Yasufumi Kato

Novel epidermal growth factor receptor mutation-specific antibodies for non-small cell lung cancer: immunohistochemistry as a possible screening method for epidermal growth factor receptor mutations.

Background: Epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) predict better outcome to EGFR tyrosine kinase inhibitors. The most common mutations are exon 19 deletions (most frequently E746–A750) and L858R point mutation in exon 21. Here, we evaluated the accuracy of novel EGFR mutation-specific antibodies in a Japanese cohort with NSCLC and compared with direct DNA sequencing and clinical outcome. Materials and Methods: Immunohistochemistry (IHC) using antibodies specific for the E746–A750 and L858R mutations in EGFR was performed on tissue microarrays of tumors from 70 gefitinib treated NSCLC patients. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21. Results: DNA sequencing showed EGFR mutations in 41 patients (58.6%) and exon 19 deletions in 18 patients (25.7%), 11 of 18 (61%) had a deletion in the range of E746–A750 and 12 (17.1%) had exon 21 mutations (L858R). IHC showed, for the E746–A750 and L858R mutations, sensitivity (81.8 and 75%), specificity (100 and 96.6%), positive predictive value (100 and 81.8%), and negative predictive value (96.7 and 94.9%). Analysis for objective response rates and survival were not correlated to IHC staining, although the combined staining showed nonsignificant trends toward better overall survival for patients with EGFR mutations. Conclusions: The mutation-specific IHC antibodies have high sensitivity and specificity for predefined EFGR mutations and may be suitable for screening for these predefined mutations. However, negative IHC results require further mutation analyses before excluding EGFR-targeted therapy.

Value of integrated positron emission tomography revised using a phantom study to evaluate malignancy grade of lung adenocarcinoma: a multicenter study.

The malignant biological behavior of small‐sized lung adenocarcinomas remains obscure, although understanding this feature is important for selecting appropriate treatment. In the current study, the authors evaluated malignancy grades of small adenocarcinomas using fluorodeoxyglucose‐positron emission tomography/computed tomography (PET/CT) in addition to high‐resolution CT (HRCT) and pathological analysis in a multicenter setting.

Early detection and screening of lung cancer

Accounting for 28% of all cancer deaths and causing 1.3 million deaths worldwide every year, lung cancer is the most lethal cancer. Diagnosing and treating cancer at its early stages, ideally during precancerous stages, could increase the 5-year survival rate by three- to four-fold with a potential for cure. Thus far, no screening method has been shown to decrease disease-specific mortality rate. The present review describes the rationale and issues related to early lung cancer screening, the management of screen-detected primary cancers and different approaches that have been tested for screening. These include imaging techniques, bronchoscopies, molecular screenings from different noninvasive or invasive sources, such as blood, sputum, bronchoscopic samples and exhaled breath.

EGFR Protein Expression in Non-Small Cell Lung Cancer Predicts Response to an EGFR Tyrosine Kinase Inhibitor - A Novel Antibody for Immunohistochemistry or AQUA Technology

Introduction: Epidermal growth factor receptor (EGFR) protein expression in non–small cell lung cancer (NSCLC) is not recommended for predicting response to EGFR tyrosine kinase inhibitors (TKI) due to conflicting results, all using antibodies detecting EGFR external domain (ED). We tested the predictive value of EGFR protein expression for response to an EGFR TKI with an antibody that detects the intracellular domain (ID) and compared fluorescence-based Automated QUantitative Analysis (AQUA) technology to immunohistochemistry (IHC). Methods: Specimens from 98 gefitinib-treated NSCLC Japanese patients were evaluated by IHC (n = 98 of 98) and AQUA technology (n = 70 of 98). EGFR ID (5B7)- and ED-specific antibodies (3C6 and 31G7) were compared. Results: EGFR expression evaluated with 5B7 was significantly higher in responders versus nonresponders to gefitinib both with IHC and with AQUA. ED-specific antibodies did not significantly predict response. Using AQUA and ID-specific antibody resulted in the best prediction performance with a positive and negative predictive value (PPV/NPV) for responders of 50% and 87%, respectively. EGFR expression with ID-specific antibody and AQUA also predicted responders in EGFR-mutated patients. Increased EGFR expression with the ID antibody is associated with increased median progression free survival (PFS; 11.7 months vs. 5.0, log rank, P = 0.034) and overall survival (OS; 38.6 vs. 14.9, P = 0.040) from gefitinib therapy. Conclusions: EGFR protein expression using an ID-specific antibody specifically predicts response to gefitinib in NSCLC patients, including in EGFR-mutated patients, and increased PFS/OS from gefitinib. These data suggest that the choice of diagnostic antibody and methodology matters to predict response and outcome to specific therapies. The potential clinical application needs further validation. Clin Cancer Res; 17(24); 7796–807. ©2011 AACR.

