Somcharoen Saeteng

The prognostic value of ERCC1 and RRM1 gene expression in completely resected non-small cell lung cancer: tumor recurrence and overall survival

Background The roles of excision repair cross-complementing group 1 gene (ERCC1) expression and ribonucleotide reductase subunit M1 gene (RRM1) expression in completely resected non-small cell lung cancer (NSCLC) are still debatable. Previous studies have shown that both genes affected the overall survival and outcomes of patients who received platinum-based chemotherapy; however, some studies did not show this correlation. The aim of this study was to evaluate the prognostic values of ERCC1 and RRM1 gene expression in predicting tumor recurrence and overall survival in patients with completely resected NSCLC who received adjuvant chemotherapy and in those who did not. Patients and methods A retrospective cohort study was conducted in 247 patients with completely resected NSCLC. All patients had been treated with anatomic resection (lobectomy or pneumonectomy) with systematic mediastinal lymphadenectomy between January 2002 and December 2011 at Chiang Mai University Hospital, Chiang Mai, Thailand. They were divided into two groups: recurrence and no recurrence. Protein expression of ERCC1 and RRM1 was determined by immunohistochemistry. Correlations between clinicopathologic variables, including ERCC1 and RRM1 expression and tumor recurrence, were analyzed. Univariate and multivariate Cox proportional hazards regression analysis stratified by nodal involvement, tumor staging, intratumoral blood vessel invasion, intratumoral lymphatic invasion, and tumor necrosis was used to identify the prognostic roles of ERCC1 and RRM1. Results ERCC1 and RRM1 expression did not demonstrate prognostic value for tumor recurrence and overall survival in patients with completely resected NSCLC. In patients who did not receive adjuvant chemotherapy treatment, those with high ERCC1 and high RRM1 expression seemed to have greater potential for tumor recurrence and shorter overall survival than did those who had low ERCC1 and low RRM1 (hazard ratio [HR] =1.7, 95% confidence interval [CI] =0.6–4.3, P=0.292 and HR =1.6, 95% CI =0.5–4.5, P=0.411, respectively). In contrast, in patients who received adjuvant chemotherapy treatment, those with high ERCC1 and high RRM1 expression seemed to have benefited from adjuvant chemotherapy and showed good overall survival compared with those who had low ERCC1 and low RRM1 (HR =0.8, 95% CI = 0.4–1.8, P=0.612 and HR = 0.4, 95% CI = 0.1–2.4, P=0.325, respectively). Subgroup analysis in patients whose first-line metastatic chemotherapy failed demonstrated that ERCC1 expression and RRM1 expression were not prognostic factors for tumor recurrence and overall survival; however, patients who had high ERCC1 and high RRM1 expression seemed to have benefited from first-line chemotherapy treatment (HR =0.7, 95% CI =0.3–1.8, P=0.458). Conclusion ERCC1 expression and RRM1 expression were not prognostic of tumor recurrence and overall survival in patients with completely resected NSCLC, either with or without adjuvant chemotherapy. Prospective studies that include a larger number of patients are needed for definite conclusions.

Nodal involvement pattern in resectable lung cancer according to tumor location

The aim in this study was to define the pattern of lymph node metastasis according to the primary tumor location. In this retrospective cohort study, each of the operable patients diagnosed with lung cancer was grouped by tumor mass location. The International Association for the Study of Lung Cancer nodal chart with stations and zones, established in 2009, was used to define lymph node levels. From 2006 to 2010, 197 patients underwent a lobectomy with systematic nodal resection for primary lung cancer at Chiang Mai University Hospital. There were 123 male and 74 female patients, with ages ranging from 16– 85 years old and an average age of 61.31. Analyses of tumor location, histology type, and nodal metastasis were performed. The locations were the right upper lobe in 63 patients (31.98%), the right middle lobe in 18 patients (9.14%), the right lower lobe in 30 patients (15.23%), the left upper lobe in 55 patients (27.92%), the left lower lobe in 16 patients (8.12%), and mixed lobes (more than one lobe) in 15 patients (7.61%). The mean tumor size was 4.45 cm in diameter (range 1.2–16.5 cm). Adenocarcinoma was the most common histological type, which occurred in 132 cases (67.01%), followed by squamous cell carcinoma in 41 cases (20.81%), bronchiolo alveolar cell carcinoma in nine cases (4.57%), and large cell carcinoma in seven cases (3.55%). Eighteen cases (9.6%) had skip metastasis (mediastinal lymph node metastasis without hilar node metastasis). Adenocarcinoma and intratumoral lymphatic invasion were the predictors of mediastinal lymph node metastases. There were statistically significant differences between a tumor in the right upper lobe and the right lower lobe. However, there were no statistically significant differences between tumors in the other lobes. In conclusion, tumor location is not a precise predictor of the pattern of nodal metastasis. Systematic lymph node dissection is the only way to accurately determine lymph node status. Further studies are required for evaluation and conclusions.

