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Zhengfei Zhu,
Weiwei Yu,
Hecheng Li,
Kuaile Zhao,
Weixin Zhao,
Yawei Zhang,
Menghong Sun,
Qiao Wei, Haiquan Chen,
Jiaqing Xiang,
Xiaolong Fu
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ABSTRACT: BACKGROUND: The presence of nodal skip metastasis (NSM) has been found to be of clinical importance in non-small cell lung cancer, but the study of this phenomenon in esophageal carcinoma is relatively rare. The purpose of this study was to identify risk factors influencing NSM and to assess its prognostic value in thoracic esophageal squamous cell carcinoma (ESCC). METHODS: A total of 207 patients with thoracic ESCC who underwent three-field lymphadenectomy and who had lymph node metastasis were reviewed. Associations of NSM occurrence with the clinicopathological characteristics of patients and primary tumors were evaluated using logistic regression analysis. The influence of NSM on the overall survival (OS) was assessed by log-rank tests and Cox regression analysis. RESULTS: NSM were present in 58 (26 %) patients. No factor was significantly associated with the incidence of NSM except for the location of primary tumor. There were no NSMs in the 29 patients from our study with upper thoracic ESCC, and the rates of tumors occurrence in the middle and lower third of the esophagus were 38.9 and 14.9 %, respectively. The median OS was 30 months, and no significant difference in OS was found between the patients with or without NSM (p = 0.767). Only N status was found to be the independent risk factor for OS by Cox multivariate analysis. CONCLUSIONS: NSM is common in thoracic ESCC, especially in patients with tumors located in the middle and lower third of the esophagus. However, the presence of NSM did not predict prognosis.
Annals of Surgical Oncology 05/2013; · 4.17 Impact Factor
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Ling Li,
Shuhua Ren,
Yingjian Zhang,
Yihui Guan,
Jun Zhao,
Jun Liu,
Qun Wang,
Gang Chen, Haiquan Chen,
Jiaqing Xiang,
Xiaolong Fu
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ABSTRACT: BACKGROUND AND OBJECTIVE: The aims of our study were to evaluate the occult nodal metastasis in clinical stage I patients by PET/CT, further investigate the potential risk factors for nodal involvement, since a successful prediction could be helpful in selection appropriate candidates for SABR or limited surgery. METHODS: We retrospectively reviewed the records of 189 patients who diagnosed as clinical stage I NSCLC by (18)F-FDG PET/CT from January 2004 to July 2011. All patients underwent lobectomy and systematic lymph node dissection and preoperative (18)F-FDG PET/CT scanning. The prevalence of occult nodal metastasis in patients as clinical N0 was analyzed according to clinicopathological factors such as tumor location, tumor size, tumor subtype, grade of differentiation and primary tumor SUVmax. Risk factors for occult nodal metastasis were defined by univariate and multivariate analysis. RESULTS: Occult nodal metastasis was detected in 18.0% (34/189) of the patients. SUVmax of the primary tumor and tumor size were independent predictors of occult nodal metastasis for patients with clinical N0 NSCLC by FDG PET/CT. Accordingly we divided our patients into three groups: group 1 (low-risk group) ~T≤3cm and SUVmax≤4.3; group 2 (moderate-risk group) ~T≤3cm and SUVmax>4.3 or SUVmax≤4.3 and T>3cm; group 3 (high-risk group) ~T>3cm and SUVmax>4.3. The occult lymph node metastasis rate in groups 1, 2, 3 was 1/82 (1.2%), 19/75 (25.3%) and 14/32 (43%) respectively. CONCLUSIONS: T1-2N0M0 NSCLC patients by PET/CT showing larger tumor size and high SUVmax constitute a high-risk group for occult nodal metastasis. The combined information of primary tumor SUVmax and tumor size before treatment have potential values in the clinic. These findings would be helpful in selection of SABR or limited surgery candidates.
Lung cancer (Amsterdam, Netherlands) 05/2013; · 3.14 Impact Factor
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The Journal of thoracic and cardiovascular surgery 03/2013; 145(3):896-7. · 3.41 Impact Factor
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Journal of Clinical Oncology 01/2013; · 18.37 Impact Factor
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ABSTRACT: BACKGROUND: During the past two decades, many studies have sought to find reliable predictors of N0 status in small-sized lung cancers. However, the way of tumor size measurement was usually not clearly stated, and controversy remains as to whether systematic lymph node dissection should be performed in patients with subcentimeter tumors. METHODS: We reviewed correlations between lymph node involvement and clinicopathological variables in 243 small peripheral non-small cell lung cancers with their size measured in fresh specimens before formalin fixation. Histologic subtypes of adenocarcinomas were classified in line with the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification. RESULTS: Incidence of N1 and N2 nodal involvement was 5.3 and 6.6 %, respectively. N2 disease was present in a proportion of subcentimeter tumors (2/53, 3.8 %). No lymph node metastasis was revealed in squamous cell carcinomas, adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma, or invasive mucinous adenocarcinoma. Collectively, the five cell types accounted for 34.6 % of all the small peripheral cases. CONCLUSIONS: Precise measurement of tumor size in fresh tissues revealed that tumor size was not a reliable predictor of N0 status. However, through histologic classification, systematic lymph node dissection might be avoided in more than one third of small peripheral NSCLC.
