associated with shorter DSS (7.0 months vs. not reached, P<0.0001) and OS (7.0 vs. 12.0 months, P<0.0001) compared to ESCC. Race, SEER stage, surgery, RT, and chemotherapy were identified as predictors of DSS and were incorporated into the nomogram model together with age. The validation of the model using C-index (0.751 and 0.706, respectively) and calibration curves reflected the better discrimination power of the model. In addition, DCA supported the favorable potential clinical effect of the predictive model. Lastly, a risk classification based on the nomogram also verified the reliability of the model. Conclusions: ENEC and ESCC exhibit distinct clinicopathological features. Patients with ENEC experience significantly poorer survival outcomes compared to those with ESCC. Surgical intervention, radiation therapy, and chemotherapy significantly improve OS and DSS for ENEC patients. The nomogram prediction model, constructed based on age, race, stage, and treatment regimen, demonstrates accurate and effective predictive capabilities for prognostic factors in ENEC patients.

[Prognosis of patients with adrenocortical carcinoma].

OBJECTIVE: To investigate the prognosis and influencing factors of patients with adrenocortical carcinoma. METHODS: Thirty-five patients (20 males and 15 females) with biopsy-diagnosed adrenocortical carcinoma were followed retrospectively. Cox proportional hazards regression analysis was performed to identify factors that influenced the prognosis of the patients. RESULTS: Three patients were classified as stage I, 15 as stage II, 12 as stage III, and 5 as stage IV. Fourteen patients were still alive and 21 died at the end of the follow-up. The patients had a median survival time of 33 months, with a survival rate of 77.1%, 62.5%, and 38.3% for the first year, second year, and fifth year respectively. The univariate analysis found no significant differences in survival rates with gender, tumor location (left or right adrenal), diameter (> or = 10 cm or <10 cm) of tumor, functionality of tumor, smoking, hypertension and hypokalemia (P > 0.05). The multivariate analysis revealed that being male, younger than 50 years, non-smoking and early-stage of tumor were significant protective factors for the survival of patients with adrenocarcinoma. Patients at stage III and stage II had 52 and 3 times higher mortality than those at stage I, respectively. CONCLUSION: Clinical stage and age are the main factors that influence the survival of patients with adrenocortical carcinoma. Patients younger than 50 years and those with an earlier stage of tumor would have a better prognosis.

Neoantigen: A Promising Target for the Immunotherapy of Colorectal Cancer.

At present, there are various treatment strategies for colorectal cancer, including surgery, chemotherapy, radiotherapy, and targeted therapy. In recent years, with the continuous development of immunotherapy, immune checkpoint inhibitors (ICIs) can significantly improve the treatment of advanced colorectal cancer patients with high levels of microsatellite instability. In addition to ICIs, neoantigens, as a class of tumor-specific antigens (TSA), are regarded as new immunotherapy targets for many cancer species and are being explored for antitumor therapy. Immunotherapy strategies based on neoantigens include tumor vaccines and adoptive cell therapy (ACT). These methods aim to eliminate tumor cells by enhancing the immune response of host T-cells to neoantigens. In addition, for MSS colorectal cancer, such "cold tumors" with low mutation rates and stable microsatellites are not sensitive to ICIs, whereas neoantigens could provide a promising immunotherapeutic avenue. In this review, we summarized the current status of colorectal cancer neoantigen prediction and current clinical trials of neoantigens and discussed the difficulties and limitations of neoantigens-based therapies for the treatment of CRC.

Immunotherapy for a POLE Mutation Advanced Non-Small-Cell Lung Cancer Patient.

Currently, the predictive role of POLE mutations for immunotherapy is under intense investigation. The POLE gene encodes one of the four subunits of DNA polymerase important for DNA replication and repair. POLE mutations are related to other favorable predicative factors such as high expression of PD-L1, high TMB, and infiltration of CD8+ cells in the tumor microenvironment. No formal clinical trials studied the efficacy of immunotherapy in lung patients harboring POLE mutation, and only few cases were mentioned in the literature. Moreover, lung cancer patients are prone to brain metastasis, which is notorious for the unresponsiveness to chemotherapy. The efficacy of immunotherapy for brain metastasis is still controversial. Here, we described a case of a POLEmt non-small-cell lung cancer (NSCLC) patient with brain metastasis who was treated with immunotherapy. His brain lesions disappeared after treatment. Our report strongly supported the benefit of immune-combined therapy for advanced NSCLC patients with POLE mutation, even with brain metastasis.

Zoledronic acid enhances the efficacy of immunotherapy in non-small cell lung cancer.