Prognostic factors of tumor recurrence in completely resected non-small cell lung cancer

Background Patients with completely resected non-small cell lung cancer (NSCLC) have an excellent outcome; however tumor recurs in 30%–77% of patients. This study retrospectively analyzed the clinicopathologic features of patients with any operable stage of NSCLC to identify the prognostic factors that influence tumor recurrence, including intratumoral blood vessel invasion (IVI), tumor size, tumor necrosis, and intratumoral lymphatic invasion. Methods From January 2002 to December 2011, 227 consecutive patients were enrolled in this study. They were divided into two groups: the “no recurrence” group and the “recurrence” group. Recurrence-free survival was analyzed by multivariable Cox regression analysis, stratified by tumor staging, chemotherapy, and nodal involvement. Results IVI, tumor necrosis, tumor diameter more than 5 cm, and nodal involvement were identified as independent prognostic factors of tumor recurrence. The hazard ratio (HR) of patients with IVI was 2.1 times higher than that of patients without IVI (95% confident interval [CI]: 1.4–3.2) (P = 0.001).The HR of patients with tumor necrosis was 2.1 times higher than that of patients without tumor necrosis (95% CI: 1.3–3.4) (P = 0.001). Patients who had a maximum tumor diameter greater than 5 cm had significantly higher risk of recurrence than patients who had a maximum tumor diameter of less than 5 cm (HR 1.9, 95% CI: 1.0–3.5) (P = 0.033). Conclusion IVI, tumor diameter more than 5 cm, and tumor necrosis are prognostic factors of tumor recurrence in completely resected NSCLC. Therefore, NSCLC patients, with or without nodal involvement, who have one or more prognostic factors of tumor recurrence may benefit from adjuvant chemotherapy for prevention of tumor recurrence.

Retrospective Study of ALK Rearrangement and Clinicopathological Implications in Completely Resected Non- small Cell Lung Cancer Patients in Northern Thailand: Role of Screening with D5F3 Antibodies

BACKGROUND Anaplastic lymphoma kinase (ALK) gene rearrangement in non-small cell lung cancer (NSCLC) has been intensively studied. The gold standard for ALK detection is FISH, but this is not routinely conducted in clinical practice, so that the IHC method has a role. The aim of this study was to identify the incidence of ALK rearrangement and risk or prognostic factors for ALK positivity using both of IHC and FISH methods. MATERIALS AND METHODS From January 2008 to December 2012, 267 completely resected NSCLC patients in Chiang Mai University Hospital were enrolled in this study. Clinical and pathological variables and outcomes of treatment were retrospectively reviewed. IHC and FISH were used to evaluate ALK rearrangement. Sensitivity and specificity of IHC were analyzed. Multivariable analysis was used to identify clinico-pathological correlations with positive results of IHC and clinical outcomes. RESULTS Twenty-two (8.2%) of 267 specimens were IHC-positive for ALK with intense cytoplasmic staining, whereas only 10 (3.8%) were FISH-positive. Sensitivity, specificity and the positive likelihood ratio with IHC were 80.0%, 94.9%, and 15.8 respectively. Age less than 55 years (RR 4.4, 95%CI 1.78-10.73, p value=0.001) and presence of visceral pleural invasion (VPI) (RR 2.9, 95%CI 1.21-6.78, p value =0.017) were identified as risk factors for ALK rearrangement with FISH. There were no statistically significant differences in other clinical and pathological variables. ALK rearrangement was not a prognostic factor for tumor recurrence or overall survival. CONCLUSIONS The incidences of ALK positivity in completely resected NSCLCs in northern Thailand were 8.2% by IHC and 3.8% by FISH. IHC with mouse monoclonal, Ventana D5F3 antibody can be used as a screening tool before FISH method because of high specificity and high positive likelihood ratio. Age less than 55 years and VPI are risk factors for ALK positivity.