Annals of Surgical Oncology 12/2012; · 4.17 Impact Factor
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Rui Wang,
Haichuan Hu,
Yunjian Pan,
Yuan Li,
Ting Ye,
Chenguang Li,
Xiaoyang Luo,
Lei Wang,
Hang Li,
Yang Zhang,
Fei Li,
Yongming Lu,
Qiong Lu,
Jie Xu,
David Garfield,
Lei Shen,
Hongbin Ji,
William Pao,
Yihua Sun, Haiquan Chen
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ABSTRACT: PURPOSEThe RET fusion gene has been recently described in a subset of non-small-cell lung cancers (NSCLCs). Because we have limited knowledge about these tumors, this study was aimed at determining the clinicopathologic characteristics of patients with NSCLC harboring the RET fusion gene. PATIENTS AND METHODS
We examined the RET fusion gene in 936 patients with surgically resected NSCLC using a reverse transcriptase polymerase chain reaction (PCR) plus quantitative real-time PCR strategy, with validation using immunohistochemical and fluorescent in situ hybridization assays. A subset of 633 lung adenocarcinomas was also studied for EGFR, KRAS, HER2, and BRAF mutations, as well as ALK rearrangements. Patient characteristics, including age, sex, smoking history, stage, grade, International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society classification of subtypes of lung adenocarcinoma, and relapse-free survival, were collected.ResultsOf 936 patients with NSCLC, the RET fusion gene was exclusively detected in 13 patients (11 of 633 patients with adenocarcinomas and two of 24 patients with adenosquamous cell carcinomas). Of the 13 patients, nine patients had KIF5B-RET, three patients had CCDC6-RET, and one patient had a novel NCOA4-RET fusion. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%; P = .029 for RET v ALK, P = .007 for RET v EGFR), with a tendency to be younger (≤ 60 years; 72.7%) and never-smokers (81.8%) and to have solid subtype (63.6%) and a smaller tumor (≤ 3 cm) with N2 disease (54.4%). The median relapse-free survival was 20.9 months. CONCLUSIONRET fusion occurs in 1.4% of NSCLCs and 1.7% of lung adenocarcinomas and has identifiable clinicopathologic characteristics, warranting further clinical consideration and targeted therapy investigation.
Journal of Clinical Oncology 11/2012; · 18.37 Impact Factor
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Hang Li,
Yunjian Pan,
Yuan Li,
Chenguang Li,
Rui Wang,
Haichuan Hu,
Yang Zhang,
Ting Ye,
Lei Wang,
Lei Shen,
Yihua Sun, Haiquan Chen
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ABSTRACT: PURPOSE: We performed this analysis to reveal the association between six well-identified oncogenic driver mutations and clinical and pathological features in lung adenocarcinomas from smokers. It may have the potentiality to optimize existing treatment strategies and clinical trial design. METHODS: In this series, 230 resected lung adenocarcinomas from smoker (>100 cigarettes in lifetime) at single center (Shanghai Cancer Center, Shanghai, China) were tested for mutation in EGFR, KRAS, BRAF, HER2, EML4-ALK and PIK3CA. Further we compared the mutation frequency with sex, age at diagnosis, stage, differentiation, smoking dose, and histological subtype. RESULTS: Among 230 smokers, we detected 100 (43.5%) EGFR mutations, 38 (16.5%) KRAS mutations, 8 (3.5%) PIK3CA mutations, 7 (3.0%) BRAF mutations and 7 (3.0%) EML4-ALK fusions. No HER2 mutation was found. EGFR mutations occurred at a significantly higher frequency in patients with smoking dose ≤20 pack-years (p<0.001) or age ≥60 years old at diagnosis (p=0.018). Smoking dose >20 pack-years and age <60 years old at diagnosis were associated with the presence of KRAS mutation. With regard to association between histological subtypes and driver mutation frequency, EGFR mutation had positive correlation with histological subtype micropapillary (p=0.003), lepidic (p=0.011), as well as papillary (p=0.05) predominant adenocarcinoma. Negative correlation was found between EGFR mutation and solid predominant (p<0.001), as well as invasive mucinous adenocarcinoma (IMA) (p=0.006). Besides, KRAS mutation had positive correlation with IMA (p=0.043). The frequency of EGFR mutation decreased with increasing tobacco dose. In contrast, higher frequency of KRAS mutations was observed with increasing tobacco dose. Generally, the frequency of these driver mutations tested in our study decreased with increasing smoking dose. CONCLUSIONS: This study represents the first comprehensive and concurrent analysis of these six well-identified driver mutations in a large cohort of lung adenocarcinoma from East-Asian smokers. Our molecular data in conjunction with the clinical and pathological features indicated that prospective genotyping of lung adenocarcinomas from smokers for these genetic alterations could lead to rationally chosen targeted therapy in the overwhelming majority of cases.
