Dysplastic Stem Cell Plasticity Functions as a Driving Force for Neoplastic Transformation of Precancerous Gastric Mucosa.

BACKGROUND & AIMS: Dysplasia carries a high risk of cancer development; however, the cellular mechanisms for dysplasia evolution to cancer are obscure. We have previously identified 2 putative dysplastic stem cell (DSC) populations, CD44v6neg/CD133+/CD166+ (double positive [DP]) and CD44v6+/CD133+/CD166+ (triple positive [TP]), which may contribute to cellular heterogeneity of gastric dysplasia. Here, we investigated functional roles and cell plasticity of noncancerous Trop2+/CD133+/CD166+ DSCs initially developed in the transition from precancerous metaplasia to dysplasia in the stomach. METHODS: Dysplastic organoids established from active Kras-induced mouse stomachs were used for transcriptome analysis, in vitro differentiation, and in vivo tumorigenicity assessments of DSCs. Cell heterogeneity and genetic alterations during clonal evolution of DSCs were examined by next-generation sequencing. Tissue microarrays were used to identify DSCs in human dysplasia. We additionally evaluated the effect of casein kinase 1 alpha (CK1α) regulation on the DSC activities using both mouse and human dysplastic organoids. RESULTS: We identified a high similarity of molecular profiles between DP- and TP-DSCs, but more dynamic activities of DP-DSCs in differentiation and survival for maintaining dysplastic cell lineages through Wnt ligand-independent CK1α/ß-catenin signaling. Xenograft studies demonstrated that the DP-DSCs clonally evolve toward multiple types of gastric adenocarcinomas and promote cancer cell heterogeneity by acquiring additional genetic mutations and recruiting the tumor microenvironment. Last, growth and survival of both mouse and human dysplastic organoids were controlled by targeting CK1α. CONCLUSIONS: These findings indicate that the DSCs are de novo gastric cancer-initiating cells responsible for neoplastic transformation and a promising target for intervention in early induction of gastric cancer.

Prognostic Impact of Frozen Section Investigation and Extent of Proximal Safety Margin in Gastric Cancer Resection.

BACKGROUND AND AIMS: Guidelines propose different extents of macroscopic proximal margin for gastric cancer and frozen margin investigation in selected cases, but data is lacking. This study was to evaluate the necessary extent of macroscopic proximal margin, accuracy of frozen margin investigation, and prognostic impact of tumor-free proximal margin length in pT2-pT4 gastric cancer. STUDY DESIGN: Proximal and distal frozen margins were routinely investigated intraoperatively in all pT2-pT4 gastric cancers resected between 2011 and 2017. Macroscopic and microscopic proximal margin lengths were correlated. For R0-resections, survival analysis was performed for distal gastrectomy (DG) with microscopic proximal margin length ≤3 cm versus >3 cm. RESULTS: Overall, 1484 patients were included. Microscopic proximal margin lengths were macroscopically more often misestimated in diffuse histology (P = 0.0004), but extent of underestimation in centimeter was similar to intestinal and mixed/undetermined type (P = 0.134). Fifteen cases (1.0%) resulted in R1-resection, 10 at distal, and 5 at proximal margin but none with macroscopic proximal margin ≥3 cm and negative frozen section. Overall agreement of frozen margin and final pathology was 2951/2968 (99.4%). Proximal margin length in DG did not correlate with survival or recurrence in R0-resected patients. DISCUSSION: Diffuse histology is at higher risk for underestimation of proximal margin length, but extent of underestimation is similar in other Laurén subtypes. If ≥3 cm macroscopic proximal margin length is applied with intraoperative frozen margin confirmation, R1-resection can be avoided. CONCLUSION: In pT2-T4a gastric cancer, proximal margin of ≥3 cm plus frozen margin confirmation provides high oncological safety. In DG patients with R0-resection, proximal margin length does not correlate with survival or recurrence.

Alterations in the Rho pathway contribute to Epstein-Barr virus-induced lymphomagenesis in immunosuppressed environments.