Completely Resected N0 Non-Small Cell Lung Cancer: Prognostic Factors Affecting Long-Term Survival

Background. Although early stage non-small cell lung cancer (NSCLC) has an excellent outcome and correlated with good long-term survival, up to 15 percent of patients still relapse postoperatively and die. This study is conducted to identify prognostic factors that may affect the long-term survival in completely resected N0 NSCLC. Methods. Medical records of 124 patients with completely resected N0 NSCLC were retrospectively reviewed. Prognostic factors affecting long-term survival were analyzed by the Kaplan-Meier method and Cox proportional hazards analysis. Results. Overall five-year survival rate was 48 percent. Multivariable analysis revealed stage of disease, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastases, and skin metastases as significant prognostic factors affecting long-term survival. The hazard ratio (HR) of tumor necrosis, tumor recurrence, brain metastasis, adrenal metastases, and skin metastases was 2.0, 2.3, 7.6, 4.1, and 8.3, respectively, and all P values were less than 0.001. Conclusions. Our study shows stage of disease, tumor necrosis, tumor recurrence, brain metastasis, adrenal metastasis, and skin metastasis as the independent prognostic factors of long-term survival in pathological N0 NSCLC. Early stage NSCLC patients without nodal involvement or presented with tumor necrosis should benefit from adjuvant chemotherapy, and sites of metastasis could predict the long-term survival as described.

Comparative clinical outcomes after thymectomy for myasthenia gravis: Thoracoscopic versus trans-sternal approach.

BACKGROUND Thymectomy is an effective treatment option for long-term remission of myasthenia gravis. The superiority of the trans-sternal and thoracoscopic surgical approaches is still being debated. The aims of this study are to compare postoperative outcomes and neurologic outcomes between the two approaches and to identify prognostic factors for complete stable remission (CSR). METHODS Myasthenia gravis patients who underwent thymectomy with trans-sternal or thoracoscopic approach in MahaRaj Nakorn Chiang Mai Hospital, Chiang Mai, Thailand between January1, 2006 and December 31, 2013 were retrospectively reviewed. The endpoints were postoperative outcomes and cumulative incidence function for CSR. The analysis was performed using multilevel model, Coxs proportional hazard model, and propensity score. RESULTS Ninety-eight patients were enrolled in this study: 53 in the thoracoscopic group and 45 in the trans-sternal group. There were no significant differences between groups in composite postoperative complications, surgical time, ventilator support days, and length of intensive care unit stay. Intraoperative blood loss and length of hospital stay were significant less in the thoracoscopic group. The CSR and median time to remission were not significantly different between the two approaches. Prognostic factors for CSR were nonthymoma (hazard ratio: 3.5, 95% confidence interval: 1.01-12.22) and presence of pharmacological remission (hazard ratio: 24.3, 95% confidence interval: 3.27-180.41). CONCLUSION Thoracoscopic thymectomy is safe and provides good neurologic outcomes in comparison to the trans-sternal approach. Two predictive factors should be considered for CSR. Further prospective studies with a larger sample size and longer follow-up period are warranted to confirm these results.

