Dong Kwan Kim

Clinicopathologic implication of ALK rearrangement in surgically resected lung cancer: A proposal of diagnostic algorithm for ALK-rearranged adenocarcinoma

BACKGROUNDnTo characterize the clinicopathologic features of ALK-rearranged lung cancer, and suggest a molecular test protocol for lung adenocarcinoma in the small biopsy specimen.nnnMETHODSnIn 735 NSCLC surgical specimens, clinicopathologic features, ALK protein over-expression by immunohistochemistry (IHC), and ALK rearrangement by fluorescence in situ hybridization (FISH) as well as EGFR and KRAS mutation studies were analyzed.nnnRESULTSnOf the 735 NSCLC cases, 28 (3.8%) were ALK FISH-positive. ALK rearrangement, EGFR and KRAS mutation were mutually exclusive. ALK rearrangement was significantly higher in adenocarcinomas (6.8%, p<0.001), younger age (p<0.0007), women (7.6%, p<0.001), and never-smokers (8.9%, p<0.001) with no gender difference in the adenocarcinoma or never-smoker subgroup. ALK FISH-positivity was not associated with disease recurrence (HR, 0.79; 95% CI, 0.42-1.49) or overall survival (HR, 0.61; 95% CI, 0.24-1.55). However, ALK-rearranged lung cancer tended to show more frequent lymph node metastasis despite its lower T stage. Similar to EGFR-mutated lung cancer, ALK-rearranged lung cancer was enriched in adenocarcinoma, women, and never-smokers. The results of ALK IHC and FISH obtained from tissue microarray (TMA)/biopsy specimens and whole sections after resection were concordant.nnnCONCLUSIONnALK rearrangement was not a significant prognostic factor in surgically resectable NSCLC. The clinical profiles of ALK-rearranged lung cancer patients overlapped with those of EGFR-mutated patients. Therefore, we suggest that simultaneous tests for ALK IHC and EGFR mutation (Chungs SNUBH molecular test protocol), which has important implications for the storage and use of small biopsy or cytology samples for genetic analysis.

ROS1 Receptor Tyrosine Kinase, a Druggable Target, is Frequently Overexpressed in Non-Small Cell Lung Carcinomas Via Genetic and Epigenetic Mechanisms

BackgroundMicroarray analyses have revealed significantly elevated expression of the proto-oncogene ROS1 receptor tyrosine kinase in 20–30xa0% of non-small cell lung carcinomas (NSCLC). Selective and potent ROS1 kinase inhibitors have recently been developed and oncogenic rearrangement of ROS1 in NSCLC identified.MethodsWe performed immunohistochemical evaluation of expression of ROS1 kinase and its downstream molecules in 399 NSCLC cases. ROS1 expression in primary and recurring lesions of 92 recurrent NSCLC cases was additionally analyzed. To elucidate mechanism of expression, two ROS1-nonexpressing NSCLC cell lines (Calu6 and H358) and fresh frozen tissues from 28 consecutive NSCLC patients were examined for ROS1 promoter methylation status and ROS1 expression.ResultsOverall expression rate of ROS1 was 22xa0% (19xa0% for adenocarcinomas and 25xa0% for nonadenocarcinomas) in NSCLC. ROS1 expression was a worse prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. In recurred NSCLC, ROS1 expression was significantly higher in recurring tumors (38xa0%) than primary tumors (19xa0%). Two NSCLC cell lines showed increased ROS1 expression after treatment with 5-aza-2′deoxycytidine and/or trichostatin A. Among the 14 adenocarcinomas examined, two (14xa0%) showed more than twice the level of ROS1 expression in tumor tissue than was observed in matched normal tissue and statistically significant differences in the ROS1 promoter methylation level.ConclusionsA subset of NSCLC revealed overexpression of ROS1 receptor tyrosine kinase, possibly in relation to epigenetic changes. ROS1 expression was an independent prognostic factor for overall survival in adenocarcinomas of stage I NSCLC. Further studies are needed to validate our results.