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphomas (EBV+-DLBLs) tend to occur in immunocompromised patients, such as the elderly or those undergoing solid organ transplantation. The pathogenesis and genomic characteristics of EBV+-DLBLs are largely unknown because of the limited availability of human samples and lack of experimental animal models. We observed the development of 25 human EBV+-DLBLs during the engraftment of gastric adenocarcinomas into immunodeficient mice. An integrated genomic analysis of the human-derived EBV+-DLBLs revealed enrichment of mutations in Rho pathway genes, including RHPN2, and Rho pathway transcriptomic activation. Targeting the Rho pathway using a Rho-associated protein kinase (ROCK) inhibitor, fasudil, markedly decreased tumor growth in EBV+-DLBL patient-derived xenograft (PDX) models. Thus, alterations in the Rho pathway appear to contribute to EBV-induced lymphomagenesis in immunosuppressed environments.

Identification of a molecular signature of prognostic subtypes in diffuse-type gastric cancer.

BACKGROUND: Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for diffuse-type GC have been identified. Here, we aim to identify a prognostic and predictive signature of diffuse-type GC heterogeneity. METHODS: We analyzed RNA-seq-based transcriptome data to identify a molecular signature in 150 gastric tissue samples including 107 diffuse-type GCs. The predictive value of the signature was verified using other diffuse-type GC samples in three independent cohorts (n = 466). Log-rank and Cox regression analyses were used to estimate the association between the signature and prognosis. The signature was also characterized by somatic variant analyses and tissue microarray analysis between diffuse-type GC subtypes. RESULTS: Transcriptomic profiling of RNA-seq data identified a signature which revealed distinct subtypes of diffuse-type GC: the intestinal-like (INT) and core diffuse-type (COD) subtypes. The signature showed high predictability and independent clinical utility in diffuse-type GC prognosis in other patient cohorts (HR 2.058, 95% CI 1.53-2.77, P = 1.76 × 10-6). Integrative mutational and gene expression analyses demonstrated that the COD subtype was responsive to chemotherapy, whereas the INT subtype was responsive to immunotherapy with an immune checkpoint inhibitor (ICI). Tissue microarray analysis showed the practical utility of IGF1 and NXPE2 for predicting diffuse-type GC heterogeneity. CONCLUSIONS: We present a molecular signature that can identify diffuse-type GC patients who display different clinical behaviors as well as responses to chemotherapy or ICI treatment.

microRNA-30a arbitrates intestinal-type early gastric carcinogenesis by directly targeting ITGA2.

BACKGROUND: Spasmolytic polypeptide-expressing metaplasia (SPEM) is considered a precursor lesion of intestinal metaplasia and intestinal-type gastric cancer (GC), but little is known about microRNA alterations during metaplasia and GC developments. Here, we investigate miR-30a expression in gastric lesions and identify its novel target gene which is associated with the intestinal-type GC. METHODS: We conducted in situ hybridization and qRT-PCR to determine miR-30a expression in gastric tissues. miR-30a functions were determined through induction or inhibition of miR-30a in GC cell lines. A gene microarray was utilized to confirm miR-30a target genes in GC, and siRNA-mediated target gene suppression and immunostaining were performed. The Cancer Genome Atlas data were utilized to validate gene expressions. RESULTS: We found down-regulation of miR-30a during chief cell transdifferentiation into SPEM. MiR-30a level was also reduced in the early stage of GC, and its level was maintained in advanced GC. We identified a novel target gene of miR-30a and ITGA2, and our results showed that either ectopic expression of miR-30a or ITGA2 knockdown suppressed GC cell proliferation, migration, and tumorigenesis. Levels of ITGA2 inversely correlated with levels of miR-30a in human intestinal-type GC. CONCLUSION: We found down-regulation of miR-30a in preneoplastic lesions and its tumor-suppressive functions by targeting ITGA2 in GC. The level of ITGA2, which functions as an oncogene, was up-regulated in human GC. The results of this study suggest that coordination of the miR-30a-ITGA2 axis may serve as an important mechanism in the development of gastric precancerous lesions and intestinal-type GC.

Pylorus-preserving gastrectomy for early cancer involving the upper third: can we go higher?