Lung cancer (Amsterdam, Netherlands) 10/2012; · 3.14 Impact Factor
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Yan Feng,
Ye Wang,
Zuoyun Wang,
Zhaoyuan Fang,
Fei Li,
Yijun Gao,
Hongyan Liu,
Tian Xiao,
Fuming Li,
Yang Zhou,
Qiwei Zhai,
Xiaolong Liu,
Yihua Sun,
Nabeel Bardeesy,
Kwok-Kin Wong, Haiquan Chen,
Zhi-Qi Xiong,
Hongbin Ji
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ABSTRACT: Somatic mutation of the tumor suppressor gene LKB1 occurs frequently in lung cancer where it causes tumor progression and metastasis, but the underlying mechanisms remain mainly unknown. Here we demonstrate that the oncogene NEDD9 is an important downstream mediator of lung cancer progression evoked by LKB1 loss. In de novo mouse models, RNAi-mediated silencing of Nedd9 inhibited lung tumor progression, whereas ectopic NEDD9 expression accelerated this process. Mechanistically, LKB1 negatively regulated NEDD9 transcription by promoting cytosolic translocation of its suppressor CRTC1 from the nucleus. Notably, ectopic expression of either NEDD9 or CRTC1 partially reversed the inhibitory function of LKB1 on metastasis of lung cancer cells. In clinical specimens, elevated expression of NEDD9 was associated with malignant progression and metastasis. Collectively, our results decipher the mechanism through which LKB1 deficiency promotes lung cancer progression and metastasis, and provide a mechanistic rationale for therapeutic attack of these processes.
Cancer Research 10/2012; · 7.86 Impact Factor
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ABSTRACT: SESSION TYPE: Cancer Global Case Report PostersPRESENTED ON: Tuesday, October 23, 2012 at 01:30 PM - 02:30 PMINTRODUCTION: We describe here a unique case of collision tumor of metastatic rectal adenocarcinoma and primary pulmonary adenocarcinoma, in which the two components were juxtaposed to each other and presented as an isolated pulmonary noduleCASE PRESENTATION: The patient is a 60-year-old female non-smoker who was conducted Dixon surgery for rectal adenocarcinoma in our hospital four months ago. She denied any complains of coughing, wheezing and chest pain. During her postoperative follow up, the serum carcinoembryonic antigen (CEA) level was slightly declined from 113.08 preoperatively to 101.40ug/l. Serum CA19-9 was fallen from 41.40U/ml to normal range. However, follow up investigations 4 months postoperatively showed an newly-developed solitary pulmonary nodule at computed tomography scan (CT) which presented an approximate 3cm lobulated and spicular-circumscribed ground-glass opacity containing slightly-enhanced solid component with air bronchogram in the right lower lung (Fig.1). A CT-guided fine needle aspiration biopsy suggested a primary pulmonary adenocarcinoma. Then the patient underwent right lower lobectomy and mediastinal lymph node dissection. A histopathologic analysis confirmed a diagnosis of collision tumor of metastatic rectal adenocarcinoma and primary pulmonary adenocarcinoma with an interlobar lymph node metastasis. Histologically, the tumor was composed of two components, a pulmonary adenocarcinoma and a metastatic rectal adenocarcinoma. The pulmonary adenocarcinoma accounted for 90% of the total tumor distribution, while a metastatic rectal adenocarcinoma accounted for a very small area measuring 0.3cm × 0.2cm. The pulmonary adenocarinoma consisted of well-differentiated adenocarcinoma showing a lepidic pattern in which alveolar septa were lined by relatively uniformed malignant pneumocytes . The metastatic rectal adenocarcinoma consisted of columnar cells arranged in an acinar or gland pattern with central necrosis (Fig.2C). The two components were juxtaposed to each other without transition in between. Immunohistochemistry (IHC) was performed on paraffin-embedded sections using the standard EnVision method. The pulmonary adenocarcinoma component was strongly positive for CK7 and TTF-1 but was negative for CDX2 and CK20. The metastatic rectal adenocarcinoma component was positive for CDX2 and CK20 but was negative for CK7 and TTF-1DISCUSSION: Since imaging and/or laboratory examination cannot differentiate primary lung tumor from metastatic tumor, the history of malignant disease and pathological comparison with the patient's prior histological sections are reliable for the diagnosis of this entity. In the present case, metastatic rectal adenocarcinoma should be distinguished from primary pulmonary adenocarcinoma with enteric differentiation. It is still difficult to distinguish between primary pulmonary adenocarcinoma with enteric differentiation and secondary colorectal adenocarcinoma due to the similar morphology. Utilizing immunohistochemistry staining may be the only reliable method for differentiating the metastatic lesion from primary one. CK20 and CDX2 are positive in almost all colorectal carcinoma but is also detectable in fewer than 10% of primary lung adenocarcinoma (especially cases of adenocarcinoma with enteric differentiation). TTF-1 is expressed in the majority of lung adenocarcinoma and nearly all thyroid adenocarinoma but is rarely seen in colorectal adenocarinoma. CK7 is also expressed in the majority of lung adenocarcinoma but is negative in colorectal adenocarcinoma. In the present case, the metastatic rectal adenocarcinoma was positive for CDX2, CK20 but was negative for CK7 and