A novel Galleria mellonella experimental model for zoonotic pathogen Brucella.

Brucellosis is a major threat to public health and animal husbandry. Several in vivo vertebrate models, such as mice, guinea pigs, and nonhuman primates, have been used to study Brucella pathogenesis, bacteria-host interactions, and vaccine efficacy. However, these models have limitations whereas the invertebrate Galleria mellonella model is a cost-effective and ethical alternative. The aim of the present study was to examine the invertebrate G. mellonella as an in vivo infection model for Brucella. Infection assays were employed to validate the fitness of the larval model for Brucella infection and virulence evaluation. The protective efficacy of immune sera was evaluated by pre-incubated with a lethal dose of bacteria before infection. The consistency between the mouse model and the larval model was confirmed by assessing the protective efficacy of two Brucella vaccine strains. The results show that G. mellonella could be infected by Brucella strains, in a dose- and temperature-dependent way. Moreover, this larval model can effectively evaluate the virulence of Brucella strains in a manner consistent with that of mammalian infection models. Importantly, this model can assess the protective efficacy of vaccine immune sera within a day. Further investigation implied that haemolymph played a crucial role in the protective efficacy of immune sera. In conclusion, G. mellonella could serve as a quick, efficient, and reliable model for evaluating the virulence of Brucella strains and efficacy of immune sera in an ethical manner.

Radiotherapy prognosis-associated gene GCNT3 promotes the proliferation, migration and invasion of lung adenocarcinoma cells.

Lung cancer is a life-threatening malignant tumour that is prevalent worldwide. Here, the GCNT3 gene in lung adenocarcinoma was studied via public databases, and cytology and molecular biology experiments were performed to further explore the role of this gene in lung adenocarcinoma. In this study, abnormally high GCNT3 expression levels were observed in tumour tissues compared with normal tissues at both the mRNA and protein levels. In the pancancer analysis, abnormal GCNT3 expression was observed in many tumour types. Moreover, the survival analysis revealed that among patients receiving radiotherapy, those with high GCNT3 expression levels had a worse prognosis. Cell and molecular biology experiments showed that the proliferation, migration and invasion capabilities of the A549 cell line were decreased after knockdown of GCNT3, and epithelial-mesenchymal transformation was significantly inhibited. In subsequent studies, we found that the sensitivity of cells to radiotherapy was enhanced after GCNT3 knockdown. Overall, our findings reveal that GCNT3 is an important factor affecting the radiotherapy sensitivity of lung adenocarcinoma, and GCNT3 inhibition deserves further study as a radiotherapy sensitising strategy.

A novel built-in adjuvant metallothionein-3 aids protein antigens to induce rapid, robust, and durable immune responses.

Adjuvants are crucial components of vaccines that can enhance and modulate antigen-specific immune responses. Herein, we reported for the first time that human metallothionein-3 (MT3), a low molecular weight cysteine-rich metal-binding protein, was a novel promising adjuvant candidate that could help protein antigens to induce rapid, effective, and durable antigen-specific immune responses. In the present study, MT3 was fused to outer membrane protein 19 (Omp19) of Brucella abortus (MT3-Omp19, MO) and C fragment heavy chain (Hc) of tetanus neurotoxin (MT3-Hc, MH), respectively. The results showed that MT3 as a built-in adjuvant increased the Omp19- or Hc-specific antibody responses by 100-1000 folds in seven days after primary immunization. Compared to other commercially available adjuvants, MT3 could stimulate earlier (4 days after primary injection) and stronger (10-100 folds) antibody response with lower antigen dose, and its adjuvanticity relied on fusion to antigen. Although the mechanism was not clear yet, the fusion protein MO was observed to directly activate DCs, promote germinal center formation and improve the speed of Ig class switching. Interestingly, our subsequent study found that other members of the mammalian MT family (human MT1 or murine MT3 for examples) also had potential adjuvant effects, but their effects were lower than human MT3. Overall, this study explored a new function of human MT3 as a novel built-in adjuvant, which may have important clinical application potential in vaccine development against global pandemics.

YTHDF2 Inhibits the Migration and Invasion of Lung Adenocarcinoma by Negatively Regulating the FAM83D-TGFß1-SMAD2/3 Pathway.

