Hyun-Sung Lee

Real-time Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Mediastinal Staging of Non-Small Cell Lung Cancer: How Many Aspirations Per Target Lymph Node Station?

OBJECTIVE The goal of this study was to determine the optimal number of aspirations per lymph node (LN) station during endobronchial ultrasound (EBUS)-guided transbronchial needle aspiration (TBNA) for maximum diagnostic yield in mediastinal staging of non-small cell lung cancer (NSCLC) in the absence of rapid on-site cytopathologic examination. METHODS EBUS-TBNA was performed in potentially operable NSCLC patients with mediastinal LNs accessible by EBUS-TBNA (5 to 20 mm). Every target LN station was punctured four times. RESULTS We performed EBUS-TBNA in 163 mediastinal LN stations in 102 NSCLC patients. EBUS-TBNA confirmed malignancy in 41 LN stations in 30 patients. Two malignant LN stations were missed in two patients. The sensitivity, specificity, positive predictive value, negative predictive value (NPV), and accuracy of EBUS-TBNA in predicting mediastinal metastasis were 93.8%, 100%, 100%, 96.9%, and 97.9%, respectively. Sample adequacy was 90.1% for one aspiration, and it reached 100% for three aspirations. The sensitivity for differentiating malignant from benign LN stations was 69.8%, 83.7%, 95.3%, and 95.3% for one, two, three, and four aspirations, respectively. The NPV was 86.5%, 92.2%, 97.6%, and 97.6% for one, two, three, and four aspirations, respectively. Maximum diagnostic values were achieved in three aspirations. When at least one tissue core was obtained by the first or second aspiration, the sensitivity and NPV of the first two aspirations were 91.9% and 96.0%, respectively. CONCLUSIONS Optimal results can be obtained in three aspirations per LN station in EBUS-TBNA for mediastinal staging of potentially operable NSCLC. When at least one tissue core specimen is obtained by the first or second aspiration, two aspirations per LN station can be acceptable.

Transbronchial and Transesophageal Fine-Needle Aspiration Using an Ultrasound Bronchoscope in Mediastinal Staging of Potentially Operable Lung Cancer

OBJECTIVE We performed this study to evaluate the role of transesophageal endoscopic ultrasound with bronchoscope-guided fine-needle aspiration (EUS-B-FNA) following endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the mediastinal staging of lung cancer. METHODS In this prospective study, we applied transbronchial and transesophageal ultrasonography using an ultrasound bronchoscope on patients with confirmed or strongly suspected potentially operable non-small cell lung cancer. Following EBUS-TBNA, EUS-B-FNA was used for mediastinal nodes that were inaccessible or difficult to access by EBUS-TBNA. The accessibility by EBUS-TBNA and EUS-B-FNA to mediastinal nodal stations having at least one node ≥ 5 mm was also checked. RESULTS In 150 patients, we performed EBUS-TBNA and EUS-B-FNA on 299 and 64 mediastinal nodal stations, respectively. Among 143 evaluable patients, EBUS-TBNA diagnosed mediastinal metastasis in 38 patients. EUS-B-FNA identified mediastinal metastasis in three additional patients. Surgery diagnosed mediastinal metastasis in four more patients. The sensitivity, negative predictive value, and diagnostic accuracy of EBUS-TBNA in the detection of mediastinal metastasis were 84.4%, 93.3%, and 95.1%, respectively. These values for the combined approach of EBUS-TBNA and EUS-B-FNA increased to 91.1%, 96.1%, and 97.2%, respectively, although the differences were not statistically significant (P = .332, P = .379, and P = .360, respectively). Among 473 mediastinal nodal stations having at least one node ≥ 5 mm that were evaluated, the proportion of accessible mediastinal nodal stations by EBUS-TBNA was 78.6%, and the proportion increased to 84.8% by combining EUS-B-FNA with EBUS-TBNA (P = .015). CONCLUSION Following EBUS-TBNA in the mediastinal staging of potentially operable lung cancer, the accessibility to mediastinal nodal stations increased by adding EUS-B-FNA and an additional diagnostic gain might be obtained by EUS-B-FNA. TRIAL REGISTRATION clinicaltrials.gov, NCT00741247.