BACKGROUND: Pylorus-preserving gastrectomy (PPG) is commonly performed for early gastric cancer (EGC) located in middle third of the stomach. We investigated the surgical, oncological, and functional outcomes of PPG involving the upper third of stomach. METHODS: We included all patients of the period 2013-2016 who underwent PPG, distal subtotal gastrectomy (DSG), and total gastrectomy (TG) for EGC involving the upper third by carefully defining the localization. Surgical, oncological, and functional outcome analyses included postoperative morbidity, lymph-node metastasis, tumor recurrence, postoperative body weight, body mass index, hemoglobin, total protein, albumin, quantification of intraabdominal fat, and gallstone development. RESULTS: Overall, 288 cases were analyzed: 145 PPG, 61 DSG, and 82 TG. In the study period, patients potentially underwent PPG for EGC involving the upper third, if enough proximal remnant stomach was found whilst achieving a sufficient proximal margin. PPG resulted in less operation time (p < 0.001), less blood loss (p = 0.002) and lower postoperative morbidity compared to TG. For lymph-node (LN) stations being resected in all groups, no difference was found in number of resected LN. Recurrence-free survival was similar for all groups. PPG showed advantages regarding postoperative body weight, hemoglobin, total protein, albumin in postoperative 6 and 12 month follow-up. Lowest decrease of abdominal fat area after 12 months was seen for PPG. Gallstone incidence was significantly lower after PPG compared to TG (p < 0.001). CONCLUSIONS: For EGC involving the upper third, PPG can be another good option with lower postoperative morbidity, better functional outcomes, and same oncological safety.

Recurrence Pattern and Lymph Node Metastasis of Adenocarcinoma at the Esophagogastric Junction.

BACKGROUND: The surgical approach for adenocarcinoma of the esophagogastric junction (AEJ) still is controversial despite revised tumor-node-metastasis (TNM) classification. This study aimed to evaluate the oncologic outcome of a routine transhiatal approach for AEJ in terms of recurrence and lymph node (LN) metastasis of AEJ. METHODS: Recurrence patterns and LN metastasis of a single, primary AEJ (n = 463) treated by a surgical resection using a transhiatal approach without routine complete mediastinal LN dissection or routine splenectomy were analyzed respectively. To validate current treatment for recurrence, a validation index of recurrence (ViR; overall survival/incidence of solitary recurrence factor) was developed. RESULTS: The overall recurrence rate for AEJ was 20.3%, which did not differ significantly between AEJ II (20.8%; n = 125) and AEJ III (20.1%; n = 338). Mediastinal recurrence did not differ significantly among the subtypes of AEJ, irrespective of gastroesophageal junction involvement. Splenic hilar LN recurrence-free survival did not differ significantly between the gastrectomy-only group, the gastrectomy-plus-splenectomy group, and the gastrectomy plus distal pancreatectomy group. The solitary recurrence rate for the mediastinal LN was 0.7% for AEJ, and the overall median survival with that recurrence was 30.5 months. The ViR for mediastinal LN recurrence (43.6) was higher than for regional LN (20.9) or distant LN (14.6) metastasis. CONCLUSION: In terms of LN metastasis and recurrence, a transhiatal approach without complete mediastinal LN dissection can be acceptable, and routine splenectomy is not necessary for AEJ II or AEJ III arising within the stomach.

Comprehensive genome- and transcriptome-wide analyses of mutations associated with microsatellite instability in Korean gastric cancers.

Microsatellite instability (MSI) is a critical mechanism that drives genetic aberrations in cancer. To identify the entire MS mutation, we performed the first comprehensive genome- and transcriptome-wide analyses of mutations associated with MSI in Korean gastric cancer cell lines and primary tissues. We identified 18,377 MS mutations of five or more repeat nucleotides in coding sequences and untranslated regions of genes, and discovered 139 individual genes whose expression was down-regulated in association with UTR MS mutation. In addition, we found that 90.5% of MS mutations with deletions in gene regions occurred in UTRs. This analysis emphasizes the genetic diversity of MSI-H gastric tumors and provides clues to the mechanistic basis of instability in microsatellite unstable gastric cancers.

Is preoperative staging enough to guide lymph node dissection in clinically early gastric cancer?