OBJECTIVE: YTH domain family 2 (YTHDF2) is an important N6-methyladenosine (m6A) reader, but its role in lung adenocarcinoma remains elusive. This study assessed its function in lung adenocarcinoma. METHODS: YTHDF2 expression in lung adenocarcinoma was explored using public databases, such as The Cancer Genome Atlas (TCGA) and the Clinical Proteomic Tumour Analysis Consortium (CPTAC). The effect of YTHDF2 on a lung adenocarcinoma cell line was explored by performing cytological and molecular experiments. Molecules downstream of YTHDF2 were identified using proteomics, and the related pathways were verified through cytological and molecular biology experiments. RESULTS: YTHDF2 expression was upregulated in lung adenocarcinoma, and patients with high YTHDF2 expression experienced prolonged overall survival. In two lung cancer cell lines, YTHDF2 knockdown inhibited proliferation but promoted migration, invasion, and the epithelial-mesenchymal transition. The proteomic analysis identified 142 molecules downstream of YTHDF2, and 11 were closely related to survival. Further experiments revealed that YTHDF2 inhibited expression of the family with sequence similarity 83D (FAM83D)-TGFß1-SMAD2/3 pathway components. This study is the first to show that YTHDF2 regulated the downstream TGFß1-SMAD2/3 pathway through FAM83D in lung adenocarcinoma. CONCLUSION: YTHDF2 inhibits the migration and invasion of lung adenocarcinoma cells by regulating the FAM83D-TGFß1-pSMAD2/3 pathway, which may play an important role in lung cancer metastasis.

[Efficacy of Osimertinib Combined with Bevacizumab in Advanced Non-small Cell 
Lung Cancer Patients with Acquired EGFR T790M Mutation].

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) capable of overcoming non-small cell lung cancer (NSCLC) with EGFR T790M mutation. Although the addition of bevacizumab to 1st generation EGFR-TKIs confers a significant improvement in progression-free survival (PFS) in treatment-naive EGFR mutant NSCLC patients, osimertinib plus bevacizumab combination failed to show prolongation in the phase 2 study WJOG8715L. Data of such combination in Chinese patients are still lacking. This study aimed to explore the efficacy of the addition of bevacizumab to osimertinib as second-line therapy in real-world data, and to evaluate the role of anti-angiogenesis plus osimertinib combination therapeutic strategies in pretreated Chinese NSCLC patients with acquired EGFR T790M mutation. METHODS: A total of 42 advanced NSCLC patients with acquired EGFR T790M mutation after prior EGFR-TKIs treatment were collected between January 2020 to August 2021, with 16 cases treated with osimertinib plus bevacizumab and 26 cases treated with osimertinib. The treatment effect of patients were analyzed. RESULTS: The objective response rate (ORR) in combination group and osimertinib group were 43.8% and 50.0% respectively (P=0.694). No statistically significant difference in median PFS (14.0 mon vs 13.0 mon, P=0.797) and overall survival (OS) (29.0 mon vs 26.0 mon, P=0.544) between the combination group and osimertinib group were observed. Prior history of bevacizumab was identified as an independent predictor of PFS (P=0.045) and OS (P=0.023). CONCLUSIONS: Our study demonstrated that adding bevacizumab to osimertinib could not show advantages in PFS and OS in pretreated NSCLC patients harboring EGFR T790M-mutation.

Durable response to immunotherapy plus chemotherapy in a patient with untreated, brain-metastatic, EGFR exon 20 insertion mutation lung adenocarcinoma: A case report.

RATIONAL: Epidermal growth factor receptor (EGFR) 20 exon insertion is the second most common EGFR aberrations in non-small cell lung cancer (NSCLC). Despite some novel EGFR inhibitors, clinically obtainable management for this subset of patients remains an unmet need. there are no previous reports of upfront combination therapy with immunotherapy and chemotherapy for lung adenocarcinoma with brain metastasis harboring EGFR 20 insertion. PATIENT CONCERNS: A 56-year-old man who sought care for dry cough was diagnosed with lung adenocarcinoma with brain metastases indicating a poor prognosis. DIAGNOSIS: Next-generation sequencing of lung biopsied tissue revealed an EGFR exon 20 in-frame insertion (P772_H773insYNP+H773Y). INTERVENTIONS: The patient started treatment of pemetrexed and carboplatin plus programmed cell death-1 inhibitor sintilimab in November 2019. OUTCOMES: The patient achieved partial responses both intra- and extra-cranially. After 6 cycles of treatment, the patient accepted sintilimab plus pemetrexed every 3 weeks as maintenance therapy, which was well-tolerated without any toxicity and is still ongoing after 18 months since initiation of 1st-line treatment. LESSONS: This is the first case report of the clinical benefit of upfront immune checkpoint inhibitors (ICIs) plus chemotherapy for a brain metastatic NSCLC patient harboring EGFR exon 20 insertion mutation. Further study is needed to validate the predictor involved in responders to ICIs-based therapy with EGFR mutations.

