Hyeong Ryul Kim

Identification of new ALK and RET gene fusions from colorectal and lung cancer biopsies

Applying a next-generation sequencing assay targeting 145 cancer-relevant genes in 40 colorectal cancer and 24 non–small cell lung cancer formalin-fixed paraffin-embedded tissue specimens identified at least one clinically relevant genomic alteration in 59% of the samples and revealed two gene fusions, C2orf44-ALK in a colorectal cancer sample and KIF5B-RET in a lung adenocarcinoma. Further screening of 561 lung adenocarcinomas identified 11 additional tumors with KIF5B-RET gene fusions (2.0%; 95% CI 0.8–3.1%). Cells expressing oncogenic KIF5B-RET are sensitive to multi-kinase inhibitors that inhibit RET.

Inhibition of ALK, PI3K/MEK, and HSP90 in Murine Lung Adenocarcinoma Induced by EML4-ALK Fusion Oncogene

Genetic rearrangements of the anaplastic lymphoma kinase (ALK) kinase occur in 3% to 13% of non-small cell lung cancer patients and rarely coexist with KRASor EGFR mutations. To evaluate potential treatment strategies for lung cancers driven by an activated EML4-ALK chimeric oncogene, we generated a genetically engineered mouse model that phenocopies the human disease where this rearranged gene arises. In this model, the ALK kinase inhibitor TAE684 produced greater tumor regression and improved overall survival compared with carboplatin and paclitaxel, representing clinical standard of care. 18F-FDG-PET-CT scans revealed almost complete inhibition of tumor metabolic activity within 24 hours of TAE684 exposure. In contrast, combined inhibition of the PI3K/AKT and MEK/ERK1/2 pathways did not result in significant tumor regression. We identified EML4-ALK in complex with multiple cellular chaperones including HSP90. In support of a functional reliance, treatment with geldanamycin-based HSP90 inhibitors resulted in rapid degradation of EML4-ALK in vitro and substantial, albeit transient, tumor regression in vivo. Taken together, our findings define a murine model that offers a reliable platform for the preclinical comparison of combinatorial treatment approaches for lung cancer characterized by ALK rearrangement.

Salvage Esophagectomy for Locoregional Failure After Chemoradiotherapy in Patients With Advanced Esophageal Cancer

BACKGROUND Definitive chemoradiotherapy is associated with high local treatment failure rates, and surgical resection may be an appropriate salvage therapy. However, the efficacy and safety of salvage esophagectomy have not been elucidated fully. The clinical outcomes of salvage esophagectomy for locoregional failure after chemoradiotherapy were assessed. METHODS Twelve patients who underwent salvage esophagectomy after chemoradiotherapy between January 2003 and November 2010 were included in this retrospective analysis. Baseline demographics and survivals of these patients were compared with 21 patients who did not receive salvage esophagectomy for locoregional failure only after chemoradiotherapy, identified from our own previous prospective trials. RESULTS The median age was 62.5 years (range 50 to 69) and all patients had squamous cell carcinoma. The median radiation dose was 54.0 Gy (range 41.4 to 66.0) and the median interval between completion of chemoradiation and surgery was 8.0 months (range 2.0 to 32.9). There were no in-hospital deaths. Pulmonary complication was the most common postoperative morbidity (42%), and anastomotic leakage occurred in 1 patient (8%). With a median follow-up period of 29.3 months (range 5.8 to 73.0), the overall 3-year survival rate was 58%. Patients with early pathologic stage disease (T1/2 and N0) showed significantly prolonged survival (p=0.03) compared with those with advanced pathologic stage (T3/T4 or N1). Patients with salvage esophagectomy had prolonged event-free survival and overall survival compared with those patients with locoregional failure who received primary chemotherapy or boost radiotherapy (p<0.001). CONCLUSIONS While salvage esophagectomy for locoregional failure after chemoradiotherapy should be employed with great caution, it appears to be a feasible and effective therapeutic option for highly selected patients, especially with early pathologic stage disease. Salvage esophagectomy can be recommended as the only current curative treatment option for patients with locoregional failure after chemoradiotherapy.

Risk Factors of Postoperative Acute Kidney Injury in Patients Undergoing Esophageal Cancer Surgery

OBJECTIVE The purpose of this study was to identify perioperative risk factors for postoperative acute kidney injury (AKI) in patients undergoing esophageal cancer surgery. DESIGN A retrospective analysis of the prospectively collected medical data. SETTING A tertiary care university hospital. PARTICIPANTS All consecutive adult patients (n=595) who underwent elective esophageal surgery for cancer between January 2005 and April 2012. INTERVENTIONS None. MEASUREMENTS AND MAIN RESULTS AKI was defined by the AKI Network criteria based on serum creatinine changes within the first 48 hours after esophageal cancer surgery. The relationship between perioperative variables and AKI was evaluated using multivariate logistic regression. Postoperative AKI developed in 210 (35.3%) patients. Risk factors for AKI were body mass index (odds ratio [OR] 1.07; 95% confidence interval [CI] 1.01-1.14), preoperative serum albumin level (OR 0.52; 95% CI 0.33-0.84), use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers (OR 1.35; 95% CI 1.05-1.75), colloid infusion during surgery (OR 1.11; 95% CI 1.06-1.18), and postoperative 2-day C-reactive protein (OR 1.05; 95% CI 1.01-1.09). Postoperative AKI was associated with prolonged length of hospital stay. CONCLUSIONS Postoperative AKI is common in patients undergoing esophageal surgery for cancer. Closer evaluation and monitoring in patients with risk factors for AKI may be warranted.