BACKGROUND: Limited by the accuracy of preoperative staging, some cases of gastric cancer invading the muscularis propria (pT2) are underestimated as early gastric cancer (EGC) in the preoperative assessment. The aim of this present study was to determine prognostic factors and to propose indications for limited lymph node dissection in patients with clinically EGC (cEGC). METHODS: Patients of cEGC (n = 2072) who were postoperatively diagnosed as pT1 (cT1pT1, n = 1858) and pT2 (cT1pT2, n = 214) from 2005 to 2009 at Seoul National University Hospital were retrospectively analyzed. RESULTS: There was no difference in 5-year survival rate between the cT1pT1 and cT1pT2 group (95.5 % vs. 92.5 %, P = 0.059), and both groups had better overall survival than pT2 patients who were preoperatively diagnosed as locally advanced gastric cancer (cT2-4pT2), whose 5-year survival rate was 78.0 % (P < 0.001). Multivariate analysis indicated lymph node metastasis (LNM) was the independent prognostic factor for cEGC (P < 0.001). In cEGC patients, three preoperative factors, including N stage by multidetector-row computed tomography (MDCT) (P < 0.001), preoperative histological type (P < 0.001), and tumor size (P < 0.001), were associated with LNM by multivariate analysis. Regarding the possibility of LNM, low-risk (4.4 %) and high-risk (17.3 %) groups were developed based on weighted scores of the aforementioned independent three variables. Among 52 patients in the low-risk group, the extension of LNM was limited to the perigastric area. CONCLUSIONS: Comprehensive evaluation based on MDCT, preoperative histological type, and tumor size is an effective method to predict LNM and guide tailored LN dissection for cEGC.

Comparison of Surgical Outcomes of Robot-Assisted and Laparoscopy-Assisted Pylorus-Preserving Gastrectomy for Gastric Cancer: A Propensity Score Matching Analysis.

BACKGROUND: The three-dimensional view and articulating devices in robot system might have a benefit performing the delicate procedure of pylorus-preserving gastrectomy. This study was conducted to evaluate the feasibility and safety of robot-assisted pylorus-preserving gastrectomy (RAPPG) and to compare the perioperative outcomes and oncologic safety between RAPPG and laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) for middle-third early gastric cancer. METHODS: Between June 2008 and December 2013, we retrospectively collected data of 68 patients with RAPPG and propensity score matched 68 patients with LAPPG for the treatment of early gastric cancer at Seoul National University Hospital. The covariates for propensity score matching were: age, sex, American Society of Anesthesiologists score, body mass index, and operators. Clinicopathologic characteristics and surgical outcomes were compared between the two groups. RESULTS: All RAPPG cases were performed successfully without open or laparoscopic conversion. Patient demographics and perioperative outcomes did not differ between the two groups except in operation time (258.3 vs. 193.9 min; P < 0.001). There was no significant difference in complication rates between the two groups (19.1 vs. 22.1 %; P = 0.671). The mean number of examined lymph nodes (33.4 vs. 36.5; P = 0.153), and the mean number of lymph nodes at each station was not different between the two groups. CONCLUSIONS: RAPPG can be a safe treatment option for middle-third early gastric cancer in terms of surgical complications and oncologic outcomes. However, RAPPG has no benefit over LAPPG in this study.

Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis.

BACKGROUND AND OBJECTIVE: About 9% of gastric carcinomas have Epstein-Barr virus (EBV) in the tumour cells, but it is unclear whether viral presence influences clinical progression. We therefore examined a large multicentre case series for the association of tumour EBV status with survival after gastric cancer diagnosis, accounting for surgical stage and other prognostic factors. METHODS: We combined individual-level data on 4599 gastric cancer patients diagnosed between 1976 and 2010 from 13 studies in Asia (n=8), Europe (n=3), and Latin America (n=2). EBV positivity of tumours was assessed by in situ hybridisation. Mortality HRs for EBV positivity were estimated by Cox regression models stratified by study, adjusted for distributions of sex (71% male), age (mean 58 years), stage (52% tumour-node-metastasis stages III or IV), tumour histology (49% poorly differentiated, 57% Lauren intestinal-type), anatomic subsite (70% non-cardia) and year of diagnosis. Variations by study and continent were assessed using study-specific HRs for EBV positivity. RESULTS: During median 3.0 years follow-up, 49% of patients died. Stage was strongly predictive of mortality, with unadjusted HRs (vs stage I) of 3.1 for stage II, 8.1 for stage III and 13.2 for stage IV. Tumour EBV positivity was 8.2% overall and inversely associated with stage (adjusted OR: 0.79 per unit change). Adjusted for stage and other confounders, EBV positivity was associated with lower mortality (HR, 0.72; 95% CI 0.61 to 0.86), with low heterogeneity among the study populations (p=0.2). The association did not significantly vary across patient or tumour characteristics. There was no significant variation among the three continent-specific HRs (p=0.4). CONCLUSIONS: Our findings suggest that tumour EBV positivity is an additional prognostic indicator in gastric cancer. Further studies are warranted to identify the mechanisms underlying this protective association.