Robot-assisted laparoscopic retroperitoneal lymph node dissection with concomitant inferior vena cava thrombectomy for metastatic mixed testicular germ cell cancer: a case report.

BACKGROUND: The robot-assisted laparoscopic management of post-chemotherapy retroperitoneal metastasis and inferior vena cava tumor thrombus secondary to testicular cancer is a challenging task for urologists. CASE PRESENTATION: A pathological examination of a 36-year-old Caucasian man who had undergone a right radical orchiectomy showed mixed testicular germ cell cancer (70% embryonal cancer and 30% seminoma); he had undergone four prior courses of cisplatin, etoposide, and bleomycin chemotherapy and was found to have residual retroperitoneal enlarged lymph nodes close to the right renal hilum and a 9.8 cm inferior vena cava tumor thrombus (pT1, N2, M1, S2). Pre-surgical three-dimensional image reconstruction was performed based on contrast computed tomography data. The inferior vena cava tumor thrombus was found in the vena cava at the level of the celiac trunk and the inferior mesenteric artery. Our patient accepted treatment with robot-assisted laparoscopic retroperitoneal lymph node dissection with concomitant inferior vena cava thrombectomy and cava reconstruction on September 12, 2018. During the procedure, a drop-in robotic ultrasound probe was used to define the thrombus. Vena cavoscopy using a flexible ureteroscope found that the tumor thrombus adhered to the cava wall in all directions. The tumor thrombus was dissected free from the inferior vena cava lumen, and vena cava reconstruction was achieved using the da Vinci™ Si HD surgical system. The operative time was 550 minutes. The intraoperative estimated blood loss was 2300 ml. Intraoperative blood transfusions consisted of 10 units of red blood cells (Clavien-Dindo grade II). No Clavien-Dindo grade III or above perioperative complications occurred. The length of hospital stay was 7 days. Pathology revealed no viable cancer cells in any of the residual lymph node tissues or in the vena cava tumor thrombus. CONCLUSION: This is the first case of robot-assisted laparoscopic retroperitoneal lymph node dissection with concomitant inferior vena cava thrombectomy and reconstruction for metastatic mixed testicular germ cell cancer published to date. This complicated surgical procedure was facilitated by the innovative usage of three-dimensional image reconstruction for defining the vena cava tumor thrombus, a robotic ultrasound probe for intraoperatively defining the vena cava tumor thrombus, and vena cavoscopy using a flexible ureteroscope.

[Efficacy and Toxicity of Metronomic Oral Vinorelbinen in Advanced Non-small Cell Lung Cancer after Failure to Multiple-lines Treatments].

BACKGROUND: The development of new treatments beyond first-line in metastatic non-small cell lung cancer (NSCLC) contributed to the increase in overall survival. Metronomic chemotherapy involves several mechanisms of anti-tumor with less toxicity. Oral vinorelbine has paved the way for innovative treatment strategies through metronomic regimens. Therefore, this study assessed the efficacy and safety of metronomic oral vinorelbinen in advanced NSCLC after failure to multiple-lines treatments. METHODS: Our retrospective study enrolled 26 patients who received metronomic oral vinorelbinen. Survival factors were evaluated by univariate regression analysis. RESULTS: The median follow-up time was 4 months (range 2-12). The median number of treatment cycles was 2 (range 1-8). No patient achieved complete remission, 2 cases (8%) partial remission, 11 cases (42%) stable disease, 13 cases (50%) progression disease. Overall response rate was 8% and disease control rate was 50%. The median progression-free survival (PFS) was 2 months. In univariate analysis, patients with performance status (PS)=1 had a statistically significantly longer PFS than patients with PS=2. Gender, age, smoking status and histology were not prognostic factors according to PFS. Treatment was well tolerated with rare serious toxicity. No grade 4 adverse events (AEs) or occurrences of intolerable toxicity were observed. There was no treatment-related death and none of the study patients required hospitalization for treatment-related adverse events. CONCLUSIONS: Metronomic oral vinorelbinen is effective in advanced NSCLC after the failure of multiple lines treatments with an acceptable AE profile, especially in patients with high PS.
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[Association between the epidermal growth receptor status and the efficacy of
 first-line chemotherapy in patients with advanced non-small cell lung cancer].

