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Administration of cimetidine, an H2-receptor antagonist, increases blood alcohol concentrations. This has been attributed to decreased gastric first-pass metabolism of ethanol caused by cimetidine's inhibitory effect on gastric alcohol dehydrogenase (σ-ADH) activity. Molecular studies on σ-ADH showed that a point mutation might occur at position 287 (G → T) of the σ-ADH gene in Japanese deficient type of σ-ADH activity. To clarify the relationship between firstpass metabolism of ethanol and polymorphism of σ-ADH, we analyzed the nucleotide sequence at positions 287 and 294 of σ-ADH in 11 individuals who were administered ethanol orally before and after treatment with cimetidine. Higher blood ethanol levels after cimetidine administration were found in 4 of 11 cases (group A), whereas high blood ethanol levels were observed in 7 of 11 cases (B group), irrespective of cimetidine administration. Genetic polymorphisms at position 287 and 294 were not observed in all subjects. Even in 59 Japanese men with various alcoholic liver diseases, no polymorphisms at position 287 were observed by restriction-length polymorphisms with Ava II digestion after polymerase chain reaction. [ABSTRACT FROM AUTHOR]

The incidence of complications following pulmonary resection using an automatic stapler was studied in 348 consecutive patients. A parallel-jaw stapler with two staple lines was used in group A (133 males, 101 females, mean age 66 years) between 1990 and 1995, and a hinged-jaw stapler with three staple lines in group B (70 males, 44 females, mean age 67 years) in 1995-1997. The incidence of bronchopleural fistula was 0.4% (1 patient) in group A and nil in group B. The incidence of intraoperative air leak requiring interrupted suture closure was 4.7% (11 patients) in group A and nil in group B (p < 0.05). Postoperative bronchopleural fistula did not develop in any of the cases, and there was no mortality. For management of the bronchial stump after pulmonary resection, the newer device firing three rows of staples is superior to the two-row device. [ABSTRACT FROM AUTHOR]

Extralobar pulmonary sequestration was incidentally detected in a 65-year-old man. Preoperatively, the lesion presented as a posterior mediastinal mass. At operation the mass was found to be attached to the paravertebral region at the level of the seventh thoracic vertebra by a feeding artery originating from the descending aorta. Only two cases of extralobar pulmonary sequestration in the posterior mediastinum have been previously reported. [ABSTRACT FROM AUTHOR]

In the lung, acinic cell carcinoma (ACC) is a rare form of tumor. Reported herein is a unique bronchial gland-type tumor diagnosed as well-differentiated ACC that developed in the B9 bronchus of the left lung. Various immunohistochemical and histochemical staining partly satisfied the diagnosis of ACC. Moreover, this tumor contained various sizes of mucous cysts lined by columnar mucous cells, which produced abundant mucin positive for Alcian blue, which is usually present in mucoepidermoid carcinoma. Therefore, the present case is a unique tumor having a broad spectrum of cell differentiation from the terminal duct-–acinar unit to the striated duct and excretory duct. This is the first case of unique bronchial gland-type tumor with mixed histological features of ACC and mucoepidermoid carcinoma. [ABSTRACT FROM AUTHOR]

The space around the staple line after lung surgery is at high risk of nontuberculosis Mycobacterium pulmonary disease (NTM-PD). Solitary nodules of NTM-PD around the staple line are difficult to distinguish from lung cancer. There is no clear identification from laboratory data and radiologic findings without histological examination. In the present case, we misdiagnosed the pulmonary granulomas with Mycobacterium avium complex pulmonary disease (MAC-PD) as a recurrence of lung cancer. We conducted radiation therapy. The pulmonary granulomas with MAC-PD were exacerbated by irradiation. The effects of radiation therapy for MAC-PD are unknown. When radiation therapy is performed for the patient coexistence with MAC-PD, we should pay attention to exacerbation of MAC-PD. [ABSTRACT FROM AUTHOR]

