EGFR-TKI治疗时机对晚期肺腺癌患者总生存的影响

目的:探索不同时机应用EGFR-TKI(一线治疗VS二/三线治疗)对晚期肺腺癌患者总生存的影响.方法:回顾性分析V期肺腺癌患者的临床资料.比较一线治疗组与二/三线治疗组的临床基线特征、近期疗效等方面的差异.结果:EGFR-TKI二/三线治疗组的总生存时间显著优于一线治疗组,在其它方面无显著差异.结论:EGFR-TKI二/三线治疗可能要优于一线治疗.     

FHIT基因在肺癌中的缺失与HPV感染的研究

目的　探讨肺癌发生的分子生物学机制。方法　采用逆转录 -巢式聚合酶链反应 (reverse tapepolymerasechainreaction)的方法对 42例肺癌及 10例正常肺组织中的FHIT(Fragilehistidinetriad)基因的缺失情况进行检测 ,并用PCR技术检测了肺癌组织中人乳头状瘤病毒 (humanpapillomavirus ,HPV)的DNA片段。 结果　 66.7% (2 8/4 2 )肺癌组织中检测到FHIT基因的缺失 ,而正常组织中未检测到FHIT基因的缺失 ,二者差别有显著意义 (P <0 .0 1)。 42例肺癌组织中有 8例检测到HPV的片段 ,阳性率为 19% (8/4 2 ) ,正常组织中未检测到HPV的片段 ,且在 8例HPV阳性的标本中均有FHIT基因缺失。结论　 (1)FHIT基因的缺失在肺癌的发生中起一定的作用。 (2 )FHIT基因的缺失与肺癌的不同病理分型、分化程度、临床分期无关。与吸烟有一定的相关性。 (3 )HPV的感染与肺癌的发生有一定关系 ,且与FHIT基因缺失有正相关关系。     

Prognostic significance of grading in lung adenocarcinoma

BACKGROUND:

Although grading has prognostic significance for many tumor types, a prognostically significant grading system for lung adenocarcinoma has not yet been established. The aim of this study was to evaluate histologic characteristics included in tumor grading systems, establish optimal cutoff values that have the strongest association with overall survival, and develop a grading system incorporating the histopathologic characteristics that the authors found to have prognostic significance in patients with lung adenocarcinoma.

METHODS:

The authors studied lung adenocarcinomas from 85 consecutive patients, and evaluated the percentage of solid pattern (as a reflection of tumor architecture), the degree of cytologic atypia, and the mitotic count.

RESULTS:

In univariate analysis, overall survival was associated significantly with sex (P = .045), age (P = .0008), tumor status (P < .0001), lymph node status (P = .02), solid pattern (P = .046), and cytologic atypia (P = .01), but not with mitotic count (P = .26). On the basis of optimal cutoff values, the authors found that a solid pattern ≥90% and severe cytologic atypia were the best discriminators of worse outcome. A grading score, computed as the sum of the architecture score and cytologic atypia score (2 = well differentiated, 3 = moderately differentiated, 4 = poorly differentiated), was a significant predictor of overall survival in univariate analysis (median overall survival times, 72.4, 39.5, and 8.7 months for well, moderately, and poorly differentiated adenocarcinoma, respectively; P = .0001). Moreover, grading was an independent predictor of survival in multivariate analysis (P = .002).

CONCLUSIONS:

The authors describe a grading system that incorporates the percentage of solid pattern and degree of the cytologic atypia that is an independent predictor of survival in patients with lung adenocarcinoma. Cancer 2010. © 2009 American Cancer Society.     

Lymph node ratio and preoperative CA 19-9 levels predict overall survival and recurrence-free survival in patients with resected pancreatic adenocarcinoma

AIM:Clinicopathologic factors predicting overall survival (OS) would help identify a subset to benefit from adjuvant therapy. METHODS: One hundred and sixty-nine patients patients from 1984 to 2009 with curative resections for pancreatic adenocarcinoma were included. Tumors were staged by American Joint Committee on Cancer 7th edition criteria. Univariate and multivariable analyses were performed using Kaplan-Meier methodology or Cox proportional hazard models. Log-rank tests were performed. Statistical inferences were assessed by two-sided 5% significance level. RESULTS: Median age was 67.1 (57.2-73.0) years with equal gender distribution. Tumors were in the head (89.3%) or body/tail (10.7%). On univariate analysis, adjuvant therapy, lymph node (LN) ratio, histologic grade, negative margin status, absence of peripancreatic extension, and T stage were associated with improved OS. Adjuvant therapy, LN ratio, histologic grade, number of nodes examined, negative LN status, and absence of peripancreatic extension were associated with improved recurrence-free survival (RFS). On multivariable analysis, LN ratio and carbohydrate antigen (CA) 19-9 levels were associated with OS. LN ratio was associated with RFS. CONCLUSION: The LN ratio and CA 19-9 levels are independent prognostic factors following curative resections of pancreatic cancer.     

Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx

Although studies have established human papillomaviruses (HPVs) as a risk factor for oral and oropharyngeal cancer, it is not clear whether viral infection affects survival in head and neck malignancies. This investigation examined the relationship between HPV and survival in carcinomas of the oral cavity and oropharynx. Formalin-fixed, paraffin-embedded tumor specimens from 139 newly diagnosed cases were tested for HPVs by PCR and DNA sequencing. Patient and tumor characteristics were obtained from questionnaires, pathology reports and cancer registries. Odds ratios (ORs) and relative risks (RRs) were based on logistic and Cox regression models, respectively. HPVs were detected in 21% of the tumors; 83% were HPV-16. Greater risk of HPV infection was associated with males (OR = 2.9, 95% CI = 1.0-8.6), a history of oral-genital sex (OR = 4.2, 95% CI = 1.5-11.7), and oropharyngeal tumors (OR = 10.4, 95% CI = 3.5-31.2). As tobacco usage increased, the odds of HPV detection decreased (OR = 0.97/pack-year, 95% CI = 0.96-0.99). HPV infected patients had better overall survival (RR = 0.3, 95% CI = 0.1-0.8) than those with HPV-negative tumors. There was an interaction between gender and HPV for overall (p = 0.05) and disease-specific (p = 0.03) survival that suggested that HPV infected males had better prognosis than HPV-negative males, but this was not the case among females. HPV status was identified as an independent prognostic factor in oral and oropharyngeal cancers. This result appeared to be gender-specific, suggesting the need for further study of the interaction between HPV and gender on survival.     

Progression-free survival and one-year milestone survival as surrogates for overall survival in previously treated advanced non-small cell lung cancer

The advent of immunotherapy leads to greater availability of effective subsequent treatments and extended survival in previously treated advanced non-small cell lung cancer (NSCLC), complicating the evaluation of overall survival (OS) in second-line NSCLC trials. Here, we aimed to assess the surrogacy of progression-free survival (PFS) and milestone survival for OS in second-line NSCLC trials investigating chemotherapy, targeted therapy and immunotherapy, respectively. We systemically searched for active-controlled, second-line NSCLC trials. The milestone time point was set at one-year based on pre-analysis. A two-stage meta-analytic validation model was adopted to assess associations between surrogate endpoint (SE) and OS and associations between treatment effects on SE and OS. Treatment effects on SE and OS were expressed as PFS hazard ratios (HR_PFS), 1 yr-milestone ratio (Ratio_1y-SUR) and HR_OS. Subgroup analyses stratified by treatment types and trial publication years evaluated the surrogacy in different clinical contexts. The study included 50 trials with 22,804 patients. One-year survival strongly correlated with OS (R²[95% confidence interval]: one-year survival -median OS = 0.707 [0.704–0.708]; Ratio_1y-SUR-HR_OS = 0.829 [0.828–0.831]). No correlation was established between PFS and OS (median PFS-median OS = 0.100 [0.098–0.101]; HR_PFS-HR_OS = 0.064 [0.059–0.069]), except in immunotherapy subgroup (HR_PFS-HR_OS = 0.835 [0.791–0.918]). In subgroup analyses, surrogacy of one-year survival persisted in different clinical contexts, and the disassociation between PFS and OS persisted in recent trials. One-year milestone survival showed strong surrogacy for OS in second-line NSCLC trials. Although no association was identified between PFS and OS, the strong HR_PFS-HR_OS correlation in immunotherapy trials indicates the potential of PFS as a SE in NSCLC trials involving immunotherapies.     

Development and validation of a five-gene model to predict postoperative brain metastasis in operable lung adenocarcinoma

One of the most common sites of extra-thoracic distant metastasis of nonsmall-cell lung cancer is the brain. Our study was performed to discover genes associated with postoperative brain metastasis in operable lung adenocarcinoma (LUAD). RNA seq was performed in specimens of primary LUAD from seven patients with brain metastases and 45 patients without recurrence. Immunohistochemical (IHC) assays of the differentially expressed genes were conducted in 272 surgical-resected LUAD specimens. LASSO Cox regression was used to filter genes related to brain metastasis and construct brain metastasis score (BMS). GSE31210 and GSE50081 were used as validation datasets of the model. Gene Set Enrichment Analysis was performed in patients stratified by risk of brain metastasis in the TCGA database. Through the initial screening, eight genes (CDK1, KPNA2, KIF11, ASPM, CEP55, HJURP, TYMS and TTK) were selected for IHC analyses. The BMS based on protein expression levels of five genes (TYMS, CDK1, HJURP, CEP55 and KIF11) was highly predictive of brain metastasis in our cohort (12-month AUC: 0.791, 36-month AUC: 0.766, 60-month AUC: 0.812). The validation of BMS on overall survival of GSE31210 and GSE50081 also showed excellent predictive value (GSE31210, 12-month AUC: 0.682, 36-month AUC: 0.713, 60-month AUC: 0.762; GSE50081, 12-month AUC: 0.706, 36-month AUC: 0.700, 60-month AUC: 0.724). Further analyses showed high BMS was associated with pathways of cell cycle and DNA repair. A five-gene predictive model exhibits potential clinical utility for the prediction of postoperative brain metastasis and the individual management of patients with LUAD after radical resection.     

Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis

This study investigated regional variations in the contribution made by different human papilloma (HPV) types to invasive cervical cancer (ICC). A total of 85 studies using polymerase chain reaction to estimate HPV prevalence in ICC were identified. Data on HPV prevalence were extracted separately for squamous cell carcinoma (SCC) and for adeno- and adenosquamous-carcinoma (ADC). A total of 10 058 cases (8550 SCC, 1508 ADC) were included in pooled analyses. The most common HPV types in ICC were, in order of decreasing prevalence, HPV16, 18, 45, 31, 33, 58, 52, 35, 59, 56, 6, 51, 68, 39, 82, 73, 66 and 70. In SCC, HPV16 was the predominant type (46-63%) followed by HPV18 (10-14%), 45 (2-8%), 31 (2-7%) and 33 (3-5%) in all regions except Asia, where HPV types 58 (6%) and 52 (4%) were more frequently identified. In ADC, HPV prevalence was significantly lower (76.4%) than in SCC (87.3%), and HPV18 was the predominant type in every region (37-41%), followed by 16 (26-36%) and 45 (5-7%). The overall detection of HPV DNA was similar in different regions (83-89%). A majority of ICC was associated with HPV16 or 18 in all regions, but approximately a quarter of all ICC cases were associated with one of 16 other HPV types, their distribution varying by region.     

Human papillomavirus infection and lymphoma incidence using cervical conization as a surrogate marker: a Danish nationwide cohort study

Persistent human papillomavirus (HPV) infection may promote carcinogenesis by hyperactivation of the immune system. We, therefore, explored the associations between HPV infection and risk of Hodgkin and non‐Hodgkin lymphoma in a nationwide cohort study using conization as a surrogate marker. We identified all Danish women who underwent conization between 1978 and 2011. We computed standardized incidence ratios and 95% confidence intervals for Hodgkin and non‐Hodgkin lymphoma based on national cancer incidence rates. Among 87 435 women who underwent conization, we noted an increased incidence of Hodgkin (standardized incidence ratio 1.48, 95% confidence interval 1.05–2.02) but only a slight increase for non‐Hodgkin lymphoma (standardized incidence ratio 1.10, 95% confidence interval 0.97–1.25). As measured by conization, HPV infection is associated with an increased risk of lymphoma. This association may be attributable to a chronic immune activation induced by persistent HPV infection and/or failure of the immune system both to clear HPV infection and to control lymphoma development. Copyright © 2015 John Wiley & Sons, Ltd.     

人肺腺癌多西他赛耐药机制的研究

深入研究肺腺癌对多西他赛(docetaxel,DTX)耐药的分子机制,不仅有助于筛选出可用于临床指导DTX个体化用药的分子靶标,也可为耐药的干预策略研究提供研究方向.笔者课题组采用体外逐步提高DTX浓度的方法诱导建立了稳定传代的人肺腺癌SPC-A1耐DTX细胞系SPC-A1/DTX,并从细胞形态、化疗敏感性、增殖、凋亡、细胞周期、药物转运等方面比较了亲本细胞与耐药细胞间的差异.进一步通过基因芯片及miRNA芯片分析,筛选出耐药细胞中差异表达显著的基因(如ING4)以及miRNA(如miR-200b、miR-100),在体内、外模型中进行功能获得性和(或)缺失性研究,证实ING4表达下调、miR-200b/E2F3及miR-100/Plk-1通路的异常参与了肺腺癌细胞DTX耐药表型的形成.     