BACKGROUND: Status of epidermal growth factor receptor (EGFR) gene is a predictor of response to EGFR tyrosine kinase inhibitor (TKI). However, little is know about the relationship between EGFR status and response to chemotherapy. We evaluated the prediction value of EGFR mutation status on response to first-line chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC). METHODS: The data of 181 patients with stage IIIb/IV NSCLC who diagnosed by histopathology from January 10, 2006 to December 20, 2013 in Beijing Chest Hospital, Capital Medical University were collected. The relationships between EGFR gene status, clinical characteristics and response and progression-free survival (PFS) were analyzed. RESULTS: All of the 181 patients' EGFR statuses were determined. 75 (41.4%) patients harbored EGFR-activating mutations and 106 (58.6%) patients were EGFR wild-type. All patients received first-line chemotherapy. The objective response rate (ORR) was 26.0% and disease control rate (DCR) was 70.2%. Patients with EGFR-activating mutations had a higher DCR than patients with EGFR wild-type (84.0% vs 60.4%, P=0.001) did. Subgroup analysis showed that the ORR and DCR in patients with EGFR exon 19 deletions were remarkably higher than those with EGFR wild-type (P = 0.049, 0.002, respectively). The DCR in patients with EGFR exon 21 L858R mutation was significantly higher than that in patients with EGFR wild-type (P=0.010). 168 patients were available for response evaluation in all of 181 patients and median PFS was 4.3 mo. The PFS of patients with adenocarcinoma was significantly higher than that patients with squamous cell carcinoma (4.7 mo vs 3.0 mo, P=0.036). The PFS in patients harbored EGFR-activating mutations was significantly higher than that in the patients with EGFR wild-type (6.3 mo vs 3.0 mo, P=0.002). The PFS of patients with a performance status (PS) of 0-1 was significantly higher than that in patients with a PS of 2 (4.4 months vs. 0.7 months, P= 0.016). Cox multivariate analysis indicates the EGFR-activating mutation is an independent factor affecting PFS (HR=0.654, 95%CI: 0.470-0.909, P=0.012). CONCLUSIONS: EGFR-activating mutation is a predictor for PFS of first-line chemotherapy in advanced NSCLC patients.
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miR-30b and miR-30c expression predicted response to tyrosine kinase inhibitors as first line treatment in non-small cell lung cancer.

BACKGROUND: Aberrantly expressed microRNAs are a hallmark of cancer, and microRNA expression profiling is associated with tumor progression and response to chemotherapy, suggesting their potential application as prognostic and predictive biomarkers. The role of microRNAs in lung cancer remains elusive. It has been recently reported that epidermal growth factor receptor (EGFR) and hepatocyte growth factor receptor (MET) tyrosine kinase can regulate expression of specific microRNAs including miR-30b, miR-30c, miR-221, miR-222, miR-103 and miR-203, and induce tumorigenesis and gefitinib resistance in lung cancers. We intend to study the role of miR-30b and miR-30c expression in predicting response to tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC). METHODS: We have therefore retrospectively examined expression of miR-30b miR-30c in 41 formalin fixed paraffin embedded tissue samples from NSCLC patients when TKIs were used as first line therapy. RESULTS: We found a significant correlation between expression of miR-30b and miR-30c. Furthermore, miR-30b and miR-30c expression correlated with short-term response. Kaplan-Meier analysis further revealed that the expression of miR-30b and miR-30c predicted progression free survival and the overall survival rate in the examined cohort. CONCLUSION: Our study identified miR-30b and miR-30c as useful prognostic predictors in NSCLC patients who underwent first line treatment with TKIs.