Objectives: Various drug‐sensitivity markers have been reported to be associated with tumor progression and chemotherapy resistance. Detailed expression profiles of sensitivity markers for cytotoxic chemotherapy in pulmonary large cell neuroendocrine carcinoma (LCNEC) remain unclear. Herein, we aimed to clarify the correlation between the expression of drug‐sensitivity markers and clinicopathological features, prognostic impact, and status of tumor immunity in patients with LCNEC. Methods: We retrospectively analyzed the correlation between clinicopathological features and the expression of drug‐sensitivity‐related markers, including vascular endothelial growth factor 2 (VEGFR2), thymidylate synthase (TS), tubulin beta 3 class III (TUBB3), topoisomerase I (Topo‐I), and Topo‐II in 92 surgically resected LCNEC samples. Furthermore, we examined the prognostic significance of expression of these and their correlation with the immune cell status. Results: Overall, high expression of TS, TUBB3, VEGFR2, Topo‐I, and Topo‐II was detected in 50 (54%), 31 (34%), 23 (25%), 65 (71%), and 36 (39%) samples, respectively. Univariate and multivariate analyses revealed that advanced pathological T and N factors, positive lymphatic permeation, and Topo‐II expression were independent unfavorable prognosticators for recurrence‐free survival, and advanced pathological T and N factors, Topo‐II positive expression, and TS positive expression were independent unfavorable prognosticators for overall survival. In terms of correlation with immune cell status, higher expression of VEGFR2 was closely linked to negative PD‐L1 expression. Conclusions: These findings suggest that elevated Topo‐II and TS expression may contribute to poor outcomes through protumoral biology in patients with LCNEC, and elevated VEGFR2 expression might negatively impact tumor immune reactions in LCNEC. [ABSTRACT FROM AUTHOR]

In the present study, K-ras mutation was investigated in 156 neogenetic epithelia that appeared in the lesion of subpleural fibrosis in order to elucidate the close relationship of lung cancer development with pulmonary interstitial pneumonia. The neogenetic epithelia were histologically subclassified into six types: (i) ciliated bronchial epithelium (CBE); (ii) squamous metaplastic epithelium (SME); (iii) cuboidal immature epithelium (CIE); (iv) stratified immature epithelium (SIE); (v) mucus cell epithelium (MCE); and (vi) intestinal metaplastic epithelium (IME). K-ras mutation was detected in 9.6% of neogenetic epithelia overall; 21% of CIE, 12% of SIE, 16% of SME, but not in other types of neogenetic epithelia. Immunohistochemically, CIE and SIE frequently expressed surfactant apoprotein and SME was characteristic to carcinoembryonic antigen expression. According to Ki-67 immunostain, CIE, SIE and SME are likely to grow faster than other histological types of epithelia. K-ras mutation was seen exclusively in codon 12 with predominant G to A and G to C substitutions without any G to T transversions, results which are somewhat different to previous studies in lung cancers. The present study clearly demonstrated that K-ras mutation appeared in certain histological types of neogenetic epithelia, but raised the question of whether K-ras mutation in neogenetic epithelia during the inflammatory reparative process might be an early genetic event in lung carcinogenesis. [ABSTRACT FROM AUTHOR]

Herein, we report the first case of a patient with lung cancer with an aberrant medial basal segmental pulmonary artery (A7b) behind the superior segmental pulmonary vein (V6) who underwent right superior segment (S6) segmentectomy via uniportal video-assisted thoracoscopic surgery (uVATS). A 56-year-old man with a right lower lobe pure ground-glass nodule (GGN), measuring 12 mm in diameter on computed tomography (CT) had an aberrant A7b branching from the basal pulmonary artery, which was located behind the V6 as detected on 3D CT. The right S6 segmentectomy, via uVATS, for the GGN was performed. The postoperative course was uneventful. The final pathological diagnosis was invasive adenocarcinoma (p-T1bN0M0, stage IA2) with no evidence of disease recurrence at 3-month follow-up. Thoracic surgeons should be aware of the possibility of damaging the A7b when dividing the V6 for S6 segmentectomy, especially during uVATS because of insufficient dorsal visibility. [ABSTRACT FROM AUTHOR]

Spontaneous pneumothorax occurring in patients with pulmonary arteriovenous malformations (PAVMs) caused by hereditary hemorrhagic telangiectasia (HHT) is extremely rare. We report a case of spontaneous pneumothorax in a PAVM patient. A 26-year-old man with previously diagnosed HHT and multiple small PAVMs presented with chest pain and dyspnea and was referred to our hospital. Chest X-ray showed a left-sided pneumothorax. Computed tomography (CT) showed apical bullae on both sides of the upper lobe. We clarified the location of PAVMs by 3D-CT to avoid the massive bleeding caused by careless grasping of PAVMs and unintentional incomplete resection of the PAVMs during the pneumothorax surgery. Considering the risk of exacerbation, the patient underwent bullectomy of the left upper lobe. The postoperative histopathological examination indicated that the pneumothorax occurred spontaneously in the HHT patient. We should clarify the location of PAVMs to avoid bleeding caused by the grasping of PAVMs during surgery. [ABSTRACT FROM AUTHOR]