BACKGROUND: Only a minority of patients benefit from immune checkpoint inhibitors (ICIs) therapy, although they have become the standard of care for patients of non-small cell lung cancer (NSCLC) without driver mutations. Zoledronic acid (ZA) enhances the anti-tumor efficacy of endocrine therapy, chemotherapy and targeted therapy. However, little is known about the effect of ZA on the clinical outcomes of ICIs, or its possible mechanisms. METHODS: Patients with advanced NSCLC treated with ICIs alone or in combination with ZA were recruited. The clinical efficacy was compared between the two cohorts. We used an LL2 mouse model to confirm the combined effects of ZA with ICIs. Immune cell populations and cytokines in the tumor microenvironment and circulation were assayed and analyzed. RESULTS: The median PFS for the patients treated with and without ZA was 5.4 months and 2.8 months, respectively. The combination group showed a higher rate of disease control. In the mouse LL2 lung cancer model, tumor growth was significantly inhibited in mice treated with the combination treatment. More CD8 + IFN-γ + T cells and γδ T cells, and fewer CD11b cells were found in the circulation and TILs in the combination group. Anti-tumor cytokines INF-γ and IL-18 were elevated in the sera after combination therapy. CONCLUSION: Our study provides preclinical and clinical evidence to show that ZA could improve the therapeutic effects of ICIs. This effect was likely related to the activation of immune cells and elevated cytokines, which provided a new way to improve the effect of ICIs therapy, and is worth exploring further.

Toxicities of Immunotherapy for Small Cell Lung Cancer.

Small cell lung cancer (SCLC), composing 15-20% of lung cancer, is a fatal disease with extremely poor prognosis. In the past two decades, etoposide platinum doublet chemotherapy remained the only choice of therapy, with disappointing overall survival ≤1 year for the metastatic disease. Novel treatments including immunotherapy are urgently needed and extensively explored. Recently, in two phase III trials, atezolizumab and durvalumab were shown to bring survival benefit to patients. While immunotherapy brings better outcome, it is accompanied by adverse events different from traditional treatments. Although these immune-related adverse events (irAEs) are generally mild and can be managed, some irAEs (myocarditis, pneumonitis) may be severe and even life-threatening. Accompanying with the increasing application of immunotherapy in clinical practice, the irAEs should not be overlooked. In this review, the irAEs profile in clinical trials of immunotherapy for SCLC will be summarized, also its unique features compared with irAEs in other malignancies will be explored. This review may be helpful for the appropriate clinical use of immunotherapy for SCLC.

Novel applications of platelet concentrates in tissue regeneration (Review).

Numerous studies have explored the suitability of biocompatible materials in regenerative medicine. Platelet concentrates are derived from centrifuged blood and are named according to their biological characteristics, such as platelet-rich plasma, platelet-rich fibrin and concentrated growth factor. Platelet concentrates have gained considerable attention in soft and hard tissue engineering. Indeed, multiple components of autologous platelet concentrates, such as growth factors, fibrin matrix and platelets, serve essential roles in wound healing. Current studies are focused on cutting-edge strategies to meet the requirements for tissue restoration by improving the properties of autologous platelet concentrates. In the present review, applications of platelet concentrates for tissue engineering are discussed, presenting a selection of recent advances and novel protocols. In addition, several aspects of these strategies, such as the advantages of lyophilized platelet concentrates and the combination of platelet concentrates with biomaterials, stem cells or drugs are discussed. The present review aims to summarize novel strategies using platelet concentrates to improve the outcomes of wound healing.

Major pathological response after neoadjuvant immunotherapy in esophageal spindle cell carcinoma: A case report.

Esophageal spindle cell carcinoma (ESpCC) is a rare subtype of esophageal carcinoma, accounting for 1% of all esophageal malignancies. The clinical outcome is unknown due to the lack of treatment options. Here, we present the case of a 60-year-old male with initially unresectable ESpCC, in which platinum-based concurrent chemoradiotherapy was unsuccessful. He was subsequently treated with neoadjuvant immunotherapy and after surgery achieved a complete pathological response; therefore, neoadjuvant immunotherapy might be a novel option for ESpCC patients.

Pulmonary Lymphoepithelioma-Like Carcinoma Treated with Immunotherapy or Chemotherapy: A Single Institute Experience.