Staple Line Coverage After Bullectomy for Primary Spontaneous Pneumothorax: A Randomized Trial

BACKGROUNDnThoracoscopic wedge resection is generally accepted as a standard surgical procedure for primary spontaneous pneumothorax. Because of the relatively high recurrence rate after surgery, additional procedures such as mechanical pleurodesis or visceral pleural coverage are usually applied to minimize recurrence, although mechanical pleurodesis has some potential disadvantages. The aim of this study was to clarify whether an additional coverage procedure on thexa0staple line after thoracoscopic bullectomy prevents postoperative recurrence compared with additional pleurodesis.nnnMETHODSnA total of 1,414 patients in 11 hospitals with primary spontaneous pneumothorax undergoing thoracoscopic bullectomy were enrolled. After bullectomy with staplers, patients were randomly assigned to either the coverage group (nxa0= 757) or the pleurodesis group (nxa0= 657). In the coverage group, the staple line was covered with absorbable cellulose mesh and fibrin glue. The pleurodesis group underwent additional mechanical abrasion on the parietal pleura.nnnRESULTSnThe coverage group and the pleurodesis group showed comparable surgical outcomes. After a median follow-up of 19.5 months, the postoperative 1-year recurrence rate was 9.5% in the coverage group and 10.7% in the pleurodesis group. The 1-year recurrence rate requiring intervention was 5.8% in the coverage group and 7.8% in the pleurodesis group. The coverage group showed better recovery from pain.nnnCONCLUSIONSnIn terms of postoperative recurrence rate, visceral pleural coverage after thoracoscopic bullectomy was not inferior to mechanical pleurodesis. Visceral pleural coverage may potentially replace mechanical pleurodesis, which has potential disadvantages such as disturbed normal pleural physiology.

Surgical management of pulmonary adenocarcinoma presenting as a pure ground-glass nodule.

OBJECTIVESnWith recent advances in radiology, the detection of ground-glass nodules (GGNs) has become increasingly common. However, there still is no consensus on management, especially on the need for systemic lymph node (LN) dissection. The purpose of this study was to evaluate the surgical outcomes on the basis of the extent of resection of the primary lesion and mediastinal LN dissection and to carefully suggest appropriate treatment strategies in the patients with pulmonary adenocarcinoma presenting as pure ground-glass opacities.nnnMETHODSnFrom January 2006 to December 2010, 1267 patients with pulmonary adenocarcinoma, including adenocarcinoma in situ, underwent curative-intent surgical resection. Among these patients, pure GGNs were confirmed in 48 patients on preoperative chest computed tomography (CT) by an experienced radiologist, and 42 underwent systemic LN dissection or sampling. We retrospectively reviewed the perioperative data and postoperative outcomes.nnnRESULTSnThe median age of the patients was 56 (range, 35-78) years, and 26 (54.2%) patients were male. The median size of the nodules was 12 (5-30) mm, and 8 (16.7%) had multiple lesions at the time of operation. The median duration between the initial diagnosis and operation was 4 (0-45) months. Preoperative positron emission tomography/CT was taken in 36 (75.0%) patients, which showed no significant metabolic uptake. For curative resection, lobectomy was performed in 32 (66.7%) patients, segmentectomy in 4, and wedge resection in 12. Clear resection margins were reported in all patients. Forty-two patients underwent systemic mediastinal LN dissection or sampling, and the median number of dissected LNs was 23 (7-53). No LN was reported as positive for malignancy. The median follow-up duration after the first operation was 39 (23-77) months, and there were no cases of late mortality, local recurrence or nodal recurrence. Recurrent GGNs have been developed in 6 (12.5%) patients.nnnCONCLUSIONSnFor pure GGNs, limited resection can be performed when complete resection is obtained, as it was sufficient for cure and especially because there is high probability of multiple lesions. We were unable to demonstrate any additional therapeutic benefit with mediastinal LN dissection in patients with pure GGNs.

SRSF5: a novel marker for small-cell lung cancer and pleural metastatic cancer.