Background: To report the follow up data and clinical outcomes of the JME study (UMIN 000008177), a prospective, multicenter, molecular epidemiology examination of 876 surgically resected non‐small‐cell lung cancer (NSCLC) cases, and the impact of somatic mutations (72 cancer‐associated genes) on recurrence‐free survival (RFS) and overall survival (OS). Methods: Patients were enrolled between July 2012 and December 2013, with follow up to 30th November 2017. A Cox proportional hazards model was used to assess the impact of gene mutations on RFS and OS, considering sex, smoking history, age, stage, histology, EGFR, KRAS, TP53, and number of coexisting mutations. Results: Of 876 patients, 172 had ≥2 somatic mutations. Median follow‐up was 48.4 months. On multivariate analysis, number of coexisting mutations (≥2 vs 0 or 1, HR = 2.012, 95% CI: 1.488‐2.695), age (≥70 vs <70 years, HR = 1.583, 95% CI: 1.229‐2.049), gender (male vs female, HR = 1.503, 95% CI: 1.045‐2.170) and pathological stage (II vs I, HR = 3.386, 95% CI: 2.447‐4.646; ≥III vs I, HR = 6.307, 95% CI: 4.680‐8.476) were significantly associated with RFS, while EGFR mutation (yes vs no, HR = 0.482, 95% CI: 0.309‐0.736), number of coexisting mutations (≥2 vs 0 or 1, HR = 1.695, 95% CI: 1.143‐2.467), age (≥70 vs <70 years, HR = 1.932, 95% CI: 1.385‐2.726), and pathological stage (II vs I, HR = 2.209, 95% CI: 1.431‐3.347; ≥III vs I, HR = 5.286, 95% CI: 3.682‐7.566) were also significant for OS. Conclusion: A smaller number of coexisting mutations, earlier stage, and younger age were associated with longer RFS and OS, while EGFR mutations were significantly associated with improved OS. [ABSTRACT FROM AUTHOR]

Various drug-sensitivity markers are potentially responsible for tumor progression and chemotherapy resistance in cancer patients with both epithelial and sarcomatous components; however, the clinicopathological significance of drug-sensitivity markers in patients with pulmonary pleomorphic carcinoma (PPC) remains unknown. Here, we clarified the prognostic impact of these drug-sensitivity markers in PPC by performing immunohistochemical and clinicopathologic analyses of samples from 105 patients with surgically resected PPC in order to evaluate levels of vascular endothelial growth factor 2 (VEGFR2), stathmin 1 (STMN1), tubulin β3 class III (TUBB3), thymidylate synthetase (TS), topoisomerase II (Topo-II), glucose-regulated protein, and 78 kDa (GRP78)/binding immunoglobulin protein (BiP). We observed the rates of high expression for VEGFR2, STMN1, TUBB3, TS, Topo-II, and GRP78/BiP were 33% (39/105), 35% (37/105), 61% (64/105), 51% (53/105), 31% (33/105), and 51% (53/105) of the samples, respectively. Moreover, multivariate analysis identified VEGFR2 and GRP78/BiP as significant independent markers for predicting worse prognosis. These findings suggested elevated VEGFR2 and decreased GRP78/BiP levels as independent factors for predicting poor outcomes following surgical resection in patients with PPC. [ABSTRACT FROM AUTHOR]

