Hee Jin Jang

Significant Association of Oncogene YAP1 with Poor Prognosis and Cetuximab Resistance in Colorectal Cancer Patients

Purpose: Activation of YAP1, a novel oncogene in the Hippo pathway, has been observed in many cancers, including colorectal cancer. We investigated whether activation of YAP1 is significantly associated with prognosis or treatment outcomes in colorectal cancer. Experimental Design: A gene expression signature reflecting YAP1 activation was identified in colorectal cancer cells, and patients with colorectal cancer were stratified into two groups according to this signature: activated YAP1 colorectal cancer (AYCC) or inactivated YAP1 colorectal cancer (IYCC). Stratified patients in five test cohorts were evaluated to determine the effect of the signature on colorectal cancer prognosis and response to cetuximab treatment. Results: The activated YAP1 signature was associated with poor prognosis for colorectal cancer in four independent patient cohorts with stage I–III disease (total n = 1,028). In a multivariate analysis, the impact of the YAP1 signature on disease-free survival was independent of other clinical variables [hazard ratio (HR), 1.63; 95% confidence interval (CI), 1.25–2.13; P < 0.001]. In patients with stage IV colorectal cancer and wild-type KRAS, IYCC patients had a better disease control rate and progression-free survival (PFS) after cetuximab monotherapy than did AYCC patients; however, in patients with KRAS mutations, PFS duration after cetuximab monotherapy was not different between IYCC and AYCC patients. In multivariate analysis, the effect of YAP1 activation on PFS was independent of KRAS mutation status and other clinical variables (HR, 1.82; 95% CI, 1.05–3.16; P = 0.03). Conclusions: Activation of YAP1 is highly associated with poor prognosis for colorectal cancer and may be useful in identifying patients with metastatic colorectal cancer resistant to cetuximab. Clin Cancer Res; 21(2); 357–64. ©2014 AACR.

Tumor necrosis as a prognostic factor for stage IA non-small cell lung cancer

BACKGROUND In stage IA non-small cell lung cancer (NSCLC), lobectomy and mediastinal lymph node dissection is considered the standard treatment. However, 20% to 30% of patients have cancer recurrences. The purpose of this study was to determine the patterns and risk factors for recurrence in patients with stage IA NSCLC. METHODS We retrospectively reviewed the medical records of 201 patients who had confirmed stage IA NSCLC by lobectomy and complete lymph node dissection. RESULTS There were 131 male patients with a mean age of 60.68±9.26 years. The median follow-up period was 41.4 months. Recurrences were reported in 16 patients. One hundred fourteen and 87 patients were T1a (≤2 cm) and T1b (>2 cm to ≤3 cm), respectively. The pathologic results were as follows: adenocarcinomas and bronchioloalveolar carcinomas (n=134); squamous cell carcinomas (n=57); and other diagnoses (n=10). Tumor necrosis and lymphatic invasion were significant adverse risk factors for recurrence based on univariate analysis. Multivariate analysis showed that tumor necrosis was the only significant risk factor to predict cancer recurrence (hazard ratio, 4.336; p=0.032). The 5-year overall survival was 94.8% for necrosis-negative patients and 86.2% for necrosis-positive patients (p=0.04). The 5-year disease-free survival was 92.1% for necrosis-negative patients and 78.9% for necrosis-positive patients (p=0.016). CONCLUSIONS Tumor necrosis was shown to be an adverse risk factor for survival and recurrence in patients with stage IA NSCLC. Thus, close observation and individualized adjuvant therapy might be helpful for patients with stage IA NSCLC with tumor necrosis.