OBJECTIVESnSR-splicing factors (SRSFs) play important roles in oncogenesis. However, the expression of SRSF 5-7 proteins in lung cancer (LC) is unclear, and their use in the diagnosis of pleural diseases has never been assessed. We evaluated SRSF 5-7 protein levels in LC and their diagnostic potential for cancer cells in lung and pleural effusion (PE) and, for the dysregulated SRSFs, investigated their neutralization effect on LC.nnnMATERIALS AND METHODSnSRSF 5-7 levels in lung tissue and PE cell lysate samples (n=453) were compared with the results of conventional tumor markers. Knockdown of SRSF gene expression was performed using small interfering RNAs on small-cell LC (SCLC) cell lines.nnnRESULTSnIn lung tissue analysis, SRSF 5-7 levels were up-regulated in LC samples compared with non-tumoral lung tissue samples; they were markedly higher in SCLC than in adenocarcinoma or squamous cell carcinoma. SRSF5 showed the highest detection accuracy (89%) for total LC, and it was superior to that (74%) of carcinoembryonic antigen [CEA, a commonly used non-SCLC (NSCLC) marker]. Notably, the detection accuracies of the three SRSFs for SCLC were all 100% and higher than that (69%) of a pro-gastrin-releasing peptide (a well-known SCLC marker). In PE cell analysis, the detection accuracy (86%) of SRSF5 for malignant cells was highest among SRSFs and comparable to that (83%) of CEA. SRSF5 additionally detected 70% of CEA-missed non-NSCLC cases. Down-regulation of the SRSFs induced mild (SRSF5 and SRSF7) to remarkably (SRSF6) reduced cell proliferation.nnnCONCLUSIONSnOur results demonstrated the up-regulated expression of SRSF 5-7 proteins in LC with much more profound up-regulation in SCLC than in NSCLC and suggest that up-regulation of the SRSFs is related to SCLC proliferation. Moreover, we identified SRSF5 as a novel detection marker for SCLC and pleural metastatic cancer cells.

Postoperative adjuvant chemotherapy and radiotherapy for stage II and III non-small cell lung cancer (NSCLC)

The role of postoperative adjuvant chemo-radiotherapy in the treatment of patients with non-small cell lung cancer (NSCLC) remains unclear. This study was undertaken to evaluate the survival outcomes, relapse patterns, prognostic factors and complications of postoperative adjuvant MVP chemotherapy and radiotherapy. The study involved some 96 patients who had undergone curative resection of stage II and III NSCLC between 1991 and 1996. Among these, 94 patients who completed their adjuvant treatment were analyzed. Surgery consisted of pneumonectomy (33%), single lobectomy (54%) or bilobectomy (13%). Within 4 weeks of curative resection, two cycles of MVP chemotherapy (mitomycinC 8 mg/m(2), vinblastine 8 mg/m(2), cisplatin 60 mg/m(2)) were started at 4 weeks intervals. Conventionally fractionated radiotherapy was given 3 weeks after chemotherapy to a total dose of 50 Gy in completely resected patients and 55-60 Gy in patients with positive resection margins. The TNM classification of the AJCC, as revised in 1997, was used for pathologic staging. The number of patients at AJCC stages IIa, IIb, IIIa, and IIIb were four, 40, 45, and five, respectively. A pathologically positive bronchial resection margin was found in nine patients. At the time of analysis, death was recorded in 29 patients (31%), though five had died without evidence of lung cancer. Overall 2, 3, and 5-year-survival rates for all patients were 74.2, 70.2, and 65%, respectively, and locoregional disease-free survival (LRDFS) rates were 88.6, 83.7, 74.3%, at 2, 3, and 5-years, distant metastasis disease-free survival (DMDFS) rates were 67.7, 65.0, and 63.6%, respectively. In the multivariate model, a primary tumor size of more than 5 cm and the level of pathologically positive nodes were found to be associated with poor overall survival, LRDFS and DMDFS. Although positive bronchial resection margin affected overall survival, LRDFS and DMDFS were unaffected. With respect to the first site of relapse, distant metastasis occurred more frequently (N=33, 35%) than locoregional recurrence (N=15, 16%). Grade 3 esophagitis in two patients and weight loss of more than 10% in five patients were observed during adjuvant treatment. Grade 4 pulmonary toxicity was observed in one patient after radiotherapy and this patient ultimately died 5 months after treatment. The postoperative adjuvant MVP chemotherapy and radiotherapy regimen showed relatively low locoregional recurrence and distant metastasis rates and good survival with acceptable toxicity. A prospective randomized trial, which compares this regimen to surgery alone or postoperative adjuvant radiotherapy is needed.

