Woo-Ho Kim

Evaluation of the Seventh American Joint Committee on Cancer/International Union Against Cancer Classification of gastric adenocarcinoma in comparison with the sixth classification

The seventh TNM staging system for gastric cancer of the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC) had a more detailed classification than the sixth TNM staging system for both the tumor (T) and lymph nodes (N). The authors compared survival rates assessed by the seventh staging system with those by the sixth system.

Analysis of long-term survivors after surgical resection for pancreatic cancer.

Objectives: The purpose of this study was to determine the outcome of surgical resection for pancreatic cancer and to characterize the clinicopathologic features of actual long-term survivors. Methods: Of the 789 pancreatic cancer patients, we retrospectively analyzed 242 patients who underwent an operation between 1985 and 1999. Surgical resection with curative intent was performed in 123 patients. We analyzed the overall results of surgical treatment, compared the clinicopathologic features between long-term and short-term survivors, and reevaluated the histological slides of the long-term survivors. Results: Median survival and cumulative 5-year survival rate after surgical resection were 14.8 months and 12.1%. Tumor size, American Joint Committee on Cancer stage, resection margin involvement, and lymph node metastases were the significant prognostic factors. Eleven patients survived for more than 5 years. Some patients with poor prognostic factors such as lymph node metastasis and big tumor size survived for more than 5 years. Histological reevaluation in the long-term survivors revealed 4 cases of variant adenocarcinoma (anaplastic carcinoma, mucinous noncystic adenocarcinoma [n = 2], and undifferentiated carcinoma). Conclusions: Active surgical resection should be attempted even in patients with poor prognostic factors. As there were various types of pathology among the long-term survivors, typical ductal adenocarcinoma of the pancreas might have a poorer survival rate.

Prognostic implications of type and density of tumour-infiltrating lymphocytes in gastric cancer

The study aims to determine whether type and density of tumour-infiltrating lymphocytes (TILs) can predict the clinical course in gastric cancer. Gastric carcinomas (n=220) were immunostained for CD3, CD8, CD20, and CD45RO and evaluated for clinicopathologic characteristics. Number of TILs that immunostained positively for each marker were counted using NIH ImageJ software. Tumours were grouped into low- and high-density groups for each marker (CD3, CD8, CD45RO). The densities of CD3+, CD8+, and CD45RO+ TILs were found to be independent predictors of lymph node metastasis by multivariate analysis with odds ratios (95% CI) of 0.425 (0.204–0.885), 0.325 (0.150–0.707), and 0.402 (0.190–0.850), respectively. Kaplan–Meier survival analysis revealed that patients in the high-density groups for CD3, CD8, and C45RO had a significantly longer survival time than the patients in the corresponding low-density groups, respectively. In multivariate survival analysis, the densities of CD3+, CD8+, and CD45RO+ TILs remained independent prognostic factors with hazard ratios (95% CI) of 0.549 (0.317–0.951), 0.574 (0.347–0.949), and 0.507 (0.298–0.862), respectively. In conclusion, density of TILs was found to be independently predictive of regional lymph node metastasis and patient survival in gastric cancer.

Anaplastic lymphoma kinase translocation: a predictive biomarker of pemetrexed in patients with non-small cell lung cancer.

Introduction: This study compared the efficacy of pemetrexed in patients with anaplastic lymphoma kinase (ALK)-positive versus ALK-negative (epidermal growth factor receptor [EGFR] mutant or wild type [WT] for both ALK and EGFR) non-small cell lung cancer (NSCLC). Methods: Patients with advanced NSCLC who received second-line pemetrexed and beyond between March 2007 and April 2010 were screened for EGFR mutations and ALK rearrangements at Seoul National University Hospital. The clinical and in vitro efficacy of pemetrexed was evaluated for each genotypic group. Results: Ninety-five NSCLC patients were genotyped as follows: 43 (45%) EGFR mutation, 15 (16%) ALK translocation, and 37 (39%) WT. The overall response rate was superior in ALK-translocated patients compared with EGFR mutant or WT patients (46.7 versus 4.7 versus 16.2%, p = 0.001). ALK-positive patients showed longer time to progression than EGFR mutant or WT patients (9.2 versus 1.4 versus 2.9 months, p = 0.001). ALK positivity alone was a significant predictor for overall response rate (hazard ratio [HR] = 0.07, 95% confidence interval [CI]: 0.01–0.32; p = 0.001) and time to progression (HR = 0.44, 95% CI: 0.24–0.80; p = 0.007). ALK positivity remained independently significant regardless of treatment line (HR = 0.43, 95% CI: 0.24–0.77; p = 0.005). Thymidylate synthase mRNA levels in ALK-positive cells were significantly lower compared with control cells (p < 0.05). Conclusion: Pemetrexed is an effective treatment in patients with ALK-positive NSCLC. ALK positivity was independently predictive of pemetrexed efficacy in NSCLC patients.