Clinical Significance of Four Molecular Subtypes of Gastric Cancer Identified by The Cancer Genome Atlas Project

Purpose: The Cancer Genome Atlas (TCGA) project recently uncovered four molecular subtypes of gastric cancer: Epstein–Barr virus (EBV), microsatellite instability (MSI), genomically stable (GS), and chromosomal instability (CIN). However, their clinical significances are currently unknown. We aimed to investigate the relationship between subtypes and prognosis of patients with gastric cancer. Experimental Design: Gene expression data from a TCGA cohort (n = 262) were used to develop a subtype prediction model, and the association of each subtype with survival and benefit from adjuvant chemotherapy was tested in 2 other cohorts (n = 267 and 432). An integrated risk assessment model (TCGA risk score) was also developed. Results: EBV subtype was associated with the best prognosis, and GS subtype was associated with the worst prognosis. Patients with MSI and CIN subtypes had poorer overall survival than those with EBV subtype but better overall survival than those with GS subtype (P = 0.004 and 0.03 in two cohorts, respectively). In multivariate Cox regression analyses, TCGA risk score was an independent prognostic factor [HR, 1.5; 95% confidence interval (CI), 1.2–1.9; P = 0.001]. Patients with the CIN subtype experienced the greatest benefit from adjuvant chemotherapy (HR, 0.39; 95% CI, 0.16–0.94; P = 0.03) and those with the GS subtype had the least benefit from adjuvant chemotherapy (HR, 0.83; 95% CI, 0.36–1.89; P = 0.65). Conclusions: Our prediction model successfully stratified patients by survival and adjuvant chemotherapy outcomes. Further development of the prediction model is warranted. Clin Cancer Res; 23(15); 4441–9. ©2017 AACR.

Inactivation of Hippo Pathway Is Significantly Associated with Poor Prognosis in Hepatocellular Carcinoma

Purpose: The Hippo pathway is a tumor suppressor in the liver. However, the clinical significance of Hippo pathway inactivation in HCC is not clearly defined. We analyzed genomic data from human and mouse tissues to determine clinical relevance of Hippo pathway inactivation in HCC. Experimental Design: We analyzed gene expression data from Mst1/2−/− and Sav1−/− mice and identified a 610-gene expression signature reflecting Hippo pathway inactivation in the liver [silence of Hippo (SOH) signature]. By integrating gene expression data from mouse models with those from human HCC tissues, we developed a prediction model that could identify HCC patients with an inactivated Hippo pathway and used it to test its significance in HCC patients, via univariate and multivariate Cox analyses. Results: HCC patients (National Cancer Institute cohort, n = 113) with the SOH signature had a significantly poorer prognosis than those without the SOH signature [P < 0.001 for overall survival (OS)]. The significant association of the signature with poor prognosis was further validated in the Korean (n = 100, P = 0.006 for OS) and Fudan University cohorts (n = 242, P = 0.001 for OS). On multivariate analysis, the signature was an independent predictor of recurrence-free survival (HR, 1.6; 95% confidence interval, 1.12–2.28: P = 0.008). We also demonstrated significant concordance between the SOH HCC subtype and the hepatic stem cell HCC subtype that had been identified in a previous study (P < 0.001). Conclusions: Inactivation of the Hippo pathway in HCC is significantly associated with poor prognosis. Clin Cancer Res; 22(5); 1256–64. ©2015 AACR.

Yes-associated protein 1 and transcriptional coactivator with PDZ-binding motif activate the mammalian target of rapamycin complex 1 pathway by regulating amino acid transporters in hepatocellular carcinoma

Metabolic activation is a common feature of many cancer cells and is frequently associated with the clinical outcomes of various cancers, including hepatocellular carcinoma. Thus, aberrantly activated metabolic pathways in cancer cells are attractive targets for cancer therapy. Yes‐associated protein 1 (YAP1) and transcriptional coactivator with PDZ‐binding motif (TAZ) are oncogenic downstream effectors of the Hippo tumor suppressor pathway, which is frequently inactivated in many cancers. Our study revealed that YAP1/TAZ regulates amino acid metabolism by up‐regulating expression of the amino acid transporters solute carrier family 38 member 1 (SLC38A1) and solute carrier family 7 member 5 (SLC7A5). Subsequently, increased uptake of amino acids by the transporters (SLC38A1 and SLC7A5) activates mammalian target of rapamycin complex 1 (mTORC1), a master regulator of cell growth, and stimulates cell proliferation. We also show that high expression of SLC38A1 and SLC7A5 is significantly associated with shorter survival in hepatocellular carcinoma patients. Furthermore, inhibition of the transporters and mTORC1 significantly blocks YAP1/TAZ‐mediated tumorigenesis in the liver. These findings elucidate regulatory networks connecting the Hippo pathway to mTORC1 through amino acid metabolism and the mechanisms potential clinical implications for treating hepatocellular carcinoma. Conclusion: YAP1 and TAZ regulate cancer metabolism and mTORC1 through regulation of amino acid transportation, and two amino acid transporters, SLC38A1 and SLC7A5, might be important therapeutic targets. (Hepatology 2016;63:159–172)