Expression of ERCC1 and class III ß-tubulin in resected non-small cell lung cancer and its correlation with platinum-based adjuvant chemotherapy.

OBJECTIVE: To explore the relationship between the expression of excision repair cross-complementation group 1 (ERCC1) and class III ß-tubulin and the clinical characteristics and overall survival of patients with non-small cell lung cancer (NSCLC). METHODS: Immunohistochemical analysis was used to determine the protein expression of ERCC1 and class III ß-tubulin in 160 completely resected NSCLC primary tumor samples, 50 of which were paired with adjacent normal tissue samples and another 40 benign lung lesion tissue samples as controls. Clinical data at baseline, disease-free survival and overall survival were also collected. Univariate and multivariate Cox models were used to analyze the risk factors. RESULTS: In 160 tumor samples, the ERCC1 and class III ß-tubulin positive rates obtained with immunohistochemistry were 46.9% and 49.4%, respectively. Both biomarkers had a higher positive rate in male patients. For patients who did not receive adjuvant chemotherapy, ERCC1 positivity was associated with longer survival (median survival time 73 vs 53 months, p=0.041), while in patients treated with platinum chemotherapy, ERCC1 positivity tended to be associated with poor survival (median survival time 41 vs 54 months, p=0.014). Class III ß-tubulin positivity was also associated with poor survival (median survival time 38 vs 58 months, p<0.001), but had no influence on the survival of patients who did not receive adjuvant chemotherapy. CONCLUSIONS: ERCC1 and class III ß-tubulin could be important survival predictors for completely resected NSCLC patients treated with adjuvant chemotherapy. Further prospective studies need to be performed to test this hypothesis in Chinese patients.

[Association between polymorphisms of ERCC1 and response in patients with advanced non-small cell lung cancer receiving cisplatin-based chemotherapy].

BACKGROUND AND OBJECTIVE: Results of studies on genetic polymorphisms of ERCC1 gene in DNA repair pathway which may affect response to platinum-based chemotherapy and survival in patients with non-small cell lung cancer are conflicting. The aim of this study is to prospectively assess the association between single nucleotide polymorphisms of C8092A and codon118 in ERCC1 and drug response in 90 patients with advanced non-small cell lung cancer treated with cisplatin-based chemotherapy. METHODS: All patients were treated with cisplatin-based chemotherapy. Genotypes of ERCC1 C8092A and codon118 were examined by sequencing, and the association between genotypes and response was evaluated. RESULTS: Genotype frequencies of ERCC1 C8092A were CC 40.0% (36/90), CA 48.9% (44/90) and AA 11.1% (10/90), frequencies of codon118 were CC 58.9% (53/90), CT 34.4% (31/90) and TT 6.7% (6/90). There was no significant difference in response rate of patients carrying with CC, compared with CA plus AA in C8092A (33.3% vs 29.6%, P = 0.71). Response rate of patients carrying with CC in ERCC1 118 was 32.1%, 24.3% with CT plus CC (P = 0.43). There was no difference in progression free survival between patients carrying with CC and CT plus TT in C8092A (5.2 months vs 5.4 months, P = 0.62). There was no difference in progression free survival between patients carrying with CC and CA plus AA (5.5 months vs 5.3 months, P = 0.59). CONCLUSION: The results suggest that there is no association between polymorphisms in ERCC1 C8092A and codon118 and response in patients with advanced non-small cell lung cancer receiving cisplatin-based chemotherapy.

[Advances in herbal volatile oil and aromatic herbs].

The herbal volatile oil and aromatic herbs are traditional Chinese medicine which have some unique characteristics of volatility, special smell, complicated chemical constituents and the water insoluble property. The aromatic herbs from different sources have biodiversity effects on the cardiovascular, central nervous, respiratory and gastrointestinal system. They also play important roles in antibiosis, anti-inflammation, anticancer, antivirus and absorption enhancement, etc. In recent years, the herbal volatile oil and aromatic herbs have been widely reported to show broad prospect in medicinal application. In order to support various developmental works, the latest research results on herbal volatile oil and aromatic herbs are reviewed in this article in respect of chemical constituents, pharmacological action, and absorption enhancement.

[A randomized study of docetaxel plus cisplatin versus paclitaxel plus cisplatin in previously untreated advanced non-small cell lung cancer.].