TTF-1, suggesting the lesion was metastatic. Molecular signatures are also helpful to differentiate metastatic from primary tumor. In the present caseCONCLUSIONS: In conclusion, we descried a rare case of cancer-to-cancer metastasis of metastatic rectal adenocarcinoma and primary pulmonary adenocarcinoma, in which two components were juxtaposed to each other and presented as an isolated pulmonary nodule.1) Chu P, Wu E, Weiss LM. Cytokeratin 7 and cytokeratin 20 expression in epithelial neoplasms: a survey of 435 cases. Mod Pathol 2000;13(9):962-72.2) Barbareschi M, Murer B, Colby TV, Chilosi M, Macri E, Loda M, et al. CDX-2 homeobox gene expression is a reliable marker of colorectal adenocarcinoma metastases to the lungs. Am J Surg Pathol 2003;27(2):141-9.DISCLOSURE: The following authors have nothing to disclose: Yiliang Zhang, Yuan Li, Hecheng Li, Lei Shen, Ye Xu, Jiaqing Xiang, Haiquan ChenNo Product/Research Disclosure InformationFudan University Shanghai Cancer Center, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):609A. · 5.25 Impact Factor
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ABSTRACT: SESSION TYPE: Biomarkers, Oncogenes and Enhanced Bronchoscopy in NSCLCPRESENTED ON: Wednesday, October 24, 2012 at 02:45 PM - 04:15 PMPURPOSE: Approximately 3-7% of non-small cell lung cancer harbored an ALK gene fusion and defines a unique tumor group that may be responsive to targeted therapy. However, the method for diagnosis ALK fusion gene has not been standardized. The breakpoint in ALK consistently occurs at exon 20 and the EML4 or other fusion partner driving the strong expression of ALK kinase region. In the present study, we developed a rapid and accurate method for detecting ALK fusion.METHODS: We analyzed the expression level in all exons of ALK by using Exon Array in an initial 81 resected lung adenocarcinomas and the results were further confirmed by using Quantitative Real-time PCR(Q-PCR) with primer sets that detect 5' non-kinase region and 3' kinase region of ALK. To validate the accuracy of Q-PCR for diagnosis ALK-rearranged lung tumors, one hundred and seventy-seven EGFR, KRAS, HER2 and BRAF mutation negative lung tumor samples were included for detecting ALK rearrangements by using Q-PCR, FISH and RT-PCR.RESULTS: ALK fusions existed in 5.8% (36 out of 617) of the adenocarcinomas and 10.8% (4 out of 37) of the adenosquamous carcinomas. Q-PCR showed excellent sensitivity and specificity (100% and 100%, respectively) for the detection of ALK-rearranged lung tumors in resected specimens. We also identified six novel ALK fusion variants, including one KIF5B-ALK(E17;A20) and five EML4-ALK variants(E6a;A19, E6a/b ins 18;A20, E17b ins 39;A20, E10a/b, E13;A20 and E17 ins 65;A20).CONCLUSIONS: Q-PCR is a rapid, accurate method for diagnosis ALK-rearranged lung tumors. Coupling of 5'RACE to this method should further facilitate the rapid identification of novel ALK fusion genes.CLINICAL IMPLICATIONS: This method showed high reproducibility, sensitivity and specificity and will facilitate the routine identification of ALK-rearranged lung adenocarcinomas in clinical practice and detect lung cancers that may be responsive to ALK inhibitors.DISCLOSURE: The following authors have nothing to disclose: Rui Wang, Yihua Sun, Haiquan ChenNo Product/Research Disclosure InformationShanghai Cancer Center, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):924A. · 5.25 Impact Factor
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Hang Li,
Yunjian Pan,
Lei Shen,
Yuan Li,
Chenguang Li,
Rui Wang,
Haichuan Hu,
Ting Ye,
Yang Zhang,
Lei Wang,
Yihua Sun, Haiquan Chen
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ABSTRACT: SESSION TYPE: Biomarkers, Oncogenes and Enhanced Bronchoscopy in NSCLCPRESENTED ON: Wednesday, October 24, 2012 at 02:45 PM - 04:15 PMPURPOSE: We performed this analysis to reveal the association between 5 well-identified oncogenic driver mutations with clinical and pathological features in lung adenocarcinomas from smokers. This document may have the potential to optimize existing treatment strategies and clinical trial design.METHODS: In this series, 230 resected lung adenocarcinoma from smokers (>100 cigarettes in a life time) at a single institution (Fudan University, Shanghai, China) were analyzed for mutation in EGFR, KRAS, BRAF, HER2 and EML4-ALK. Further we compared the mutation status with sex, age at diagnosis, stage, differentiation, smoking dose, and histological subtype.RESULTS: Among 230 smokers, we detected 100 (43.5%) EGFR mutations, 38 (16.5%) KRAS mutations, 7 (3.0%) BRAF mutations and 7 (3.0%) EML4-ALK fusions. All mutations were mutually exclusive. No HER2 mutation was found. EGFR mutations occurred significantly more common in smokers with smoking dose ≤20 pack-years (p<0.001) or ≥60 years old at diagnosis (p=0.018). Smoking dose >20 pack-years and <60 years old at diagnosis were associated with the presence of KRAS mutation. With regard to association between histological subtypes and driver mutation status, EGFR mutation had positive correlation with micropapillary (p=0.003), lepidic (p=0.011), and papillary (p=0.05) predominant adenocarcinoma, and negative correlation with solid predominant(p<0.001) and invasive mucinous adenocarcinoma (IMA) (p=0.006). IMA had a positive correlation with KRAS mutation (p=0.043).CONCLUSIONS: To our