Integrative genomics analysis reveals the multilevel dysregulation and oncogenic characteristics of TEAD4 in gastric cancer.

Tumorigenesis is a consequence of failures of multistep defense mechanisms against deleterious perturbations that occur at the genomic, epigenomic, transcriptomic and proteomic levels. To uncover previously unrecognized genes that undergo multilevel perturbations in gastric cancer (GC), we integrated epigenomic and transcriptomic approaches using two recently developed tools: MENT and GENT. This integrative analysis revealed that nine Hippo pathway-related genes, including components [FAT, JUB, LATS2, TEA domain family member 4 (TEAD4) and Yes-associated protein 1 (YAP1)] and targets (CRIM1, CYR61, CTGF and ITGB2), are concurrently hypomethylated at promoter CpG sites and overexpressed in GC tissues. In particular, TEAD4, a link between Hippo pathway components and targets, was significantly hypomethylated at CpG site cg21637033 (P = 3.8 × 10(-) (20)) and overexpressed (P = 5.2 × 10(-) (10)) in 108 Korean GC tissues compared with the normal counterparts. A reduced level of methylation at the TEAD4 promoter was significantly associated with poor outcomes, including large tumor size, high-grade tumors and low survival rates. Compared with normal tissues, the TEAD4 protein was more frequently found in the nuclei of tumor cells along with YAP1 in 53 GC patients, demonstrating the posttranslational activation of this protein. Moreover, the knockdown of TEAD4 resulted in the reduced growth of GC cells both in vitro and in vivo. Finally, chromatin immunoprecipitation-sequencing and microarray analysis revealed the oncogenic properties of TEAD4 and its novel targets (ADM, ANG, ARID5B, CALD1, EDN2, FSCN1 and OSR2), which are involved in cell proliferation and migration. In conclusion, the multilevel perturbations of TEAD4 at epigenetic, transcriptional and posttranslational levels may contribute to GC development.

Case-case comparison of smoking and alcohol risk associations with Epstein-Barr virus-positive gastric cancer.

Helicobacter pylori is the primary cause of gastric cancer. However, monoclonal Epstein-Barr virus (EBV) nucleic acid is also present in up to 10% of these tumors worldwide. EBV prevalence is increased with male sex, nonantral localization and surgically disrupted anatomy. To further examine associations between EBV and gastric cancer, we organized an international consortium of 11 studies with tumor EBV status assessed by in situ hybridization. We pooled individual-level data on 2,648 gastric cancer patients, including 184 (7%) with EBV-positive cancers; all studies had information on cigarette use (64% smokers) and nine had data on alcohol (57% drinkers). We compared patients with EBV-positive and EBV-negative tumors to evaluate smoking and alcohol interactions with EBV status. To account for within-population clustering, multilevel logistic regression models were used to estimate interaction odds ratios (OR) adjusted for distributions of sex (72% male), age (mean 59 years), tumor histology (56% Lauren intestinal-type), anatomic subsite (61% noncardia) and year of diagnosis (1983-2012). In unadjusted analyses, the OR of EBV positivity with smoking was 2.2 [95% confidence interval (CI) 1.6-3.2]. The OR was attenuated to 1.5 (95% CI 1.01-2.3) by adjustment for the possible confounders. There was no significant interaction of EBV status with alcohol drinking (crude OR 1.4; adjusted OR 1.0). Our data indicate the smoking association with gastric cancer is stronger for EBV-positive than EBV-negative tumors. Conversely, the null association with alcohol does not vary by EBV status. Distinct epidemiologic characteristics of EBV-positive cancer further implicate the virus as a cofactor in gastric carcinogenesis.

Laparoscopy-assisted pylorus-preserving gastrectomy is better than laparoscopy-assisted distal gastrectomy for middle-third early gastric cancer.