BACKGROUND: Docetaxel is an active agent in the second-line treatment for non-small cell lung cancer (NSCLC), many clinical trials have demonstrated that it has similar efficacy to common first-line regimens for NSCLC. A randomized study was conducted to compare docetaxel plus cisplatin (DC) versus paclitaxel plus cisplatin (PC) for patients with advanced non-small cell lung cancer as the first-line regimen. METHODS: Ninety patients with previously untreated advanced non-small cell lung cancer were randomly assigned to receive either DC or PC. Patients received docetaxel 75mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in DC group and paclitaxel 150mg/m(2) on day 1 and cisplatin 75mg/m(2) divided into two doses on days 2 to 3 in PC group. The cycle of two regimens was repeated every 3 weeks. Response and toxicity were evaluated in patients who completed two cycles of chemotherapy at least. RESULTS: Overall survival rate was 31.1% in DC group and 33.3 % in PC group. The median survival time was 10.2 months in DC group and 10.4 months in PC group. Median time to tumor progression was 4.4 months in DC group and 4.9 months in PC group. 1- and 2-year survival rate were 35.6% and 8.9% in DC group and 37.8% and 11.1% in PC group respectively. There were no significant differences in response rate, median survival time, median time to tumor progression and survival rate between two groups (P >0.05). Leucopenia, anemia, nausea and vomiting, and alopecia were the most common grade III and IV toxicities in DC and PC groups, there were no significant differences in grade III and IV toxicities between two groups(P >0.05). There were no treatment-related deaths in both groups. CONCLUSIONS: DC has similar response rate and survivals with PC, and its toxicity is well-tolerated. Docetaxel plus cisplatin is an effective first-line treatment of non-small cell lung cancer.

[The relationship between genetic polymorphism of GSTM1 and the outcome of chemotherapy in Chinese patients with primary lung cancer.].

BACKGROUND: GSTM1 takes part in the metabolism of environmental pollutants such as benzopyrene, other polycyclic aromatic hydrocarbons and anticancer drugs and so on. The study aims to investigate the relationship between the gene polymorphism of GSTM1 and chemotherapy as well as to study the effect to survival of Chinese patients with lung cancer. METHODS: The genotypes of GSTM1 were examined with polymerase chain reaction in 137 primary lung cancer patients accepted chemotherapy. RESULTS: GSTM1 -null genotype frequency was 58.4%(80/137). The frequency of non-null GSTM1 genotype was 41.6%(57/137). The frequency of GSTM1-null genotype was 69.05%(58/84) in the response group of chemotherapy and 41.51%(22/53) in the non-response group of chemotherapy. They were significantly different (P=0.001). In the patients with platinum chemotherapy, the frequency of GSTM1-null genotype was 65.43%(53/81) in the response group of chemotherapy and 42%(21/50) in the non-response group. There werestastically differences in them (P=0.0025). For the advanced cases, GSTM1 -null genotype frequency was 70.13% (54/77) in the response group of chemotherapy, 41.51% (22/53) in the non-response group of chemotherapy respectively and they were significantly different(P=0.001). When the chemotherapy was effective, the survival time of patients in squamous carcinoma and small cell carcinoma with non-null GSTM1 genotype (the median survival times were 42 months and 14 months respectively) were longer than those with null GSTM1 genotype (the median survival times were 6 months and 7 months respectively)(P<0.05). The survival time of adencarcinoma with non-null GSTM1 genotype and null GSTM1 genotype (the median survival times were 13 months and 11 months respectively) were comparative (P>0.05). When chemotherapy was not effective, the median survival time were not significantly different (P>0.05). CONCLUSIONS: The effect of chemotherapy of GSTM1-null genotype patients was better than that of GSTM1-postive genotype patients. The chemotherapy effect of the cases with null GSTM1 type was better than those with non-null GSTM1 type when the patients accepted platinum chemotherapy. When the chemotherapy was effective, the survival time may be related to the histological types and GSTM1 genotypes.

[Combined effects of genetic polymorphisms in cytochrome P450s and GSTM1 on lung cancer susceptibility].