knowledge, this study represents the first comprehensive and concurrent analysis of these five well-identified driver mutations in a large cohort of lung adenocarcinoma from East-Asian smokers. Our molecular data in conjunction with the clinical and pathological features indicated that prospective genotyping of lung adenocarcinomas from smokers for these genetic alterations could lead to rationally chosen targeted therapy in the overwhelming majority of cases.CLINICAL IMPLICATIONS: Our results indicate that the use of some targeted therapy of lung adenocarcinoma may be considered among some smokers with such clinical and pathological features. And it may help optimizing the design of further clinical trail.DISCLOSURE: The following authors have nothing to disclose: Hang Li, Yunjian Pan, Lei Shen, Yuan Li, Chenguang Li, Rui Wang, Haichuan Hu, Ting Ye, Yang Zhang, Lei Wang, Yihua Sun, Haiquan ChenNo Product/Research Disclosure InformationFudan University Shanghai Cancer Center, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):923A. · 5.25 Impact Factor
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ABSTRACT: SESSION TYPE: Lung Cancer IIPRESENTED ON: Monday, October 22, 2012 at 04:00 PM - 05:30 PMPURPOSE: To determine the mutation status of driver mutations in lung squamous cell carcinomas (LSCCs) and to re-clarify the mutation screening strategy in Chinese LSCC patients.METHODS: Three hundred and ten surgically resected frozen LSCC specimens and corresponding FFPE tumor blocks were collected at Fudan University Shanghai Cancer Center. A combination scheme with morphological features and IHC staining was conducted to exclude misdiagnosed adenocarcinomas and adenosquamous carcinomas. All known driver mutations, like EGFR, KRAS, BRAF, HER2, PIK3CA, AKT1, DDR2, as well as EML4-ALK and KIF5B-RET rearrangements were screened using cDNA-based sequencing. For detected EGFR/KRAS mutations, a further confirmation was performed in FFPE sections using microdissection to ascertain the real mutation component. Meanwhile, detected driver mutations and rearrangement were linked to clinical and pathological features.RESULTS: Two hundred and eighty-seven specimens, consisting of pure LSCCs and LSCCs with partial glandular component, were enrolled in mutational analysis, among which,10 EGFR mutations, 6 KRAS mutations, 1 BRAF mutation, 1 HER2 mutation, 1 AKT1 mutation, 1 DDR2 mutation, 11 PIK3CA mutations and 1 EML4-ALK fusion were identified,including1EGFR/PIK3CA and 1 KRAS/PIK3CA co-mutation. Microdissection sequencing revealed that 2 of 4 LSCC with partial glandular component specimens manifested an inconsistent mutation status between the two components. Although diagnosed as pure LSCCs by P63/TTF-1 staining, 5 of 9 specimens were failed to re-find the detected mutations, including 1 EGFR mutation and 4 KRAS mutations, which indicated that incomplete sampling or scattered glandular cells were responsible for accidently detected EGFR/KRAS mutations in pure LSCCs. Further clinical and pathological analysis showed that female, never-smoking status and peripheral location, which were usually linked with glandular component, were associated with a high mutation rate.CONCLUSIONS: EGFR/KRAS mutations should be considered as exclusive biomarkers of adenocarcinomas. Apart from exact pathological diagnosis, female, never-smoking status and peripheral location should be considered as predictors of mutations in Chinese LSCC patients.CLINICAL IMPLICATIONS: Our data has an important implication in mutation screening strategy for target therapy in Chinese LSCC patients.DISCLOSURE: The following authors have nothing to disclose: Yunjian Pan, Rui Wang, Chenguang Li, Yihua Sun, Haiquan ChenNo Product/Research Disclosure InformationFudan University Shanghai Cancer Center, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):590A. · 5.25 Impact Factor
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ABSTRACT: SESSION TYPE: Lung Cancer IIPRESENTED ON: Monday, October 22, 2012 at 04:00 PM - 05:30 PMPURPOSE: TAMs are a major component of a tumor. They produce high amounts of interleukin (IL)-10 but not IL-12, express high levels of angiogenesis factor, such as VEGF, PDGF, COX-2. TAMs also produced potent cytokines, such as MMP-9, uPA, cathepsin B, to promote cancer cells invasion and metastasis. These factors generally accepted as the marker of TAM. The aim of our study was to study the prognositic significance of TAM in non-small cell lung cancer.METHODS: TAM was isolated from 63 primary non-small lung cancer tissues by short term cultivation in serum-free medium. The mRNA expression levels of TAM markers were analyzed using real-time PCR, compared with matched normal macrophages from the 63 patients. The relationships between those gene expression levels and clinicopathological features were investigated. The TAM markers expression levels was correlated with disease-free survival.RESULTS: High levels of IL-10 in TAM significantly correlated with stage, lymph node metastasis, or histologic poor differentiation. The MMP-9 expression by TAMs were significantly higher in the late stage than the early stage. The marker IL-10, uPA and MMP-9 statistically significantly correlated with DFS (p<0.0001, p=0.011, p=0.022 respectively).CONCLUSIONS: The results of this study demonstrated that those up-regulated genes in TAMs contributed to lung cancer. A statistically significant association between shorter DFS was also seen for the patients with IL-10 and MMP-9 expression in TAM, which suggested that phenotypic expression on TAMs, like MMP9, IL-10 can be potentially used to predict prognosis as well.CLINICAL IMPLICATIONS: These data indicated that TAM expressed MMP-9 and IL-10 may contribute to tumor progression, and that they are useful prognostic markers in non-small cell lung cancer.DISCLOSURE: The following authors have nothing to disclose: Rui Wang, Jie Zhang, Haiquan ChenNo Product/Research Disclosure InformationDepartment of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):592A. · 5.25 Impact Factor