OBJECTIVE: The purpose of this study is to compare the surgical, oncologic safety and the nutritional, functional benefit of laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) with laparoscopy-assisted distal gastrectomy (LADG) for middle-third early gastric cancers (EGC). BACKGROUND: Of those patients with middle-third EGC, it is still difficult to determine which procedure is better between LADG and LAPPG despite alleged advantages of LAPPG. METHODS: For middle-third EGC, a retrospective analysis was performed comparing those who underwent LADG and those who underwent LAPPG. To evaluate surgical and oncologic safety, clinicopathologic differences including the postoperative morbidity, the pattern of lymph node metastasis and recurrence were analyzed. Postoperative protein, albumin, quantification of abdominal fat area using abdomen computed tomography, and the incidence of postoperative gallstone were compared for the evaluation of functional advantages. RESULTS: The overall postoperative morbidity rate was similar between LADG (n = 176) and LAPPG (n = 116). Delayed gastric emptying was less frequent in LADG than in LAPPG (1.7% vs 7.8%); however, the rates of all the other complications were significantly higher in LADG than in LAPPG (17.0% vs 7.8%). The number of examined lymph nodes and metastatic lymph nodes at each lymph node station was not significantly different and 3-year recurrence-free survival rates were also similar between LADG and LAPPG (98.8% vs 98.2%). Decreases in serum protein and albumin in postoperative 1 to 6 months and abdominal fat area in postoperative 1 year were significantly greater in LADG than in LAPPG. The 3-year cumulative incidence of gallstone was significantly higher in LADG than in LAPPG (6.5% vs 0.0%). CONCLUSIONS: For middle-third EGC, LAPPG can be considered as a better treatment option than LADG in terms of nutritional advantage and lower incidence of gallstone.

Napsin A is a useful marker for metastatic adenocarcinomas of pulmonary origin.

AIMS: To address whether napsin A is useful for identifying metastatic adenocarcinomas of pulmonary origin. METHODS AND RESULTS: Fifty-four cases of adenocarcinoma that metastasized from the lungs to various sites and 1762 cases of carcinoma from various organs were immunostained for napsin A, TTF-1, CK7, CK20 and CDX2 using tissue microarray. The expression patterns of napsin A and TTF-1 in metastatic pulmonary adenocarcinomas were compared with matched primary lung tumours. Napsin A and TTF-1 were expressed in 87.0% and 81.5% of the metastatic pulmonary adenocarcinomas, respectively. Although there was no significant difference in the positivity of napsin A and TTF-1 as a single marker in metastatic pulmonary adenocarcinomas, the expression scores for napsin A were much higher than those for TTF-1 (P < 0.001). Moreover, the positivity and expression scores of napsin A in primary pulmonary adenocarcinomas were maintained in metastatic adenocarcinomas better than TTF-1. Most non-pulmonary adenocarcinomas were negative for napsin A, except for renal cell carcinomas (13.4%), ovarian adenocarcinomas (7.1%) and uterine endometrial adenocarcinomas (14.5%). In particular, clear cell adenocarcinomas of ovary (68.8%) and uterus (66.7%) frequently expressed napsin A. CONCLUSIONS: These data suggest that napsin A may be a useful marker for identifying metastatic adenocarcinomas of pulmonary origin in combination with TTF-1.

Anaplastic lymphoma kinase inhibition in non-small-cell lung cancer.

BACKGROUND: Oncogenic fusion genes consisting of EML4 and anaplastic lymphoma kinase (ALK) are present in a subgroup of non-small-cell lung cancers, representing 2 to 7% of such tumors. We explored the therapeutic efficacy of inhibiting ALK in such tumors in an early-phase clinical trial of crizotinib (PF-02341066), an orally available small-molecule inhibitor of the ALK tyrosine kinase. METHODS: After screening tumor samples from approximately 1500 patients with non-small-cell lung cancer for the presence of ALK rearrangements, we identified 82 patients with advanced ALK-positive disease who were eligible for the clinical trial. Most of the patients had received previous treatment. These patients were enrolled in an expanded cohort study instituted after phase 1 dose escalation had established a recommended crizotinib dose of 250 mg twice daily in 28-day cycles. Patients were assessed for adverse events and response to therapy. RESULTS: Patients with ALK rearrangements tended to be younger than those without the rearrangements, and most of the patients had little or no exposure to tobacco and had adenocarcinomas. At a mean treatment duration of 6.4 months, the overall response rate was 57% (47 of 82 patients, with 46 confirmed partial responses and 1 confirmed complete response); 27 patients (33%) had stable disease. A total of 63 of 82 patients (77%) were continuing to receive crizotinib at the time of data cutoff, and the estimated probability of 6-month progression-free survival was 72%, with no median for the study reached. The drug resulted in grade 1 or 2 (mild) gastrointestinal side effects. CONCLUSIONS: The inhibition of ALK in lung tumors with the ALK rearrangement resulted in tumor shrinkage or stable disease in most patients. (Funded by Pfizer and others; ClinicalTrials.gov number, NCT00585195.).