Clinical significance of NQO1 C609T polymorphisms after postoperative radiation therapy in completely resected non-small cell lung cancer

PURPOSEnTo investigate the clinical significance of NQO1 C609T polymorphisms to treatment outcome after postoperative radiation therapy in completely resected non-small cell lung cancer (NSCLC).nnnMETHODSnOne hundred and sixteen, Korean-ethnic, patients who were treated with surgery and postoperative radiation therapy from February 2000 to September 2005 in Asan Medical Center (Seoul, South Korea) were analyzed. All patients received 5040cGy radiation to surgical stump, mediastinum and ipsilateral supraclavicular node. NQO1 C609T polymorphisms were examined from a peripheral blood sample in all patients. Three types of NQO1 C609T polymorphisms were designated as C/C, C/T and T/T. Chest computed tomography was routinely checked after radiation therapy at every 3 or 6 months and locoregional tumor control, distant metastasis and survival by NQO1 C609T genotype were analyzed.nnnRESULTSnThe proportion of NQO1 C609T polymorphisms was 27.6% for C/C, 53.4% for C/T and 19.0% for T/T. Most patients were men and had squamous cell carcinoma or adenocarcinoma. Median age of patients was 61 years. Major failure pattern was distant metastasis and 13 (11.2%) patients showed locoregional recurrence within the field of previous radiation therapy. Crude locoregional recurrence rate was significantly different by NQO1 genotype; 6.3% in C/C, 8.1% in C/T, and 27.3% in T/T (p=0.03), but distant metastasis was not different. Median follow-up time was 49.2 months (range: 3.4-103.5 months). Locoregional recurrence-free survival (LRRFS) was affected in T/T genotype compared with C/C or C/T genotype (p=0.01, Kaplan-Meier method), but distant metastasis-free survival (DMFS) or overall survival (OS) was not different by NQO1 genotype in univariate analysis. NQO1 genotype was also a significant factor for LRRFS (p=0.01) in multivariate analysis. Radiation-induced pneumonitis or esophagitis was tolerable in all patients and the difference by NQO1 genotype was not observed.nnnCONCLUSIONSnNQO1 C609T polymorphisms could be a predictive factor for the locoregional tumor control after postoperative radiation therapy in completely resected NSCLC.

Limited thymectomy as a potential alternative treatment option for early-stage thymoma: A multi-institutional propensity-matched study

OBJECTIVESnFor early-stage thymoma, complete thymectomy has classically been regarded as the standard treatment protocol. However, several studies have shown that limited thymectomy may be an alternative treatment option for thymoma. This study compared perioperative outcomes, survival, and recurrence rates between patients undergoing limited thymectomy and complete thymectomy.nnnMATERIALS AND METHODSnBetween January 2000 and December 2013, a total of 762 patients underwent thymectomy for stage I or II thymomas at four institutions participating in the Korean Association for Research on the Thymus. Patients were divided into two groups: limited thymectomy group (n=295) and complete thymectomy group (n=467). Comparative clinicopathological, surgical, and oncological features were reviewed retrospectively.nnnRESULTSnThe median follow-up time was 49 months (range: 0.2-189 months). A propensity score-matching analysis, based on seven variables (age, sex, surgical approach, tumor size, WHO histological type, Masaoka-Koga stage, and adjuvant radiotherapy), was performed using 141 patients selected from each group. The 5- and 10-year freedom-from-recurrence rates in the limited thymectomy group were 96.3% and 89.7%, respectively, and those in the complete thymectomy group were 97.0% and 85.0%, respectively. No significant differences in these rates were observed between groups (p=0.86). A multivariate Cox regression analysis showed that overall survival and freedom-from-recurrence rates did not significantly differ by surgery extent (p=0.27, 0.66, respectively). Perioperative outcomes were better in the limited thymectomy group.nnnCONCLUSIONnLimited thymectomy was not inferior to complete thymectomy with respect to recurrence, and had better perioperative outcomes. Limited thymectomy may be a viable treatment option for early-stage thymoma.