Purpose: We conducted a prospective study to evaluate the efficacy and safety of biweekly gemcitabine and carboplatin combination treatment in patients with resected non-small cell lung cancer (NSCLC).Methods: Patients with completely resected stage IB to IIIA NSCLC were treated with four cycles of gemcitabine (1000 mg/m2, days 1 and 15) plus carboplatin [area under the time-concentration curve (AUC) 5 mg/mL/min, day 1] every 4 weeks as adjuvant chemotherapy.Results: Forty-three patients were enrolled in this study. The median number of treatment cycles was four. The completion rate of chemotherapy was 79.1%. Major grade 3/4 hematological adverse events included leukocytopenia (27.9%) and neutropenia (53.5%), whereas non-hematological toxicities were generally mild. Ten patients (23.3%) required chemotherapy treatment schedule delay, and one patient required one dose level reduction because of drug fever. Median disease-free survival was 78.6 months [95% confidence interval (CI) 39.5-not reached (NA)] and median overall survival was not reached (95% CI 83.7-NA).Conclusions: Biweekly administration of gemcitabine and carboplatin is effective and well tolerated for patients with completely resected NSCLC as an adjuvant chemotherapy. [ABSTRACT FROM AUTHOR]

Aim Invasive thymomas are rare tumours of the anterior mediastinum. These tumours' clinical features have been the subject of much controversy. Therefore, it is necessary to elucidate the optimal management of invasive thymomas. Patients and Methods A total of 61 patients with invasive thymoma were retrospectively reviewed. Results The study group comprised 38 males (62.3 per cent) and 23 females (37.7 per cent), with a median age of 55 years (range: 28-79 years). According to the Masaoka staging, 31 patients had stage II disease (50.8 per cent), 21 patients had stage III disease (34.4 per cent), four patients had stage IVa disease (6.6 per cent) and five patients had stage IVb disease (8.2 per cent). A statistically-significant difference in the survival rate was observed between stages II and III ( P < 0.001) and between III and IV ( P < 0.001). Complete resection was performed in 43 patients (70.5 per cent). Patients who underwent complete resection showed significantly better prognosis than those with incomplete resection ( P < 0.001) and inoperable/biopsy ( P < 0.001). After initial treatment, a total of 20 patients (32.8 per cent) relapsed. The recurrence rates in stages II, III and IV were 3.2 per cent, 66.7 per cent and 55.5 per cent, respectively. Treatment for recurrence was performed in all 20 patients. Conclusion The outcome of invasive thymoma was correlated with the Masaoka stage and the extent of tumour resection. Salvage treatment for recurrent thymoma might give a moderate response rate and improve survival. A large-scale study is warranted for evaluating the role of the multimodality therapeutic approach in patients with invasive thymoma. [ABSTRACT FROM AUTHOR]

OBJECTIVES An adenosquamous carcinoma (ASC) of the lung is a relatively rare tumor. In this multi-institutional cohort study, we tested the hypothesis that an ASC exhibits more aggressive clinical behavior as compared to adenocarcinoma (AC) and squamous cell carcinoma (SC). METHODS This retrospective cohort study used a prospective database produced by the Japan National Hospital Organization Study Group for Lung Cancer over a 7-year period (operations from 1997 to 2003, follow-up data until March 2010). During that period, 4668 cases underwent an operation for various types of primary malignant lung tumors. When a sample from a tumor comprised at least 20% each of SC and AC, the case was classified as ASC. Pathologic staging was done according to the seventh edition of the International Union against Cancer (UICC) Tumor Node Matastasis (TNM) classification of malignant tumors. RESULTS We identified 114 patients with ASC (2.4%), 2993 with AC (64.2%), and 1369 with SC (29.3%). Kaplan-Meier survival curves for all stage cases, p-stage IA, IB, and IIIA tumors indicated that ASC cases had the least favorable survival. The 5-year survival rates for all stage cases were 23.3% for ASC, 58.0% for AC (p < 0.0001), and 40.8% for SC (p < 0.0001). The 5-year survival rates for p-stage IA were 42.0% for ASC, 81.8% for AC (p = 0.0005), and 63.4% for SC not significant (NS), while those for p-stage IB were 19.3%, 65.3% (p = 0.0024), and 46.8% (NS), respectively, and those for p-stage IIIA were 17.8%, 24.8% (p = 0.0154), and 18.8% (NS), respectively. There was a tendency for greater survival differences between ASC and AC in earlier tumor stages. A step-wise multivariable model demonstrated that sex, age, performance status, histology, tumor size, p-stage, operative method, and neoadjuvant/adjuvant therapy were independent prognostic factors. CONCLUSION ASC of the lung is more aggressive than AC and SC. The decreased survival of patients with ASC as compared with either of those single histology tumors suggests the need for a clinical trial of adjuvant chemotherapy that includes early-stage patients. [ABSTRACT FROM AUTHOR]