OBJECTIVE: To investigate the relationship between the gene polymorphism of metabolizing enzymes and the genetic susceptibility to lung cancer as well as to study the synergistic effects between smoking and the genes. METHODS: Peripheral blood samples were collected from 279 patients with primary lung cancer and 684 age-, nationality-, and native place-matched controls, including patients with benign diseases and healthy volunteers. PCR-RELP was used to detect the distribution of CYP1A1, 2D6, 2E1, and GSTM1 genotypes. The correlation of these genes with the sensibility to lung cancer was analyzed. RESULTS: The CYP1A1 variant allele frequency of the lung cancer group was 67.4%, significantly higher than that of the control group (55.7%, P = 0.001). GSTM1-null genotype was found to be associated with lung cancer (OR = 1.58, P = 0.002). The risk of lung cancer in the individuals carrying GSTM1-null genotype and CYP1A1 (w/m, m/m) genotype was 2.75 times that of the individuals not carrying these genotypes (P < 0.01). There were no significant differences in the frequencies of CYP2D6 and CYP2E1 genotypes between these two groups. In the heavy smokers GSTM1-null, CYP1A1, CYP2D6, and CYP2E1 genotypes increased the risk of lung cancer by 5.71 - 11.67 times (P = 0.000). CONCLUSION: The individuals who carry GSTM1-null genotype and CYP1A1 (m) genotype have an increase risk of lung cancer. The combined effect of I phase metabolizing enzymes and II phase metabolizing enzymes is observed. In heavy smokers the polymorphism of GSTM1 and CYPs affects the susceptibility to lung cancer.

[A randomized study comparing topotecan plus cisplatin versus etoposide plus carboplatin for previously untreated small cell lung cancer].

BACKGROUND: Topotecan is one of active agents for relapsed small cell lung can-cer (SCLC), some studies have shown that it is effective against SCLC as the first-line drug. This study is to assess the efficacy, toxicity and survival rate of topotecan plus cisplatin (TP) versus etoposide plus carboplatin (CE) in patients with previously untreated SCLC. METHODS: Sixty-four patients with previously untreated SCLC were randomly assigned to receive either TP or CE. Topotecan 0.75 mg/(m²×d) via a 30-min intravenous infusion on days 1 to 5 and cisplatin 25 mg/(m²×d) on days 1 to 3 with hydration were given to patients in TP group. Carboplatin 300 mg/m² on day 1 and etoposide 100 mg/d on days 1 to 5 were given to patients in CE group. Treatment was repeated every 21 days. Responses and toxicities were evaluated in patients who received two cycles of chemotherapy. Patients with limited disease SCLC received thoracic irradiation or operation after the completion of chemotherapy. RESULTS: Overall response rate was 75.0% in TP group and 68.8% in CE group. The median survival time was 10.5 months in TP group and 9.6 months in CE group. 1-, 2- and 3-year survival rate were 40.6%, 18.8% and 9.4% in TP group and 34.4%, 15.6% and 9.4% in CE group respectively. There were no significant differences in response rate, median survival time and survival rate between two groups (P > 0.05). Myelosuppression, nausea and vomiting, and alopecia were the most common toxicities, there was no significant difference in grade III and IV toxicities between two groups (P > 0.05). CONCLUSIONS: TP has similar response rate and survivals with CE, and its toxicities are acceptable. TP regimen is an effective first-line treatment for SCLC.

[Frequency of CYP2A6 gene deletion and its relation to risk of lung cancer].

BACKGROUND: Cytochrome P450 2A6 (CYP2A6) plays an important role in oxidation of nicotine and in activation of tobacco-related carcinogens. It has been suggested that individuals with defective CYP2A6 allele are at a lower risk of developing lung cancer. This study is to investigate the frequency of CYP2A6 gene deletion and the relationship of CYP2A6 genetic polymorphism with lung cancer risk in Chinese. METHODS: A case-control study which detected CYP2A6 genotype of 180 patients with lung cancer and 224 controls by PCR-based genotype assay was conducted. RESULTS: No relationship was found between the frequency of CYP2A6 gene deletion and lung cancer risk. There was only one case of CYP2A6 del/del genotype in the controls. The frequency of CYP2A6 del allele was 13.8% in the controls, and 12.8% in lung cancer cases. The CYP2A6 del/del genotype was not found in lung cancer cases. CONCLUSIONS: There is no difference in frequency of CYP2A6 gene deletion between lung cancer cases and controls.