MET in gastric carcinomas: comparison between protein expression and gene copy number and impact on clinical outcome

Background:The aim of this study was to compare gene copy number (GCN) and protein expression of MET and to evaluate their prognostic roles in gastric carcinomas.Methods:MET protein expression and gene amplification (GA) status were determined by immunohistochemistry (IHC) and silver in-situ hybridisation (SISH), respectively, in a large series of gastric carcinoma.Results:Protein overexpression was observed in 104 of 438 cases, with IHC 2+ in 94 and IHC 3+ in 10, and high polysomy of chromosome 7 and GA were found in 61 and 13 of 381, respectively. Direct comparison revealed a significant correlation between high level of protein expression and increased GCN. All cases with GA showed protein overexpression. Furthermore, all with IHC 3+ showed GA except 1, even which could be categorised as GA according to the ASCO/CAP guideline for human epidermal growth factor receptor 2 assessment. IHC 3+ and GA were significantly associated with poor prognosis.Conclusion:MET IHC reflects well on GA, and therefore, it could be a primary screening test for patient selection for anti-MET therapy if GA is a major determinant of drug responsiveness. Also, the prognostic role of MET indicates that anti-MET therapy is a very promising modality in adjuvant treatment for gastric cancer.

Nomogram Predicting Long-Term Survival After D2 Gastrectomy for Gastric Cancer

PURPOSEnThe aim of this study was to combine clinicopathologic variables associated with overall survival after gastric resection with D2 lymphadenectomy (D2 gastrectomy) for gastric cancer into a prediction nomogram.nnnPATIENTS AND METHODSnWe retrospectively analyzed 7,954 patients who underwent D2 gastrectomy for gastric cancer at Seoul National University Hospital (SNUH) in Seoul, Korea. Two thirds of the patients were randomly assigned to the training set (n = 5,300), and one third were assigned to the validation set (n = 2,654). Multivariate analysis by Cox proportional hazards regression was performed using the training set, and the nomogram was constructed. Discrimination and calibration were performed using the SNUH validation set. Additional external validation was performed using the data set (n = 2,500) from Cancer Institute Ariake Hospital (CIAH) in Tokyo, Japan.nnnRESULTSnThe multivariate Cox model identified age at diagnosis, sex, location, depth of invasion, number of metastatic lymph nodes, and number of examined lymph nodes as covariates associated with survival. In the SNUH validation set, the nomogram exhibited superior discrimination power compared with the seventh American Joint Committee on Cancer TNM classification (Harrells C-index, 0.78 v 0.69, respectively; P < .001). Calibration of the nomogram predicted survival corresponding closely with the actual survival. In the CIAH validation set, discrimination was good (C-index, 0.79), and the predicted survival was within a 10% margin of ideal nomogram.nnnCONCLUSIONnWe developed a nomogram predicting 5- and 10-year overall survival after D2 gastrectomy for gastric cancer. Validation using the SNUH and CIAH data sets revealed good discrimination and calibration, suggesting good clinical utility. The nomogram improved individualized predictions of survival.

A hypoxia-dependent upregulation of hypoxia-inducible factor-1 by nuclear factor-κB promotes gastric tumour growth and angiogenesis

Background:The underlying mechanisms involved in the activation of hypoxia-inducible factor-1 (HIF-1) in gastric cancer remain unclear. As nuclear factor-κB (NF-κB) as well as HIF-1 have been implicated in angiogenesis of various cancers, we investigated their relationship in gastric cancer.Methods:Nuclear expressions of HIF-1α and NF-κB/RelA were assessed in 251 human gastric carcinoma specimens by immunohistochemical tissue array analysis. Stable human gastric cancer cells, infected with a retroviral vector containing super-suppressive mutant form of IκBα (IκBαM), were used for animal studies as well as cell culture experiments. Xenografted tumours were measured and IκBαM effects on angiogenesis and HIF-1α activation were assessed by immunohistochemistry, western blotting, luciferase reporter assay, and semiquantitative reverse transcription–polymerase chain reaction. In addition, NF-κB effects on the HIF-1α degradation and synthesis were examined.Results:Hypoxia-inducible factor-1α activation positively correlated with RelA activation in clinical gastric cancer samples (P<0.001). The IκBαM overexpression suppressed tumour growth, microvessel density, and HIF-1α activation in xenografted tumours. Cell culture experiments showed that hypoxia-induced HIF-1α expression was reduced by NF-κB inhibition under hypoxic conditions at the translational level.Conclusion:The hypoxia-dependent activation of the NF-κB/HIF-1α/VEGF pathway contributes, at least in part, to gastric cancer promotion via enhancement of angiogenesis.

Should adenocarcinoma of the esophagogastric junction be classified as esophageal cancer? A comparative analysis according to the seventh AJCC TNM classification.