BACKGROUND: KRAS and epidermal growth factor receptor ( EGFR) mutations are thought to play an important role in the carcinogenesis of lung adenocarcinoma. However, clinicopathological findings of KRAS mutated adenocarcinoma cases have not yet been fully clarified. The authors analyzed the relationship between the KRAS mutation and corresponding clinicopathological findings, focusing on nonmucinous and mucinous bronchioloalveolar elements. METHODS: EGFR and KRAS mutations were detected in DNA samples extracted from 182 surgically resected tissues of lung adenocarcinomas by the Smart Amplification Process. The relations between gene mutation status and clinicopathological features were analyzed. All adenocarcinoma cases were divided into bronchioloalveolar carcinoma (BAC), adenocarcinoma with bronchioloalveolar features, and adenocarcinoma without BAC components (non-BAC). BAC/adenocarcinoma with bronchioloalveolar features tumors were further assessed for the presence of mucinous features. RESULTS: EGFR and KRAS mutations were found in 76 and 30 cases, respectively. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features was found in 22 cases, which included 10 nonmucinous and 12 mucinous tumors. Of 19 cases with mucinous BAC/adenocarcinoma with bronchioloalveolar features, KRAS mutations were detected in 12, but no EGFR mutation was detected. In the KRAS mutant group, BAC/adenocarcinoma with bronchioloalveolar features had significantly earlier pathological stages and more favorable prognoses than did non-BAC. Mucinous BAC/adenocarcinoma with bronchioloalveolar features showed less smoking history than did nonmucinous BAC/adenocarcinoma with bronchioloalveolar features and non-BAC. Furthermore, transversion type KRAS mutations were more common in non-BAC. CONCLUSIONS: KRAS mutated adenocarcinomas can be divided into BAC/adenocarcinoma with bronchioloalveolar features and non-BAC types. Non-BAC adenocarcinoma is related to smoking history and has a poor prognosis. BAC/adenocarcinoma with bronchioloalveolar features adenocarcinoma, however, has a more favorable prognosis, and mucinous BAC/adenocarcinoma with bronchioloalveolar features has little relationship to smoking history. Cancer 2011;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Copper sputter-deposition by a newly developed technique called rotation magnetron sputtering is introduced for copper seed layer formation on printed wiring boards (PWBs) as an alternative to the electroless copper plating, which requires many complicated process steps as well as an intentional roughness-induced process to obtain practical adhesion capability between the copper and the resin. A rough copper surface degrades high-speed signal propagation due to an increase in conductive loss, and makes difficult the realization of further miniaturization of copper wirings. Thus, a very smooth surface layer of cycloolefin resin with a low dielectric constant and a low dielectric loss is introduced for realizing high-speed signal propagation, low electrical power consumption, and very high density packaging by introducing PWBs with a new structure, which are characterized by: 1) high characteristic impedance of 100 \Omega instead of the current characteristic impedance of 50 \Omega, which decreases the electrical power consumption down by one-half and increases the packaging density up to about four times by decreasing the copper wiring width down to one-fourth of the current characteristic impedance of 50 \Omega, and 2) multi-resin step copper wiring to simultaneously establish very high density packaging by introducing 10-\mum width copper wiring with 40 \mum resin thickness and very high speed signal propagation with 80- and/or 120-\mum resin thickness copper wiring. By introducing the plasma process steps, such as radio frequency bias Ar/H{2} plasma cleaning of the resin surface as well as the exposed inner copper surface, plasma nitridation of the resin surface, deposition of copper nitride, and deposition of the copper seed layer, a copper seed layer with a very smooth surface having very strong adhesion with the resin can be obtained. This technology greatly contributes to next-generation PWBs with very high performance and very high productivity. [ABSTRACT FROM PUBLISHER]