Application of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration Following Integrated PET/CT in Mediastinal Staging of Potentially Operable Non-small Cell Lung Cancer

BACKGROUND The role of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) following integrated PET/CT scanning in mediastinal staging of non-small cell lung cancer (NSCLC) has not been assessed. METHODS We prospectively evaluated the diagnostic values of PET/CT scanning and EBUS-TBNA for mediastinal staging in 117 patients with potentially operable NSCLC with accessible mediastinal lymph nodes (diameter range, 5 to 20 mm) by EBUS-TBNA. Subgroup analysis according to histologic type was performed. RESULTS Of 30 cases of mediastinal metastasis, 27 were confirmed by EBUS-TBNA and 3 were confirmed by surgery. EBUS-TBNA results confirmed all cases with true-positive PET/CT scan findings and six of nine cases with false-negative PET/CT scan findings. The sensitivity, specificity, positive predictive value, negative predictive value (NPV), and accuracy of EBUS-TBNA in the detection of mediastinal metastasis were 90.0%, 100%, 100%, 96.7%, and 97.4%, respectively. For PET/CT scans, the values were 70.0%, 59.8%, 37.5%, 85.2%, and 62.4%, respectively (p = 0.052; p < 0.001; p < 0.001; p = 0.011; p < 0.001, respectively). In adenocarcinoma (n = 55), EBUS-TBNA detected four of six cases with false-negative PET/CT scan findings, and the NPV was higher for EBUS-TBNA than for PET/CT scans (94.6% vs 77.8%, respectively; p = 0.044). In squamous cell carcinoma (n = 53), the NPV of EBUS-TBNA and PET/CT scans were similarly high (97.9% vs 96.3%, respectively; p = 0.689). CONCLUSIONS EBUS-TBNA was an effective invasive method following PET/CT scanning in the mediastinal staging of potentially operable NSCLC. In mediastinal PET/CT scan-positive cases, EBUS-TBNA was an excellent tool for detecting mediastinal metastasis. Even in mediastinal PET/CT scan-negative cases, EBUS-TBNA can be useful for confirming mediastinal metastases, especially in adenocarcinoma.

EBUS-centred versus EUS-centred mediastinal staging in lung cancer: a randomised controlled trial

Background The impact of procedure sequence and primary procedure has not been studied in the combined application of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) in lung cancer staging. Methods In a randomised controlled trial, 160 patients with histologically confirmed or strongly suspected potentially operable non-small cell lung cancer were enrolled (Group A, n=80, EBUS-centred; Group B, n=80, EUS-centred). EBUS-TBNA and EUS-FNA with an ultrasound bronchoscope were used as the first procedures in Groups A and B, respectively, and secondary procedures (EUS-FNA in Group A, EBUS-TBNA in Group B) were added. Results Diagnostic values were evaluated in 148 patients (74 in each group). In Groups A and B the diagnostic accuracy (93.2% (95% CI 87.5% to 99.0%) vs 97.3% (95% CI 93.6% to 101.0%), p=0.245) and sensitivity (85.3% (95% CI 68.9% to 95.0%) vs 92.0% (95% CI 74.0% to 99.0%), p=0.431) in detecting mediastinal metastasis were not statistically different. In Group A, adding EUS-FNA to EBUS-TBNA did not significantly increase the accuracy (from 91.9% to 93.2%, p=0.754) or sensitivity (from 82.4% to 85.3%, p=0.742). In group B, adding EBUS-TBNA to EUS-FNA increased the accuracy (from 86.5% to 97.3%, p=0.016) and sensitivity (from 60.0% to 92.0%, p=0.008). There were no intergroup differences in procedure time, cardiorespiratory parameters during procedures, complications or patient satisfaction. Conclusions Using a combination of EBUS-TBNA and EUS-FNA in mediastinal staging, we found that diagnostic values and patient satisfaction were not different between the EBUS-centred and EUS-centred groups. However, the necessity for EBUS-TBNA following EUS suggests that EBUS-TBNA is a better primary procedure in endoscopic mediastinal staging of potentially operable lung cancer. Trial Registration number ClinicalTrials.gov number NCT01385111.

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.

Targeting Poly(ADP-Ribose) Polymerase and the c-Myb–Regulated DNA Damage Response Pathway in Castration-Resistant Prostate Cancer