Thoracoscopic Mediastinal Lymph Node Dissection for Lung Cancer

Mediastinal lymph node staging is an important component of the assessment and management of patients with operable non-small cell lung cancer and is necessary to achieve complete resection. During minimally invasive surgery, performance of an equivalent oncologic resection, including adequate lymph node dissection similar in extent to open thoracotomy, is absolutely necessary. We describe our techniques for video-assisted thoracic surgery (VATS) and Robot-assisted VATS (R-VATS) mediastinal lymph node dissection when performing thoracoscopic lobectomy for lung cancer. Between 2008 and 2011, 200 consecutive patients who underwent VATS or R-VATS lobectomies for early stage lung cancer were analyzed. In our series, we removed about 25 lymph nodes per case in both complete VATS and R-VATS. A thorough lymph node dissection in lung cancer is possible with either VATS or R-VATS technique without oncological compromise.

Patterns of Lymph Node Metastasis and Survival for Upper Esophageal Squamous Cell Carcinoma

BACKGROUND This study evaluated the clinical results, nodal metastatic patterns, and overall efficacy of esophagectomy with three-field lymph node dissection for upper esophageal squamous cell carcinoma (SCC). METHODS Between 2001 and 2008, esophagectomy was performed in 497 esophageal cancer patients, of whom 93 underwent esophagectomy with three-field lymph node dissection, without neoadjuvant treatment for upper esophageal SCC. RESULTS Of these 93 patients, 91 (97.8%) were men, the median age was 65.0 years, and 82 (88.2%) underwent R0 resection with curative intent. In-hospital mortality was 4.3%. Pathologic T N M stages were stage I, 8.6%; stage II, 16.1%; stage III, 75.3%; and stage IV, 0%. The mean numbers of total lymph nodes dissected and, of those, total metastatic lymph nodes per patient were 61.7±18.2 and 4.7±7.0, respectively. Metastases occurred to the recurrent laryngeal lymph nodes in 43.3%, to the cervical lymph nodes in 46.2%, and to abdominal lymph nodes in 24.7% of patients. Overall 5-year and disease-free survival rates were 43.5% and 34.3%, respectively, and were 50.1% and 37.6%, respectively, for R0 resection. CONCLUSIONS Recurrent laryngeal lymph node chains are those most commonly affected by nodal metastasis, and the prevalence of cervical lymph node involvement is high, at more than 40%. Esophagectomy with three-field lymph node dissection in patients with upper esophageal SCC can be performed with acceptable morbidity and mortality. Curative R0 resection for upper esophageal SCC achieved a satisfactory 5-year survival rate.

Wedge bronchoplastic lobectomy for non-small cell lung cancer as an alternative to sleeve lobectomy