Outcomes of surgery aiming at curative resection in good responder to induction chemotherapy for gastric cancer with distant metastases.

BACKGROUND: The aim of this study is to analyze the outcome of surgery with curative intent in good responder to induction chemotherapy for gastric cancer with distant metastases (M1 gastric cancer). MATERIALS AND METHODS: We reviewed M1 gastric cancer patients in whom radiologic evaluation suggests disappearance of metastatic lesion after chemotherapy and received operation from January 2000 to December 2009. Clinicopathologic variables and oncologic outcomes were evaluated. RESULTS: Of the 34 patients who underwent surgery with curative intent after chemotherapy, overall R0 resection rate was 76.5% (26/34). R0 resection rate was 88.0% (22/25) in initial one metastatic site and 44.4% (4/9) in two metastatic sites (P = 0.017). Postoperative morbidity and mortality rate were 14.7% and 0%. Recurrence rate was 61.5% (16/26) after R0 resection. Median survival was 22.9 and 7.8 months according to R0 versus non-R0 resection (P = 0.033). After R0 resection, 3-year overall survival was 51.7% in ypN0-2 stage group. CONCLUSION: The present study provides evidence that in patients with M1 gastric cancer which confined to one site who respond well to induction chemotherapy, a higher rate of R0 resection and longer survival can be expected. A multicenter cohort study is needed to explore this concept further.

Comparative analyses of overall survival in patients with anaplastic lymphoma kinase-positive and matched wild-type advanced nonsmall cell lung cancer.

BACKGROUND: The purpose of this study was to investigate the overall survival (OS) of patients with advanced ALK-positive nonsmall cell lung cancer (NSCLC) who were managed in the pre-ALK inhibitor era and to compare their survival with that of a matched case cohort of ALK wild-type (WT) patients. METHODS: Data from 1166 patients who had stage IIIB/IV NSCLC with nonsquamous histology were collected from the NSCLC database of Seoul National University Hospital between 2003 and 2009. ALK fluorescence in situ hybridization (FISH) was used to analyze 262 patients who either had the WT epidermal growth factor receptor (EGFR) or were nonresponders to previous EGFR tyrosine kinase inhibitor (TKI) therapy. Overall survival (OS) was compared between 3 groups: 1) ALK-positive patients, 2) EGFR mutation-positive patients, and 3) ALK-WT/EGFR-WT patients. Progression-free survival (PFS) after first-line chemotherapy and EGFR TKIs also was analyzed. RESULTS: Twenty-three patients were ALK-positive according to FISH analysis and did not receive ALK inhibitors during follow-up. The median OS for ALK-positive patients, EGFR mutation-positive patients, and WT/WT patients was 12.2 months, 29.6 months, and 19.3 months, respectively (vs EGFR mutation-positive patients, P = .001; vs WT/WT, P = .127). The PFS after first-line chemotherapy for the 3 groups was not different. However, the PFS for patients who received EGFR TKIs was shorter in ALK-positive patients compared with the other 2 groups (vs EGFR mutation-positive patients, P < .001; vs WT/WT, P < .021). CONCLUSIONS: In the pre-ALK inhibitor era, ALK-positive patients experienced the shortest survival, although it did not differ statistically from that of WT/WT patients. Although their responses to platinum-based chemotherapy were not different from comparator groups, ALK-positive patients were even more resistant to EGFR TKI treatment than WT/WT patients.

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.

Pyruvate kinase M2 promotes the growth of gastric cancer cells via regulation of Bcl-xL expression at transcriptional level.

PKM2 is an isoenzyme of the glycolytic enzyme pyruvate kinase that promotes aerobic glycolysis. Here, we describe an important role for PKM2 in regulating the survival of gastric cancer (GC) cells. We showed that PKM2 was overexpressed in gastric tumor tissues compared to normal tissues and its expression level was associated with poor survival of gastric cancer patients. We also showed that PKM2 affected cell survival by regulating Bcl-xL at the transcriptional level. PKM2 knockdown partially affected the stability of NF-kB subunit p65, suggesting that post-translational regulation of p65 by PKM2 is one of plausible mechanisms for the increased cell growth. Therefore, PKM2 may function as an upstream molecule that regulates p65 function and thus enhances the growth of tumor cells.