The DNA damage response is an appealing target for androgen inhibitor–resistant prostate cancer. Improving Therapy in Prostate Cancer Blocking androgen receptor (AR) signaling is standard therapy for prostate cancer, but tumor growth often recurs. Li et al. examined the gene expression profile in patient samples of primary and metastatic prostate cancer from patients in which AR signaling was blocked. Metastatic disease, which is associated with androgen inhibitor–resistant relapse, correlated with increased expression of genes encoding proteins in the DNA damage response (DDR) and MYB expression. AR and c-Myb shared a subset of target genes that encode DDR proteins; thus, c-Myb may functionally substitute for AR in the regulation of their common DDR targets. Targeting proteins within the Myb-regulated network in combination with a poly[adenosine 5′-diphosphate (ADP)–ribose] polymerase (PARP) inhibitor, which compromises the DDR, generated synergistic lethality in prostate cancer cells in culture and in mouse xenografts, suggesting potential new options for prostate cancer patients. Androgen deprivation is the standard treatment for advanced prostate cancer (PCa), but most patients ultimately develop resistance and tumor recurrence. We found that MYB is transcriptionally activated by androgen deprivation therapy or genetic silencing of the androgen receptor (AR). MYB silencing inhibited PCa growth in culture and xenografts in mice. Microarray data revealed that c-Myb and AR shared a subset of target genes that encode DNA damage response (DDR) proteins, suggesting that c-Myb may supplant AR as the dominant regulator of their common DDR target genes in AR inhibition–resistant or AR-negative PCa. Gene signatures including AR, MYB, and their common DDR-associated target genes positively correlated with metastasis, castration resistance, tumor recurrence, and decreased survival in PCa patients. In culture and in xenograft-bearing mice, a combination strategy involving the knockdown of MYB, BRCA1, or TOPBP1 or the abrogation of cell cycle checkpoint arrest with AZD7762, an inhibitor of the checkpoint kinase Chk1, increased the cytotoxicity of the poly[adenosine 5′-diphosphate (ADP)–ribose] polymerase (PARP) inhibitor olaparib in PCa cells. Our results reveal new mechanism-based therapeutic approaches for PCa by targeting PARP and the DDR pathway involving c-Myb, TopBP1, ataxia telangiectasia mutated– and Rad3-related (ATR), and Chk1.

Balloon dilatation of the pylorus for delayed gastric emptying after esophagectomy

OBJECTIVE Delayed gastric emptying after esophageal operations occurs in up to 50% of patients. A good quality of life, in long-term survivors after esophagectomy, may depend on both dietary adaptation and the improvement of intrathoracic gastric motility itself. The objective of this study was to investigate the effect of pyloric balloon dilatation on the sustained delay of gastric emptying after esophagectomy. METHODS Two hundred and fifty-seven patients underwent esophagectomy with a gastric conduit from January 2003 to December 2006. A gastric drainage procedure was routinely performed during the esophagectomy. The intrathoracic gastric emptying of solid food was evaluated by radioisotope imaging. A 50% gastric emptying time over 180 min was defined as delayed. We assessed the changes of the intrathoracic gastric emptying time, and the symptoms after balloon dilatation of the pylorus, associated with delayed gastric emptying. RESULTS Balloon dilatation of the pylorus was performed in 21 patients (8%) who had sustained symptoms of delayed gastric emptying after esophagectomy for esophageal cancer despite the use of prokinetics. The symptoms associated with delayed gastric emptying were improved after balloon dilatation of the pylorus in all patients. Pyloric balloon dilatation was performed twice in two patients. In seven of 19 patients (37%), who had a follow-up gastric emptying study, the delayed gastric emptying rate for 180 min was improved from 30% to 88%. Six patients had slightly improved results, and six patients had no increase in the rate of gastric emptying compared with the previous gastric emptying study. CONCLUSIONS After balloon dilatation of the pylorus, two thirds of patients with delayed gastric emptying show increased rates of gastric emptying as measured by radioisotope imaging. Mechanical balloon dilatation of the pylorus is a useful method to treat sustained delay of intrathoracic gastric emptying after esophagectomy.

Genomic Predictors for Recurrence Patterns of Hepatocellular Carcinoma: Model Derivation and Validation

In this study, Lee and colleagues develop a genomic predictor that can identify patients at high risk for late recurrence of hepatocellular carcinoma (HCC) and provided new biomarkers for risk stratification.

Clinical Characteristics of Malignant Pericardial Effusion Associated with Recurrence and Survival

Purpose We evaluated clinical outcomes after drainage for malignant pericardial effusion with imminent or overt tamponade. Materials and Methods Between August 2001 and June 2007, 100 patients underwent pericardiocentesis for malignant pericardial effusion. Adequate follow-up information on the recurrence of pericardial effusion and survival status was available for 98 patients. Results Recurrence of effusion occurred in 30 patients (31%), all of whom were diagnosed with adenocarcinoma. Multivariate analysis indicated that adenocarcinoma of the lung (hazard ratio [HR], 6.6; 95% confidence interval [CI], 1.9 to 22.3; p=0.003) and progressive disease despite chemotherapy (HR, 4.3; 95% CI, 1.6 to 12.0; p=0.005) were independent predictors of recurrence. Survival rates three months after pericardiocentesis differed significantly with the type of primary cancer; the rates were 73%, 18%, 90% and 30% in patients with adenocarcinoma of the lung, squamous cell carcinoma of the lung, breast cancer and other cancers, respectively. Conclusion Recurrence and survival of patients with malignant pericardial effusion are dependent on the type of primary cancer and response to chemotherapy. Patients with adenocarcinoma of the lung may be good candidates for surgical drainage to avoid repeated pericardiocentesis, but pericardiocentesis is considered effective as palliative management in patients with other cancers.