OBJECTIVES Sleeve lobectomy was introduced for patients with lung cancer whose pulmonary reserve was inadequate for pneumonectomy. However, the safety and survival benefits of wedge bronchoplastic lobectomy as an alternative to sleeve lobectomy have not been thoroughly studied. This study was performed to evaluate the safety and oncologic results of wedge bronchoplastic lobectomy for lung cancer. METHODS We retrospectively analyzed 191 patients who underwent wedge bronchoplastic lobectomy and mediastinal lymph node dissection from 2001 to 2009. RESULTS There were 174 male patients with a mean age of 61.8 ± 8.2 years. The median follow-up duration was 28 months. Nine patients showed severe postoperative complications: bronchopleural fistulas (n = 3), necrosis at the bronchoplasty site (n = 1), or obstruction (n = 5). The operative mortality rate was 3.7%. Local and regional recurrences were reported in 17 and 12 patients, respectively. The 5-year overall survival was 62.8%. The 5-year overall survival was 68.6% in N0, 64.4% in N1, and 52.6% in N2 (P = .09). The 5-year overall freedoms from local recurrence and locoregional recurrence were 85.3% and 78.9%, respectively, which did not differ by nodal status. A multivariate analysis showed that positive N1 and N2 nodes were risk factors (P = .036 and P = .042, respectively) for overall survival after wedge bronchoplastic lobectomy. CONCLUSIONS Wedge bronchoplastic lobectomy for lung cancer is a safe and feasible procedure that does not compromise oncologic principles. It can be considered an appropriate alternative to sleeve lobectomy and pneumonectomy, regardless of nodal status.

Genomic landscape associated with potential response to anti-CTLA-4 treatment in cancers

Immunotherapy has emerged as a promising anti-cancer treatment, however, little is known about the genetic characteristics that dictate response to immunotherapy. We develop a transcriptional predictor of immunotherapy response and assess its prediction in genomic data from ~10,000 human tissues across 30 different cancer types to estimate the potential response to immunotherapy. The integrative analysis reveals two distinct tumor types: the mutator type is positively associated with potential response to immunotherapy, whereas the chromosome-instable type is negatively associated with it. We identify somatic mutations and copy number alterations significantly associated with potential response to immunotherapy, in particular treatment with anti-CTLA-4 antibody. Our findings suggest that tumors may evolve through two different paths that would lead to marked differences in immunotherapy response as well as different strategies for evading immune surveillance. Our analysis provides resources to facilitate the discovery of predictive biomarkers for immunotherapy that could be tested in clinical trials.There is an urgent need to identify predictive markers for selecting responders to immunotherapy. Here, the authors describe a transcriptional predictor of immunotherapy response and assess it in genomic data from ~ 10,000 human tissues across 30 different cancer types.

Free Jejunal Graft for Esophageal Reconstruction Using End-to-Side Vascular Anastomosis and Extended Pharyngo-Jejunostomy

BACKGROUND Pharyngo-esophageal reconstruction using free jejunal grafts (FJGs) has been widely used, but the procedure is technically demanding and requires the involvement of multiple departments. We performed simplified reconstruction with FJGs using end-to-side vascular anastomosis and extended pharyngo-jejunostomy. METHODS The jejunal artery and vein were anastomosed to the neck vessels in an end-to-side fashion without microvascular anastomosis. Pharyngo-jejunostomy with extended end-to-end anastomosis was performed to reduce size mismatch. We retrospectively analyzed the medical records of 32 patients diagnosed with pharyngeal, esophageal, or pyriform sinus cancer who received a FJG. RESULTS The mean age was 61.5±9.4 years, and there were 25 male patients. Jejunal vessels were commonly anastomosed to the right common carotid artery and the right internal jugular vein (22, 68.8%). The mean ischemic times of the FJG and carotid artery clamping time were 46.5±8.1 and 15.8±4.4 minutes, respectively. During the procedure, 3 patients suffered from inadequate reperfusion of the FJG requiring removal of the initial graft and replacement with another FJG. There were no neurologic complications, postoperative deaths, or adverse events directly related to FJG except for leakage of the pharyngo-jejunostomy site in 1 patient, which was primarily repaired. During the follow-up period, 5 patients (15.6%) suffered from dysphagia, but only 3 patients had evidence of anastomotic strictures at the jejuno-esophagostomy site. Thirteen patients (40.6%) received postoperative adjuvant radiotherapy. CONCLUSIONS Our technique of FJG with end-to-side vascular anastomosis and extended pharyngo-jejunostomy is simple and safe.