BACKGROUND: Lymphoepithelioma-like carcinoma (LELC) is a rare malignant tumor of the lung. It is related to EB virus infection. Epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) are rarely found in this disease, while high level programmed cell death ligand 1 (PD-L1) expression is observed. Here a series of patients with advanced LELC treated with immunotherapy were summarized. METHODS: This retrospective, observational study was conducted in patients who were pathologically confirmed, metastatic or recurrent LELC patients. Patients were prescribed with either chemotherapy or immunotherapy, according to treating physicians' discretion. RESULTS: A total of 27 patients were included in our study, 10 with immunotherapy (ICI group) and 17 with chemotherapy (Chemo group). The objective response rates (ORR) of the two groups were 80.0% and 70.5% (p=0.678), and disease control rates (DCR) were 100% and 88.2% (p=0.516). However, the response depth was better in the ICI group. Although the cohort of patients in the ICI group was in a disadvantageous state (both up-front and salvage), the progression-free survival (PFS) was much longer (15.0 and 7.9 m, p=0.005). The 1-year PFS rate in the ICI group was also much higher (40% and 5.9%, p=0.047). CONCLUSION: This study implicated the high efficiency of ICI therapy in this disease.

Inferior outcome of bone metastasis in non-small-cell-lung-cancer patients treated with epidermal growth factor receptor inhibitors.

BACKGROUND: Targeted therapy has been established as the standard-of-care for patients with advanced non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Among patients with advanced lung cancer, 30-40% have bone metastases (BoM) at first diagnosis. However, little is known on the clinical characteristics and prognostic factors of BoM in patients with NSCLC harboring EGFR mutations. METHODS: Treatment-naive patients with advanced NSCLC harboring EGFR mutations who were prescribed tyrosine kinase inhibitors (TKIs) were screened and enrolled between June 2009 and April 2019 from West China Hospital. Patients were dichotomized according to whether they had BoM. The demographic characteristics, gene mutation status and therapeutic efficacy, including objective response rate (ORR), progression-free survival (PFS) and overall survival (OS), were collected. RESULTS: A cohort of 604 patients were enrolled. The BoM group had worse PFS (11.7 vs. 14.0 months, HR = 0.73, p = 0.00013) and OS (32.8 vs. 46.1 months, HR = 0.54, p < 0.0001) compared with the non-BoM group. No significant differences were observed in disease control rate (p = 0.407) or ORR (p = 0.537) between the two groups. The metastatic sites in the two groups exhibited obvious differences. In multivariate analysis, BoM was found to be an independent factor of worse prognosis. CONCLUSION: BoM was identified as an independent inferior prognostic factor for EGFR-TKI treatment, and may have complex biological implications.

The Ways of Isolating Neoantigen-Specific T Cells.

Immunotherapy has revolutionized the standard of care for a range of malignancies. Accumulating evidence suggests that the success of immunotherapy is likely attributable to neoantigen-specific T cells. Thus, adoptive cell therapy with these neoantigen-specific T cells is highly promising. This strategy has proven to successfully elicit tumor regression or even complete remission in metastatic cancer patients. However, a fundamental challenge is to effectively identify and isolate neoantigen-specific T cells or their T cell receptors (TCRs), from either tumor-infiltrating lymphocytes (TILs) or peripheral blood lymphocytes (PBLs), and many methods have been developed to this end. In this review, we focus on the current proposed strategies for identifying and isolating neoantigen-specific T cells.

Imaging Pattern of Diffuse Intrapulmonary Metastases in Lung Cancer Was Associated with Poor Prognosis to Epidermal Growth Factor Receptor Inhibitors.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are more frequently seen in miliary intrapulmonary metastases than EGFR wild-type non-small cell lung cancer (NSCLC). Also, small-scale retrospective studies showed that patients harboring EGFR mutation with miliary pulmonary metastases had a worse prognosis. This study aimed to explore the impact of imaging patterns on the outcomes of EGFR tyrosine kinase inhibitor (TKI) treatment. METHODS: A cohort of treatment-naive NSCLC patients harboring EGFR mutation with intrapulmonary metastases who were prescribed with TKI were enrolled. The demographic feature, clinical outcome, and CT imaging of each patient were reviewed and analyzed. RESULTS: A cohort of 174 patients were enrolled. Five intrapulmonary patterns of imaging were recognized: solid nodular, ground-glass nodular, miliary, multiple uniform nodular, and not otherwise specified. Among them, miliary and multiple uniform nodular patterns had similar poor prognosis, and, therefore, were combined as diffuse group. A worse PFS (9.0 mon, 95% CI: 8.0-10.0 mon) was observed compared with the rest (non-diffuse group, 13.3 mon, 95% CI: 10.2-16.4 mon, p<0.001, HR=0.49). The objective response rates (ORR) between the two groups were 76.8% and 84.1%, respectively, with no significant difference (p = 0.474). The OS of the diffuse and the non-diffuse group were 25.6 mon (95% CI 21.9-29.3 mon) and 35.0 mon (95% CI: 27.5-42.5, p = 0.01, HR= 0.59). Organs like bone (p=0.167), liver (p=0.513), and adrenal gland (p=0.375) were involved in similar frequencies in both groups. However, brain (p=0.070) and leptomeningeal (p=0.078) metastases were less common in the non-diffuse group with marginally statistical significance. The 2 groups contained similar missense mutations, and gene amplification was more common in the non-diffuse group. CONCLUSION: Patients with diffuse intrapulmonary metastases had inferior outcomes after TKI treatment. More aggressive treatments might be warranted for these patients.