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ABSTRACT: SESSION TYPE: Thoracic Surgery IPRESENTED ON: Monday, October 22, 2012 at 11:15 AM - 12:30 PMPURPOSE: Over the last two decades, many studies sought to find reliable predictors of N0 status in small-sized (≤2 cm in diameter) non-small cell lung cancers (NSCLC). However, the way of tumor size measurement was usually not standardized, and controversy remains as to whether systematic lymph node dissection should be performed in patients with subcentimeter tumors. Moreover, the correlations between lung adenocarcinoma subtypes in line with the new classification and lymph node metastasis have not yet been determined specifically in small peripheral tumors.METHODS: We reviewed association between lymph node involvement and clinicopathologic variables in 243 small peripheral NSCLC with their size measured in fresh specimens before formalin fixation. Histologic subtypes of adenocarcinomas were classified according to the new International Association for the Study of Lung Cancer (IASLC)/American Thoracic Society (ATS)/European Respiratory Society (ERS) lung adenocarcinoma classification.RESULTS: Incidence of N1 and N2 nodal involvement was 5.3% and 6.6%, respectively. N2 disease was present in a proportion of subcentimeter tumors (2 out of 53, 3.8%). No lymph node metastasis was revealed in squamous cell carcinomas, adenocarcinoma in situ, minimally invasive adenocarcinoma, lepidic predominant adenocarcinoma or invasive mucinous adenocarcinoma. Collectively, the five cell types accounted for 34.6% of all the small peripheral cases.CONCLUSIONS: Precise measurement of tumor size in fresh tissues revealed that tumor size was not a reliable predictor of N0 status. However, through histologic classification, systematic lymph node dissection might be avoided in more than one third of small peripheral NSCLC.CLINICAL IMPLICATIONS: Through analysis of 243 small peripheral non-small cell lung cancers with their size measured precisely in fresh specimens, we found that tumor size alone should not be criteria to rule out systematic lymph node dissection. However, through histologic classification, omission of systematic lymph node dissection might be an alternative in more than one third of small peripheral NSCLC.DISCLOSURE: The following authors have nothing to disclose: Yang Zhang, Haiquan Chen, Jiaqing Xiang, Yawei Zhang, Yihua Sun, Hong HuNo Product/Research Disclosure InformationFudan University Shanghai Cancer Hospital, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):36A. · 5.25 Impact Factor
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ABSTRACT: SESSION TYPE: Thoracic Surgery IIPRESENTED ON: Tuesday, October 23, 2012 at 04:30 PM - 05:45 PMPURPOSE: Controversy remains over the routine use of invasive (such as mediastinoscopy) or expensive (such as positron emission tomography) diagnostic procedures in stage T1 non-small cell lung cancer (NSCLC) without lymph node enlargement on computed tomography (CT) as the risk of mediastinal lymph node metastasis is comparatively low in such patients. We aimed to develop a prediction model for N2 disease in CT defined T1N0 NSCLC to aid in the decision-making process.METHODS: We reviewed the records of 530 CT defined T1N0 NSCLC patients who underwent surgical resection with systematic lymph node dissection. Correlations between N2 involvement and clinicopathological parameters were assessed using univariate analysis and binary logistic regression analysis. A prediction model was built on the basis of logistic regression analysis, and was internally validated using bootstrapping.RESULTS: Incidence of N2 disease was 16.8%. Four independent predictors were identified in multivariate logistic regression analysis and were included in the prediction model: age at diagnosis (OR = 0.974; 95% CI: 0.952-0.997), tumor size (OR = 2.769; 95% CI: 1.818-4.217), central tumor location (OR = 3.204; 95% CI: 1.512-6.790), and invasive adenocarcinoma histology (OR = 3.537; 95% CI: 1.740-7.191). Hosmer-Lemeshow test of goodness-of-fit was not significant (P = 0.784), suggesting a high concordance between predicted and observed probabilities. The area under the ROC curve, which measures the model's accuracy, was reasonable (0.726, 95% CI: 0.669-0.784). Internal validation by bootstrapping showed the bias corrected area under the ROC curve was 0.717, and the extent of "over-optimism" is minimal (0.009, 1.2%), indicating that this prediction model holds for future patients.CONCLUSIONS: We developed a four-predictor model that can estimate the probability of N2 disease in CT defined T1N0 NSCLC. This prediction model can help to determine the cost-effective utilization of mediastinal staging procedures.CLINICAL IMPLICATIONS: The predicted likelihood of N2 nodal involvement has implications for the cost-effective utilization of diagnostic procedures, such as mediastinoscopy and PET, in staging mediastinal lymph nodes in CT defined T1N0 NSCLC.DISCLOSURE: The following authors have nothing to disclose: Yang Zhang, Yihua Sun, Jiaqing Xiang, Yawei Zhang, Hong Hu, Haiquan ChenNo Product/Research Disclosure InformationDepartment of Thoracic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):49A. · 5.25 Impact Factor