Objective:The aim of this study was to evaluate the adequacy of esophageal classification for adenocarcinoma of the esophagogastric junction (AEJ) of the seventh American Joint Committee on Cancer (AJCC) TNM classification. Background:The seventh AJCC TNM classification proposed the new classification for AEJ as a part of esophageal cancer depending on the esophagogastric junction (EGJ) involvement. However, there are still many controversies over the classification system for AEJ. Methods:A review of pathologic reports and photographic findings at Seoul National University Hospital from 2003 to 2009 identified 4524 patients with single, primary adenocarcinoma of the EGJ (n = 497) and other regions of the stomach (GC, n = 4027) who underwent an operation with curative intent. We analyzed the clinicopathologic features and postoperative prognosis of AEJ using the Siewert classification and the seventh AJCC TNM classification. Results:There was no Siewert type I (AEJ I) in this study. The prognosis of AEJ was similar to that of GC. There was no difference in clinicopathologic features between AEJ II and AEJ III. Even though AEJ extending into the EGJ (AEJe) showed more advanced pathologic features than AEJ not extending into the EGJ (AEJg), the prognosis of AEJe and AEJg was not significantly different when stratified by T stage. Compared with the classification of gastric cancer applied for AEJ, esophageal classification for AEJ from the seventh AJCC TNM classification showed a loss of distinctiveness at each TNM stage. Conclusions:To evaluate the postoperative prognosis of AEJ within the stomach, AEJ II and AEJ III should be considered a part of gastric cancer irrespective of EGJ involvement.

Dissemination of Free Cancer Cells from the Gastric Lumen and from Perigastric Lymphovascular Pedicles during Radical Gastric Cancer Surgery

BackgroundManipulation and improper handling of a tumor during surgery may increase the risk of cancer cell dissemination after a curative gastrectomy. This study investigated the effect of improper handling of lymphovascular pedicles of stomach on tumor spillage during surgical procedure.MethodsThirty-eight gastric cancer patients were enrolled. Three pairs of wash samples were obtained from each patient: (1) intraperitoneal wash samples obtained before (P0) and after gastrectomy (P1), (2) intragastric wash samples obtained before any manipulation (G0) and just before resection of the stomach (G1), and (3) ex vivo wash samples obtained by rinsing resected stomach with the lymphovascular pedicles closed by clips (S0) or with the pedicles open (S1). Cytologic examination was performed from all washes, and real-time reverse transcriptase–polymerase chain reaction analysis for carcinoembryonic antigen was performed from washes P0, P1, S0, and S1.ResultsCytologic examination detected cancer cells in 34.2% (13 of 38) of G0 samples and in 39.5% (15 of 38) of G1 samples. The rate of conversion from G0-negative to G1-positive increased as T stage increased. Cytologic examination detected cancer cells in 2.6% (1 of 38) of S0 samples and in 13.2% (5 of 38) of S1 samples. The carcinoembryonic antigen mRNA level of the S1 sample was 2-fold greater than that of the S0 sample in 50.0% (7 of 14).ConclusionsFree cancer cells can be released from gastric lumen or lymphovascular pedicles opened during gastric cancer surgery, especially in advanced-stage disease. Care should be taken to minimize spillage from the gastric lumen and lymphovascular pedicles.

Clinicopathologic Characteristics and Outcomes of Patients with Anaplastic Lymphoma Kinase-Positive Advanced Pulmonary Adenocarcinoma Suggestion for an Effective Screening Strategy for These Tumors

Introduction:The purpose of this study was to analyze the clinicopathologic characteristics and outcomes of patients with anaplastic lymphoma kinase (ALK)-positive advanced pulmonary adenocarcinoma and to devise an effective screening strategy to identify such patients. Methods:We screened advanced pulmonary adenocarcinoma patients to identify ALK-positive cases. The presence of ALK rearrangements was confirmed by fluorescence in situ hybridization. Results:Of the 221 screened patients, 45 demonstrated ALK rearrangements, and these individuals were younger than the ALK-negative patients (p < 0.001). The proportion of never smokers and light smokers was found not to differ according to the ALK status (p = 0.537). Epidermal growth factor receptor (EGFR) mutations and ALK rearrangements were found to be mutually exclusive. Thyroid-transcription factor-1 (TTF-1) expression was observed in all ALK-positive tumors for which immunohistochemistry data were available. The objective response rate and progression-free survival to first-line platinum-based chemotherapy showed no significant differences between ALK-positive and ALK-negative patients. On the other hand, no patient with ALK-positive tumors achieved objective tumor responses to EGFR tyrosine kinase inhibitors (TKIs). ALK rearrangements were not found among individuals who had EGFR mutations, an objective response to a previous EGFR TKI treatment or TTF-1-negative tumors. Conclusion:The clinical outcomes of platinum-based chemotherapy were found not to differ according to the ALK status. Both smokers and never/light smokers should be candidates for ALK screening. We suggest that the exclusion of patients with activating EGFR mutations, an objective response to previous EGFR TKIs, or TTF-1-negative tumors from ALK screening could be an effective enrichment strategy for ALK-positive cases.