Long-term survival after a surgical resection of pulmonary metastases from gastric cancer: Report of a case

We describe a patient who survived for a prolonged period after repeated resections of pulmonary metastases from gastric cancer. A 59-year-old man underwent a distal gastrectomy for gastric cancer. A right middle lobectomy and a left lower lobectomy were performed for metastases from gastric cancer at 34 months and 82 months after the initial gastric resection, respectively. The patient died of cerebral infarction 65 months after the first lung resection, with no further relapse. To our knowledge, long-term survival after resection of pulmonary metastases from gastric cancer has only been reported in 3 patients previously. We herein review the literature and discuss the role of surgery in such patients.

Ultrasonic scalpel for sealing of the thoracic duct: evaluation of effectiveness in an animal model

To verify the usefulness of an ultrasonic scalpel for the sealing of lymphatic ducts, a Harmonic Ace scalpel (Ethicon Endo-Surgery, Inc, Cincinnati, OH) was tested, using the thoracic ducts in pigs. Indocyanine green was injected into the abdominal lymphatic ducts in two pigs, and the stained thoracic ducts were identified. The thoracic ducts were then divided and sealed into seven sections with a Harmonic Ace scalpel, used at a power setting of level 3. The cut ends of the thoracic ducts were evaluated macroscopically, histologically, and by measuring bursting pressure. The whole length of thoracic duct of each pig was clearly imaged by pigment. Each stump divided by the ultrasonic scalpel was completely sealed, and there was no pigment leakage from the cut end macroscopically. Histologic examination revealed that the cut end was sealed by homogenous degenerative coagulation. Bursting pressures could be determined at three cut ends of thoracic ducts and were 195 mmHg, 188 mmHg, and 203 mmHg, respectively. The thoracic ducts were reliably divided and sealed by an ultrasonic scalpel in pigs. This device is expected to be a useful tool for the surgical treatment of chylothorax.

Papillary adenoma of the lung with a peculiar raw macroscopic feature

We report a case of papillary adenoma of the lung with a peculiar raw macroscopic feature at intraoperative consultation. A 52‐year‐old man was admitted to our hospital for the evaluation of a solitary peripheral nodule in the left lower lobe which was detected with chest CT. When we took staples off from the stump of the partially resected lung in order to make a frozen section diagnosis, granular fragments leaked out from the stump. On the cut surface, the dark reddish and granular tumor grew expansively; however, hemorrhage and necrosis were absent. Histologically, granular fragments were mainly composed of papillary structures, which consisted of a single layer of cuboidal to low columnar cells with round to oval nuclei lining the surface of the fibrovascular cores. Characteristically, papillary structures lacked elastic fibers in the stroma and were packed within an elastic fiber framework derived from pre‐existing alveolar structures. We considered that high intratumoral pressure might have made the granular fragments leak out of the stump as soon as we removed staples and that peculiar macroscopic findings before fixation may be a diagnostic clue for papillary adenoma.