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ABSTRACT: SESSION TYPE: Lung Cancer IIPRESENTED ON: Monday, October 22, 2012 at 04:00 PM - 05:30 PMPURPOSE: The RET fusion gene, which is prevalent and targetable in thyroid cancer, has been recently described in a subset of non-small-cell lung cancers (NSCLCs). As we still have limited knowledge about these tumors, this study was aimed at determining the clinicopathological characteristics of patients with NSCLCs harboring the RET fusion gene.METHODS: We examined the RET fusion gene in 936 patients with surgical resected NSCLCs using a RT-PCR plus quantitative real-time PCR strategy. The subset of 633 patients with lung adenocarcinomas were also detected for EGFR, KRAS, HER2, BRAF mutations as well as ALK rearrangements. Patient characteristics including age, sex, smoking history, stage, grade, IASLC/ATS/ERS classification of subtypes of lung adenocarcinoma, and relapse-free survival were collected.RESULTS: From 936 patients with NSCLCs, the RET fusion gene was exclusively detected in 13 patients (11 out of 633 patients with adenocarcinomas, and 2 out of 24 patients with adenosquamous cell carcinomas), including 9 with KIF5B-RET, 3 with CCDC6-RET, and 1 with a novel NCOA4-RET fusions. Patients with lung adenocarcinomas with RET fusion gene had more poorly differentiated tumors (63.6%, P=0.029 for RET vs. ALK, P=0.007 for RET vs. EGFR), with a tendency to younger patients (≤60, 72.7%), never smokers (81.8%), solid subtype (63.6%), and early N2 disease(54.4%). The median relapse-free survival of the patients with RET fusion positive NSCLCs was 20.5 months.CONCLUSIONS: RET fusion occurs in 1.74% of lung adenocarcinomas and 8.33% of lung adenosquamous cell carcinomas with identifiable clinicopathological characteristics. A novel NCOA4-RET fusion detected in NSCLCs warrants further investigations.CLINICAL IMPLICATIONS: This study determined that the patients with NSCLCs harboring RET fusion gene have identifiable clinicopathological characteristics. The further understanding of this novel molecular abnormality can be therefore introduced into future trial design and clinical managements for about 12,000 patients per year worldwide (e.g. systemic mediastinum lymphadenectomy or radiation is warranted for these patients because of their early N2 disease is frequently observed).DISCLOSURE: The following authors have nothing to disclose: Haichuan Hu, Rui Wang, Yunjian Pan, Yihua Sun, Haiquan ChenThe screening of RET fusion gene used a RT-PCR plus quantitative real-time PCR strategy, which method is still considered research.Fudan University Cancer Center, Shanghai, China.
Chest 10/2012; 142(4_MeetingAbstracts):593A. · 5.25 Impact Factor
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ABSTRACT: Lymph node metastasis is among the most important prognostic factors for patients with esophageal squamous cell carcinoma after curative esophagectomy; however, the extent of lymphadenectomy is still controversial. The objective of the present study was to determine the frequency of lymphatic metastases and to study the pattern of lymph node metastasis in a large study population.
The data from 1361 patients with thoracic esophageal squamous cell carcinoma who underwent curative R0 esophagectomy were retrospectively examined. Logistic regression analysis was used to identify the factors associated with lymph node metastasis.
Of the 1361 patients, 714 (52.5%) were found to have lymph node metastasis. The frequency of lymph node metastasis increased as the tumor invasion increased. Paratracheal nodes were the most frequent metastasis nodes (15.9%). The frequency of lymph node metastasis was 9.8% in the neck, 18.0% in the upper mediastinum, 18.9% in the middle mediastinum, 11.8% in the lower mediastinum, and 28.4% in the abdomen. Of these 714 patients, 424 (31.2%) presented with 1 field involvement, 255 (18.7%) with 2 fields, and 35 (2.6%) with 3 fields involvement. Logistic regression analysis revealed tumor length (P < .001), tumor invasion (P < .001), tumor differentiation (P = .003), and lymphovascular invasion (P < .001) were risk factors for lymph node metastasis. Tumor location (P < .001), tumor invasion (P = .003), lymphovascular invasion (P = .004), and paratracheal lymph node involvement (P = .002) were identified as risk factors for cervical lymph node metastasis.
Metastases were more frequent in the abdomen than in the neck. Total mediastinal and upper abdominal lymphadenectomy should be carefully conducted. Certain factors, such as tumor location, depth of tumor invasion, lymphovascular invasion, and paratracheal lymph node involvement, might be helpful in determining the need to perform cervical lymphadenectomy in individual patients.