A promising cancer gene therapy agent based on the matrix protein of vesicular stomatitis virus.

The matrix (M) protein of vesicular stomatitis virus (VSV) plays a key role in inducing cell apoptosis during infection. To investigate whether M protein-mediated apoptosis could be used in cancer therapy, its cDNA was amplified and cloned into eukaryotic expression vector pcDNA3.1(+). The recombinant plasmid or the control empty plasmid pcDNA3.1(+) was mixed with cationic liposome and introduced into various tumor cell lines in vitro, including lung cancer cell LLC, A549, colon cancer cell CT26 and fibrosarcoma cell MethA. Our data showed that the M protein induced remarkable apoptosis of cancer cells in vitro compared with controls. Fifty micrograms of plasmid in a complex with 250 microg cationic liposome was injected intratumorally into mice bearing LLC or MethA tumor model every 3 days for 6 times. It was found that the tumors treated with M protein plasmid grew much more slowly, and the survival of the mice was significantly prolonged compared with the mice treated with the control plasmid. In MethA fibrosarcoma, the tumors treated with M protein plasmid were even completely regressed, and the mice acquired longtime protection against the same tumor cell in rechallenge experiments. Both apoptotic cells and CD8(+) T cells were widely distributed in M protein plasmid-treated tumor tissue. Activated cytotoxic T lymphocytes (CTLs) were further detected by means of (51)Cr release assay in the spleen of the treated mice. These results showed that M protein of VSV can act as both apoptosis inducer and immune response initiator, which may account for its extraordinary antitumor effect and warrant its further development in cancer gene therapy.

Severe insulin allergy after percutaneous transluminal coronary angioplasty.

BACKGROUND: Insulin therapy is essential for type 1 and inadequately controlled type 2 diabetic patients. Insulin allergies have become less common since the introduction of highly purified human recombinant insulin. There are rare reports of severe insulin allergic reactions after percutaneous transluminal coronary angioplasty (PTCA) in patients with type 2 diabetes who had no previous allergic reactions. To better understand the causes and presentation of this rare acute reaction, we present the following observed case. CASE SUMMARY: A 63-year-old Chinese man (height, 172 cm; weight, 68.5 kg) with a 17-year history of type 2 diabetes and hypertension was first admitted to the West China Hospital, Sichuan University, Sichuan, People's Republic of China, for uncontrolled type 2 diabetes. He used regular human insulin, neutral protamine Hagedorn insulin, or premixed insulin without any allergic reactions. Four months later, PTCA was performed because of an acute myocardial infarction. The patient was administered 50 mg of protamine after active abdominal bleeding due to a right external iliac artery rupture. Three months later, recurrent raised, pruritic erythema occurred at the insulin injection site immediately after injection. Four weeks later, he experienced an attack of generalized urticaria at multiple previous injection sites (abdomen, upper arms, thighs) after injecting premixed insulin. It was accompanied by dizziness and palpitations. During the following 3 months, the symptoms recurred 3 times; one time, the patient reported losing consciousness for 2 to 3 minutes. The results of a skin prick test found that he was allergic to human recombinant insulin and insulin lispro. The allergy was resolved by changing his treatment regimen from insulin to oral hypoglycemic agents. A Naranjo score of 10 suggested a definite relationship (score >or=9) between the adverse drug reaction and the insulin administration. CONCLUSIONS: We present a definite case of allergy associated with insulin and insulin lispro administration. The patient had not experienced anaphylactic reactions prior to PTCA and protamine administration.

2,2-Dimethyl-5-(2-naphthyl-amino-methyl-ene)-1,3-dioxane-4,6-dione.

There are two unique mol-ecules in the asymmetric unit of the title compound, C(17)H(15)NO(4), which are linked into chains via inter-molecular N-H⋯O and C-H⋯O inter-actions; the chains are linked via weak C-H⋯O inter-actions, forming a parallel sheet structure. The molecule is approximately planar, with dihedral angles of 19.91 (4) and 11.06 (4)° between the naphthyl ring and the amino-methyl-ene group, and between the amino-methyl-ene unit and the planar part of the dioxane ring, respectively. The dioxane ring adopts a half-boat conformation, with the C atom between the dioxane O atoms 0.595 (8) Šout of the plane through the remaining atoms. The mol-ecule has an intra-molecular N-H⋯O hydrogen bond which stabilizes the planar conformation.