Comparison of genetic and epigenetic alterations at 11 tumor suppressor loci in pulmonary sclerosing hemangioma and adenocarcinoma

ABSTRACT Pulmonary sclerosing hemangioma (SH) is an unusual tumor of pneumocytic origin. Morphologically, SH can mimic pulmonary adenocarcinomas. Here, the authors compared genetic and epigenetic aberrations in SH with those in pulmonary adenocarcinoma. Clinicopathologic characteristics, microsatellite alterations, and CpG island methylation were analyzed in pulmonary SHs (n = 24) and adenocarcinomas (n = 34) to compare their patterns of molecular abnormalities. SHs were also analyzed immunohistochemically to characterize the expression status of proteins involved in basic biologic processes. The clinical presentation of SH cases was generally benign. Both cell types of SH stained positive for thyroid transcription factor 1 (TTF-1), epithelial membrane antigen (EMA), β-catenin, E-cadherin, and vascular endothelial growth factor (VEGF). Allelic imbalances in D3S1283, D3S1234, D3S1300, D3S1285, TP53, D17S938, and D9S179 were less frequent in SH than in adenocarcinoma; rates of allelic imbalances in D20S170 and D21S1446 were not significantly different. In SH, CpG island methylation frequencies of p16INK4a (0.0%) and RASSF1A (12.5%) were significantly lower than those in adenocarcinoma (29.4% and 38.2%, respectively); the frequencies of HOX D9, D11, and D13 gene methylation in SH were 37.5%, 33.3%, and 33.3%, respectively. The results show that pulmonary SH and adenocarcinoma share similar genetic and epigenetic aberrations, but also exhibit significant differences, especially in tumor suppressor genes.

Impact of Lymph Node Dissection on Thymic Malignancies: Multi-Institutional Propensity Score Matched Analysis

Introduction: Surgical resection is a standard treatment for thymic malignancies. However, prognostic significance of nodal metastases and lymph node dissection remains unclear. The aim of this study is to determine prognostic significance of nodal metastases and the role of lymph node dissection (LND) in thymic malignancies. Methods: Between 2000 and 2013, 1597 patients who underwent thymectomy due to thymic malignancy were included. Predictive factors for nodal metastasis and prognostic significance of LND were evaluated. Patients were divided into two groups: (1) LND+ group, with intentional LND (446 patients, 27.9%); and (2) LND‐ group, without intentional LND (1151 patients, 72.1%). Propensity score matching was performed between the two groups. Results: Lymph node metastasis was identified in 20 (6.7%) of 298 patients with thymoma and 47 (31.7%) of 148 patients with thymic carcinoma. In multivariable analysis, thymic carcinoma (hazard ratio: 19.2, p < 0.001) and tumor size (hazard ratio: 1.09, p = 0.02) were significant predictive factors for lymph node metastasis. The 10‐year freedom from recurrence rate of pN1 and pN2 was significantly worse than that of pN0 (p < 0.001). LND did not increase operative mortality or complication. There was no significant difference in 10‐year freedom from recurrence rate between LND+ and LND‐ groups (82.4% versus 80.9%, p = 0.46 in thymoma; 45.7% versus 44.0%, p = 0.42 in thymic carcinoma). Conclusions: Lymph node metastasis was a significant prognostic factor in thymic malignancies. Although LND did not improve long‐term outcomes in thymic malignancies, LND played a role in accurate staging, and improved prediction of prognosis.