A nomogram-based immune-serum scoring system predicts overall survival in patients with lung adenocarcinoma

Objective:The immunoscore, which is used to quantify immune infiltrates, has greater relative prognostic value than tumor, node, and metastasis (TNM) stage and might serve as a new system for classification of colorectal cancer. However, a comparable immunoscore for predicting lung adenocarcinoma (LUAD) prognosis is currently lacking.Methods:We analyzed the expression of 18 immune features by immunohistochemistry in 171 specimens. The relationship of immune marker expression and clinicopathologic factors to the overall survival (OS) was analyzed with the Kaplan-Meier method. A nomogram was developed by using the optimal features selected by least absolute shrinkage and selection operator (LASSO) regression in the training cohort (n = 111) and evaluated in the validation cohort (n = 60).Results:The indicators integrated in the nomogram were TNM stage, neuron-specific enolase, carcino-embryonic antigen, CD8_{center of tumor (CT)}, CD8_{invasive margin (IM)}, FoxP3_CT, and CD45RO_CT. The calibration curve showed prominent agreement between the observed 2- and 5-year OS and that predicted by the nomogram. To simplify the nomogram, we developed a new immune-serum scoring system (I-SSS) based on the points awarded for each factor in the nomogram. Our I-SSS was able to stratify same-stage patients into different risk subgroups. The combination of I-SSS and TNM stage had better prognostic value than the TNM stage alone.Conclusions:Our new I-SSS can accurately and individually predict LUAD prognosis and may be used to supplement prognostication based on the TNM stage.     

Different human papillomavirus 16/18 infection in Chinese non-small cell lung cancer patients living in Wuhan, China

BACKGROUND: Inconsistency in the prevalence of infection by human papillomavirus (HPV) in lung cancer patients was found between different countries with racial and geographic variations. Our previous reports have indicated that a high-risk HPV 16/18 DNA was frequently detected in Chinese lung cancer patients living in Taichung, Taiwan (Cheng et al. Cancer Res. 2001;61:2799-803). Thus, we conducted this study to verify whether there was a similar HPV 16/18 infection prevalence in lung cancer patients from Wuhan, China. METHODS: To reduce the false positive HPV detection, the paraffin sections of 73 lung tumors and 34 non-cancer controls from Wuhan, China were collected for detection of the presence of HPV 16/18 DNA by in situ hybridization (ISH). RESULTS: Our results showed that the rates of HPV 16 and/or 18 infections in patients with lung tumors were significantly higher than in 34 non-cancer control subjects (26.0 versus 2.8% for HPV 16, P = 0.030; 23.3 versus 5.7% for HPV 18, P = 0.031; 27.7 versus 5.9% for HPV 16 or 18, P = 0.003) with a similar infection frequency of HPV 16 and 18 types in lung tumors. This result indicated that HPV 16/18 infection may be associated with lung cancer development in Chinese patients from Wuhan, China. Further statistical analyses revealed that HPV 16 or 18 infection was not correlated with any clinico-pathological parameter studied, including age, gender, smoking status, tumor type, tumor stage and tumor grades. Interestingly, smoking and male patients had a higher prevalence of HPV 16, although not reaching a statistical significance, compared with non-smoking and female patients, respectively (33.3% for smokers versus 20.0% non-smokers; 33.3% for male versus 17.6% for female). As compared with the HPV 16/18 infection in Taiwan, Chinese patients with lung cancer from Wuhan had a different HPV 16/18 infection prevalence. CONCLUSION: Difference in HPV 16/18 infection in lung cancer patients from Wuhan, China and Taichung, Taiwan suggests that HPV 16/18 might play a different role in lung cancer development among Chinese living in different areas.     

Human papillomavirus prevalence and type‐distribution in cervical glandular neoplasias: Results from a European multinational epidemiological study

Cervical glandular neoplasias (CGN) present a challenge for cervical cancer prevention due to their complex histopathology and difficulties in detecting preinvasive stages with current screening practices. Reports of human papillomavirus (HPV) prevalence and type‐distribution in CGN vary, providing uncertain evidence to support prophylactic vaccination and HPV screening. This study [108288/108290] assessed HPV prevalence and type‐distribution in women diagnosed with cervical adenocarcinoma in situ (AIS, N = 49), adenosquamous carcinoma (ASC, N = 104), and various adenocarcinoma subtypes (ADC, N = 461) from 17 European countries, using centralised pathology review and sensitive HPV testing. The highest HPV‐positivity rates were observed in AIS (93.9%), ASC (85.6%), and usual‐type ADC (90.4%), with much lower rates in rarer ADC subtypes (clear‐cell: 27.6%; serous: 30.4%; endometrioid: 12.9%; gastric‐type: 0%). The most common HPV types were restricted to HPV16/18/45, accounting for 98.3% of all HPV‐positive ADC. There were variations in HPV prevalence and ADC type‐distribution by country. Age at diagnosis differed by ADC subtype, with usual‐type diagnosed in younger women (median: 43 years) compared to rarer subtypes (medians between 57 and 66 years). Moreover, HPV‐positive ADC cases were younger than HPV‐negative ADC. The six years difference in median age for women with AIS compared to those with usual‐type ADC suggests that cytological screening for AIS may be suboptimal. Since the great majority of CGN are HPV16/18/45‐positive, the incorporation of prophylactic vaccination and HPV testing in cervical cancer screening are important prevention strategies. Our results suggest that special attention should be given to certain rarer ADC subtypes as most appear to be unrelated to HPV.