Chylothorax Complicating Pulmonary Resection for Lung Cancer: Effective Management and Pleurodesis

BACKGROUND Chylothorax associated with pulmonary resection for lung cancer, although rare, must be considered as a potential complication during thoracic surgery. In the present study, we investigated the effectiveness of a conservative approach (diet or pleurodesis) to the management of chylothorax. METHODS Between January 2000 and December 2010, 3,120 consecutive patients underwent pulmonary resection and mediastinal lymph node dissection at our institution. Among them, 67 patients with confirmed chylothorax were retrospectively reviewed. RESULTS Right-sided chylothorax was more common than left-sided chylothorax (p=0.033). All patients were initially treated with nil per os (NPO; n=46) or a low long-chain triglyceride (LCT) diet (n=21). In the NPO group, 24 patients were successfully treated with diet alone and 20 underwent pleurodesis. In the LCT group, 10 patients were successfully treated with diet alone; of the 11 remaining patients, 4 patients improved after NPO. The 7 patients who did not improve with NPO underwent pleurodesis. No significant differences in chest tube output before and after initial treatment, length of stay, or success rate were observed between patients initially treated with NPO and those receiving low LCT. All 32 pleurodeses performed in 27 patients were successful. Two patients underwent surgery without pleurodesis after dietary treatment failure. Postoperative air leakage or drainage for 5 days greater than 21.6 mL/kg were independent risk factors for dietary treatment failure. CONCLUSIONS Conservative treatment, including pleurodesis, should be the first choice of treatment for chylothorax complicating pulmonary resection.

Randomized Phase 2 Trial of S1 and Oxaliplatin-Based Chemoradiotherapy With or Without Induction Chemotherapy for Esophageal Cancer

PURPOSE To assess, in a randomized, phase 2 trial, the efficacy and safety of chemoradiotherapy with or without induction chemotherapy (ICT) of S1 and oxaliplatin for esophageal cancer. PATIENTS AND METHODS Patients with stage II, III, or IVA esophageal cancer were randomly allocated to either 2 cycles of ICT (oxaliplatin 130 mg/m(2) on day 1 and S1 at 40 mg/m(2) twice daily on days 1-14, every 3 weeks) followed by concurrent chemoradiotherapy (CCRT) (46 Gy, 2 Gy/d with oxaliplatin 130 mg/m(2) on days 1 and 21 and S1 30 mg/m(2) twice daily, 5 days per week during radiation therapy) and esophagectomy (arm A), or the same CCRT followed by esophagectomy without ICT (arm B). The primary endpoint was the pathologic complete response (pCR) rate. RESULTS A total of 97 patients were randomized (arm A/B, 47/50), 70 of whom underwent esophagectomy (arm A/B, 34/36). The intention-to-treat pCR rate was 23.4% (95% confidence interval [CI] 11.2-35.6%) in arm A and 38% (95% CI 24.5% to 51.5%) in arm B. With a median follow-up duration of 30.3 months, the 2-year progression-free survival rate was 58.4% in arm A and 58.6% in arm B, whereas the 2-year overall survival rate was 60.7% and 63.7%, respectively. Grade 3 or 4 thrombocytopenia during CCRT was more common in arm A than in arm B (35.4% vs 4.1%). The relative dose intensity of S1 (89.5% ± 20.6% vs 98.3% ± 5.2%, P=.005) and oxaliplatin (91.4% ± 16.8% vs 99.0% ± 4.2%, P=.007) during CCRT was lower in arm A compared with arm B. Three patients in arm A, compared with none in arm B, died within 90 days after surgery. CONCLUSIONS Combination chemotherapy of S1 and oxaliplatin is an effective chemoradiotherapy regimen to treat esophageal cancer. However, we failed to show that the addition of ICT to the regimen can improve the pCR rate.