The Journal of thoracic and cardiovascular surgery 08/2012; 144(4):778-86. · 3.41 Impact Factor
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ABSTRACT: OBJECTIVE: Controversy remains over the routine use of mediastinoscopy or positron emission tomography in T1 non-small cell lung cancer without lymph node enlargement on computed tomography because the risk of N2 involvement is comparatively low. We aimed to develop a prediction model for N2 disease in cT1N0 non-small cell lung cancer to aid in the decision-making process. METHODS: We reviewed the records of 530 patients with computed tomography-defined T1N0 non-small cell lung cancer who underwent surgical resection with systematic lymph node dissection. Correlations between N2 involvement and clinicopathologic parameters were assessed using univariate analysis and binary logistic regression analysis. A prediction model was built on the basis of logistic regression analysis and was internally validated using bootstrapping. RESULTS: The incidence of N2 disease was 16.8%. Four independent predictors were identified in multivariate logistic regression analysis and included in the prediction model: younger age at diagnosis (odds ratio, 0.974; 95% confidence interval, 0.952-0.997), larger tumor size (odds ratio, 2.769; 95% confidence interval, 1.818-4.217), central tumor location (odds ratio, 3.204; 95% confidence interval, 1.512-6.790), and invasive adenocarcinoma histology (odds ratio, 3.537; 95% confidence interval, 1.740-7.191). This model shows good calibration (Hosmer-Lemeshow test: P = .784), reasonable discrimination (area under the receiver operating characteristic curve, 0.726; 95% confidence interval, 0.669-0.784), and minimal overfitting demonstrated by bootstrapping. CONCLUSIONS: We developed a 4-predictor model that can estimate the probability of N2 disease in computed tomography-defined T1N0 non-small cell lung cancer. This prediction model can help to determine the cost-effective use of mediastinal staging procedures.
The Journal of thoracic and cardiovascular surgery 07/2012; · 3.41 Impact Factor
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Rui Wang,
Yunjian Pan,
Chenguang Li,
Haichuan Hu,
Yang Zhang,
Hang Li,
Xiaoyang Luo,
Jie Zhang,
Zhaoyuan Fang,
Yuan Li,
Lei Shen,
Hongbin Ji,
David Garfield,
Yihua Sun, Haiquan Chen
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ABSTRACT: Approximately 3% to 7% of non-small cell lung cancers (NSCLC) harbor an ALK fusion gene, thus defining a tumor group that may be responsive to targeted therapy. The breakpoint in ALK consistently occurs at exon 20 and EML4 or other fusion partners, thus driving a strong expression of ALK kinase domain and resulting in an unbalanced expression in 5' and 3' portions of ALK transcripts. We have developed a rapid and accurate method by simultaneously detecting the expression in 5' and 3' portions of ALK mRNA.
Quantitative real-time reverse transcriptase PCR (qRT-PCR) was used to examine expression levels of the 5' and 3' portions of ALK transcripts in177 NSCLCs, in which EGFR, KRAS, HER2, and BRAF mutations were absent. If unbalanced ALK mRNA expression was seen, ALK rearrangement was assumed to exist. ALK FISH was used to confirm the accuracy of qRT-PCR. RT-PCR and 5' RACE coupling sequencing identified the fusion variants.
Real-time RT-PCR showed excellent sensitivity and specificity (100% and 100%, respectively) for detection of ALK rearrangements in resected specimens. In addition, six novel ALK fusion variants were identified, including one KIF5B-ALK (E17;A20) and five EML4-ALK variants (E6a;A19, E6a/b ins 18;A20, E17b ins 39;A20, E10a/b, E13;A20, and E17 ins 65;A20).
Real-time RT-PCR is a rapid and accurate method for diagnosing ALK-rearranged lung cancers. Coupling of 5' RACE to this method should further facilitate rapid identification of novel ALK fusion genes.
Clinical Cancer Research 07/2012; 18(17):4725-32. · 7.74 Impact Factor
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ABSTRACT: INTODUCTION: In an effort to reduce the morbidity and mortality associated with open esophagectomy, a minimally invasive approach to esophagectomy was introduced at the University of Pittsburgh Medical Center (UPMC) in 1996. The objective of this article is to discuss the optimization and refinement of minimally invasive esophagectomy (MIE) techniques over the 15-year experience at UPMC. We also reviewed the literature on technical improvements in MIE.
Literature highlights for MIE and related meta-analyses comparing open esophagectomy and MIE were reviewed. The rationale and outcomes of techniques refinements were discussed in detail.
Most meta-analyses and systematic reviews confirm the feasibility and safety of MIE and suggest similar oncologic outcomes as compared with open esophagectomy. Since 1996, over 1,000 minimally invasive esophagectomies have been performed at UPMC. We have made several refinements to the MIE procedure that we believe significantly improved our surgical outcomes. It included adjustment of width of the gastric conduit, application of omental flap, and conversion from minimally invasive, three-hole esophagectomy to minimally invasive Ivor Lewis esophagectomy.
MIE became a mainstay in the surgical treatment of esophageal cancer at UPMC. The technical improvements detailed above make the UPMC approach to MIE a feasible, safe, and efficient procedure.
Journal of Gastrointestinal Surgery 07/2012; 16(9):1768-74. · 2.83 Impact Factor