Cancer Phenotype Diagnosis and Drug Efficacy within Japanese Health Care

An overview on targeted personalized medicine is given describing the developments in Japan of lung cancer patients. These new targeted therapies with novel personalized medicine drugs require new implementations, in order to follow and monitor drug efficacy and outcome. Examples from IRESSA (Gefitinib) and TARCEVA (Erlotinib) treatments used in medication of lung cancer patients are presented. Lung cancer is one of the most common causes of cancer mortality in the world. The importance of both the quantification of disease progression, where diagnostic-related biomarkers are being implemented, in addition to the actual measurement of disease-specific mechanisms relating to pathway signalling activation of disease-progressive protein targets is summarised. An outline is also presented, describing changes and adaptations in Japan, meeting the rising costs and challenges. Today, urgent implementation of programs to address these needs has led to a rebuilding of the entire approach of medical evaluation and clinical care.

An importance of clinical proteomics for personalized medicine of lung cancer subtypes

Mass spectrometry-based clinical proteomic analysis, combined with collection of taegeted cancerous cells laser-microdissected (LMD) from formalin-fixed paraffinembedded (FFPE) tissues, has been promising to unveil both proteins expressed and their functional networks in lung cancer subtypes. Among lung cancer subtypes, both large cell neuroendocrine carcinoma (LCNEC) of the lung and small cell lung carcinoma (SCLC) are now classified to neuroendocrine tumor (NET) but pre-therapeutic histological distinction between LCNEC and SCLC has so far been problematic, leading to adverse clinical outcome. Protein biomarker candidates for LCNEC were found to be interestingly known as cancer stem cell (CSC) markers including aldehyde dehydrogenase 1 family member A1 (ALDH1A1), and those for SCLC included novel NET marker candidates, brain acid soluble protein 1 (BASP1) and secretagogin (SEGN), and a known NET marker, neural cell adhesion molecule (CD56). For three types of lung adenocarcinomas (ACs), which are adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive asenocarcinoma (LEP), their preliminary clinical proteomic analyses revealed protein expression profiles characterizing those lung cancer subtypes. The STRING protein-protein interaction (PPI) network analysis followed by gene set enrichment (GSE) for proteins expressed significantly to the three lung AC subtypes manifested characteristic associations of cancer-related pathways, which might play consertedly important roles in progression of disease mechanisms, and which would be quite useful to understand carcinogenic processes of lung adenocarcinom. Thus outcomes from clinical proteomic analysis reveal not only biomarker protein candidates expressed significantly to a disease but also serve to elucidate disease-oriented protein-protein interaction (PPI) networks including functional networks predicted from experimentally obtained proteome datasets. Abbreviations: LCNEC: Large-Cell Neuroendocrine Lung Carcinoma, OLC: Other Large-Cell Lung Cancer, SCLC: Small-Cell Lungcancer, GGO: Focal Ground-Glass Opacity, AIS: Adenocarcinoma In Situ, MIA: Minimally Invasive Adenocarcinoma, LEP: Lepidic Predominant Invasive Adenocarcinoma, FFPE: Formalin-Fixed and Paraffin-Embedded tissue sections, MS: Mass Spectrometry, PPI: Comparative Proteomics, Protein-Protein Interaction

Immunohistochemistry detection of epidermal growth factor receptor (EGFR) exons 19 and 21 mutations in non-small cell lung cancer (NSCLC) using novel mutation specific antibodies.

10542 Background: Activating EGFR mutations have become a backbone in the therapy alogrithm for NSCLC as mutations predict significantly better response and survival to EGFR TKIs. The most common EGFR mutations in NSCLC are exon 19 deletions and the exon 21 L858R point mutation. Among the exon 19 deletions, E746-A750 occurs in 61% of cases. In this study we compared novel IHC antibodies for E764-A750 and L858R to direct DNA sequencing in specimens from Japanese patients with NSCLC treated with gefitinib. Methods: IHC using the E746-A750 and L858R mutation specific antibodies (Cell Signaling Technologies, Danvers, MA) was performed on resected NSCLC Japanese patients who were subsequently treated with gefitinib at relapse. Extracted DNA was sequenced for mutational analysis of EGFR exons 18 to 21. Results: DNA sequencing of all 70 patients showed exon 19 deletions in 18 patients (25.7%), 11 had a deletion at E746-A750, exon 20 mutations in 18 patients, exon 21 mutations in 12 (17.1%), and exon 18 mutations...