Surgical Outcomes in Small Cell Lung Cancer

Background The experience of a single-institution regarding surgery for small cell lung cancer (SCLC) was reviewed to evaluate the surgical outcomes and prognoses. Materials and Methods From July 1990 to December 2009, thirty-four patients (28 male) underwent major pulmonary resection and lymph node dissection for SCLC. Lobectomy was performed in 24 patients, pneumonectomy in eight, bilobectomy in one, and segmentectomy in one. Surgical complications, mortality, the disease-free survival (DFS) rate, and the overall survival rate were analyzed retrospectively. Results The median follow-up period was 26 months (range, 4 to 241 months), and there was one surgical mortality (2.9%). Six patients (17.6%) experienced recurrence, all of which were systemic. Eight patients died during follow-up; four died of disease progression and the other four died of pneumonia or of another non-cancerous cause. The three-year DFS rate was 79.2±2.6% and the overall survival rate was 66.4±10.5%. Recurrence or death was significantly prevalent in the patients with lymph node metastasis (p=0.001) as well as in those who did not undergo adjuvant chemotherapy (p=0.008). The three-year survival rate was significantly greater in the patients with pathologic stage I/II cancer than in those with stage III cancer (84% vs. 13%, p=0.001). Conclusion Major pulmonary resection for small cell lung cancer is feasible in selected patients. Patients with pathologic stage I or II disease showed an excellent survival rate after surgery and adjuvant treatment. Prospective randomized studies will be needed to define the role of surgery in early-stage small cell lung cancer.

Clinical feasibility and surgical benefits of video-assisted mediastinoscopic lymphadenectomy in the treatment of resectable lung cancer

OBJECTIVE This study was performed to assess the clinical feasibility and surgical outcomes of video-assisted mediastinoscopic lymphadenectomy in the treatment of resectable lung cancer. METHODS Between July 2004 and December 2009, we retrospectively analyzed 108 consecutive video-assisted mediastinoscopic lymphadenectomies in lung cancer patients from a prospectively collected database. Ninety-seven (89.8%) patients underwent combined operation during the same anesthesia and six (5.3%) patients underwent a staged operation for the resection of lung cancer and systematic lymphadenectomy. We reviewed the indication and duration of video-assisted mediastinoscopic lymphadenectomy, its complication, combined or staged operation type, the number of dissected lymph nodes and nodal stations, and pathologic staging of the mediastinal node. RESULTS Mean operative time of video-assisted mediastinoscopic lymphadenectomy was 39.8 ± 12.3 min (range of 14-85 min). Mean number of resected lymph nodes was 16.0 ± 7.7 (range of 3-37). In video-assisted mediastinoscopic lymphadenectomy, the rates of lymph node dissection of stations 4R, 4L, and 7 were 71.3%, 88.0%, and 100%, respectively, whereas the rates of dissection of lymph nodes in station 2R and 2L were only 22.2% and 17.6%, respectively. There was no operative mortality. We identified five complications of recurrent nerve palsy. CONCLUSIONS Video-assisted mediastinoscopic lymphadenectomy is a clinically feasible procedure with acceptable complication rate and provides more accurate staging of mediastinal node in lung cancer patients. It may be also an excellent supplementary technique used for complete mediastinal node dissection at minimal invasive surgery for cancer resection, especially with left-sided video-assisted thoracoscopic lobectomy.

Primary Ewing's Sarcoma of the Lung

Most cases of Ewings sarcoma are reported in the bone, and extraosseous Ewings sarcoma is an extremely rare disease. Here, we report a rare case of primary pulmonary Ewings sarcoma in a patient with hemoptysis. The patient underwent right upper lung lobe lobectomy with adjuvant chemotherapy and radiation therapy and has been free of recurrent disease for 4 years.

Association between Postoperatively Developed Atrial Fibrillation and Long-Term Mortality after Esophagectomy in Esophageal Cancer Patients: An Observational Study

Background Newly developed atrial fibrillation (AF) in patients who have undergone an esophagectomy increases the incidence of postoperative complications. However, the clinical implications of AF have not been fully elucidated in these patients. This retrospective observational study investigated the predictors for AF and the effect of AF on the mortality in esophageal cancer patients undergoing esophagectomy. Methods This study evaluated 583 patients undergoing esophagectomy, from January 2005 to April 2012. AF was defined as newly developed postoperative AF requiring treatment. The risk factors for AF and the association between AF and mortality were evaluated. The long-term mortality was the all-cause mortality, for which the cutoff date was May 31, 2014. Results AF developed in 63 patients (10.8%). Advanced age (odds ratio [OR] 1.099, 95% confidence interval [CI] 1.056–1.144, P < 0.001), preoperative calcium channel blocker (CCB) (OR 2.339, 95% CI 1.143–4.786, P = 0.020), and angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) (OR 0.206, 95% CI 0.067–0.635, P = 0.006) were associated with the incidence of AF. The Kaplan-Meier curve showed a significantly lower survival rate in the AF group compared to the non-AF group (P = 0.045), during a median follow-up of 50.7 months. The multivariable analysis revealed associations between AF and the 1-year mortality (hazard ratio [HR] 2.556, 95% CI 1.430–4.570, P = 0.002) and between AF and the long-term mortality (HR 1.507, 95% CI 1.003–2.266, P = 0.049). Conclusions In esophageal cancer patients, the advanced age and the preoperative medications (CCB, ACEI or ARB) were associated with the incidence of AF. Furthermore, postoperatively developed AF was associated with mortality in esophageal cancer patients after esophagectomy, suggesting that a close surveillance might be required in patients who showed AF during postoperative period.