Impact of lymph node management on resectable non-small cell lung cancer patients

BACKGROUND A surgical lung resection with systematic mediastinal lymph node (LN) dissection is recommended by the National Comprehensive Cancer Network guideline. However, the effective number of dissected LNs, stations and positivity is still controversial. The aim of this study is to identify the impact of total numbers, LN stations and positivity of dissected LNs on tumor recurrence and overall death in resectable non-small cell lung cancer (NSCLC). METHODS This prognostic study used a retrospective data collection design. Adult patients with clinical resectable NSCLC who underwent pulmonary resection and mediastinal lymphadenectomy at Chiang Mai University between June 2000 and June 2012 were enrolled in this study. A multilevel mixed-effects parametric survival model was used to identify the effect of numbers, LN stations and positivity of dissected LNs to tumor recurrence and mortality. RESULTS The average number of dissected LNs was 22.7±12.8. Tumor recurrence was found in 51.3% and overall mortality was 43.3%. The number of dissected LNs was a prognostic factor for tumor recurrence [HR 0.98, 95% confidence interval (CI): 0.96-0.99]. There was a significant difference at the cut-pointed value of 11 dissected LNs for tumor recurrence (HR 2.22, 95% CI: 1.26-3.92). Dissection less than 11 nodes and less than 5 stations indicated a poor prognostic factor for tumor recurrence: for 3-4 stations (HR 3.01, 95% CI: 1.22-7.42) and for 1-2 stations (HR 1.96, 95% CI: 1.04-3.72). The positivity of dissected LNs was also a prognostic factor for tumor recurrence and overall mortality (HR 1.01, 95% CI: 1.01-1.02 and HR 1.01, 95% CI: 1.01-1.03, respectively). CONCLUSIONS Eleven or more LN dissection with at least 5 stations influenced recurrent-free survival. Systematic LN dissection (SLND) should be performed not only to identify the positivity of dissected LNs but also to determine an accurate tumor nodal stage. A larger cohort should be further conducted to support these findings.

Preoperative plasmapheresis for elective thymectomy in myasthenia patient: is it necessary?

Background. Role of plasmapheresis before thymectomy remains controversial. The aim of this study is to determine the peri-operative and post-operative outcome of a thymectomy between performing and not performing a pre-operative plasmaphreresis. Patients and Methods. A retrospective chart review study was conducted in Chiang Mai University Hospital between January 2006 and December 2011. There were 86 myasthenia patients divided into two groups; Preoperative plasmapheresis group (PPG) and no preoperative plasmapheresis group (NPPG). The primary outcome involved post-operative extubation and the secondary outcome included post-operative complications, 28 day mortality and length of hospital stay. Results. Eighty-six patients were enrolled in this study. The number of patients who had a history of myasthenic crisis at any time or within one month in the PPG was significantly more than those in the NPPG. Muscle power and forced expiratory vital capacity in the NPPG was higher than that in the PPG. The postoperative extubation rate was similar in both groups. After controlling for the propensity score, there were no statistically significant differences in both of primary and secondary outcomes. Conclusion. The results of this study shows no significant differences between both groups in all outcomes, therefore the pre-operative plasmaphresis is not necessary for elective thymectomy.

Role of intrapulmonary lymph node retrieval for pathological examination in resectable non-small cell lung cancer

Lymph node (LN) metastasis is a prognostic factor for tumor recurrence and overall survival (OS) in resectable non-small cell lung cancer (NSCLC) patients (1,2).

Lung Cancer: Diagnosis and Treatment Approach

Lung cancer is one of the most common causes of cancer death in the world. There are many risk factors for lung cancer including tobacco smoking, chronic lung disease, race and ethnicity, occupational carcinogen exposure, diet and genetic factors. Until now there have been no effective modalities for the early detection of lung cancer. The National Cancer Institute recently released results from its National Lung Screening Trial (NLST) which showed that low dose CT scans compared to chest x-rays can reduce lung cancer mortality by 20 %. For accurate lung cancer staging, multi-modality approaches are used such as positron emission tomography (PET) scan, computed tomography (CT) scan, endobronchial ultrasound (EBUS) biopsy or mediastinoscope biopsy of mediastinal lymph node, pleural tapping procedure, or video-assisted thoracoscopic surgery (VATS). Multi-modality methods have a vital role in lung cancer treatment including surgery, chemotherapy, radiotherapy, targeted therapy and immunotherapy. Anatomical resection and systematic lymphadenectomy is the treatment of choice for early stage lung cancer. Neo-adjuvant chemotherapy is utilized for resectable N2 disease or adjuvant chemotherapy for pathological N2 disease and unresectable advanced disease. Targeted therapies have already been proven as highly effective and less toxic therapies for positive molecular testing in advanced disease.