Large cell neuroendocrine carcinoma (LCNEC) and small cell lung carcinoma (SCLC) are high-grade neuroendocrine carcinomas. In order to clarify the similarities and differences between these cancers, 22 cases each of LCNEC and SCLC were collected and a comparative pathological study was carried out. First, their clinicopathological characteristics were confirmed, which were very similar to those previously reported. The 5 year survival rate of LCNEC and SCLC patients was 38.3% and 29.7%, respectively. The morphological characteristics of LCNEC and SCLC were then reviewed with regard to the morphology previously used to differentiate these cancers. As a result, many morphological indicators, such as tumor cell size, nuclear/cytoplasmic ratio, nuclear molding, rosette formation, prominent nucleoli and karyolysis were confirmed to be significant indicators for distinguishing LCNEC from SCLC. On comparative immunohistochemistry, LCNEC had significantly high staining scores for the expression of keratin 7 and 18, E- and P-cadherins, β-catenin, villin 1, retinoblastoma protein (pRB), c-met and α-enolase. These results might reflect the differentiation or deviation of LCNEC toward an epithelial nature irrespective of neuroendocrine tumor lineage. In conclusion, the present comparative study of LCNEC and SCLC defined the similarities and differences between these cancers, and showed the biologically and clinicopathologically overlapping spectrum of the tumor lineage. [ABSTRACT FROM AUTHOR]

Abstract: Amino acid transport systems play an important role in cellular proliferation. L-type amino acid transporter 1 (LAT1) has been associated with tumor growth, and is highly expressed in the established tumor cell lines and primary human neoplasms. In this study, we investigated the expression of LAT1 to evaluate the malignant potential and prognostic significance in neuroendocrine (NE) tumors of the lung. Twenty-one surgically resected, large cell neuroendocrine carcinomas (LCNEC), 13 small cell lung cancers (SCLC), five atypical carcinoids (AC), and 10 typical carcinoids (TC) were enrolled in the study. LAT1 expression and Ki-67 labeling index of the NE tumors were analyzed by immunohistochemical staining. LAT1 was overexpressed in 52.4% of the LCNEC, in 46.2% of the SCLC, and in 25% of the AC. LAT1 expression in LCNEC was significantly associated with lymph node metastasis and poor outcome. Moreover, a significant correlation was found between LAT1 expression and Ki-67 in both LCNEC and SCLC. Expression of LAT1 tended to increase from low-grade to high-grade NE tumors. The present results suggest that LAT1 may play a significant role in cellular proliferation, lymph node metastasis, and poor outcome in patients with NE tumors of the lung. [Copyright &y& Elsevier]

To re-evaluate adenocarcinoma, mixed subtypes (ADMIX) of the lung, a total of 201 cases were classified into three main subgroups according to the most differentiated histological growth pattern; namely bronchioloalveolar carcinoma (BAC)-mixed, which was the most predominant (73.1%), papillary (PAP)-mixed (21.9%), and acinar-mixed (5%). The PAP-mixed was significantly male predominant and had more progressed clinicopathological features. A significant cytological difference was observed among the three subgroups. A tissue microarray was constructed and immunohistochemistry was undertaken using 15 biomarkers. Hierarchical clustering analysis was separately applied to the immunohistochemical results of ADMIX and ADMIX subgroups, and it was found that most acinar-mixed cases were placed in a separate cluster, while the BAC-mixed and PAP-mixed failed to form significant independent clusters. The antibody clustering profile for the acinar-mixed was clearly different from that for the BAC-mixed or PAP-mixed, but the PAP-mixed shared a dendrogram profile with the other two subgroups. Statistically, approximately half of the 15 biomarkers were significant for differentiating between ADMIX subgroups and between different histological growth patterns. In conclusion, ADMIX can be classified into three histopathological subgroups according to the most differentiated growth pattern, of which a PAP growth pattern might indicate more aggressive behavior than that of a BAC growth pattern. [ABSTRACT FROM AUTHOR]

Summary: Large cell neuroendocrine carcinoma (LCNEC) of the lung is a malignant neuroendocrine tumor clinicopathologically similar to and falling in-between atypical carcinoid tumor and small cell lung carcinoma (SCLC). The diagnosis of LCNEC is based mainly on a characteristic neuroendocrine morphology and biological neuroendocrine differentiation. In order to know the discrepancy between morphological and biological neuroendocrine differentiation, LCNEC was immunohistochemically and molecular biologically compared with large cell carcinoma with neuroendocrine morphology (LCCNM), which lacked only biological neuroendocrine differentiation among the criteria of LCNEC. Immunohistochemically, disruption of the RB pathway, namely a lack of RB expression and simultaneous overexpression of p16 protein, was characteristic of LCNEC, but not LCCNM. In G2/M cell cycle regulation, 14-3-3 σ expression was markedly reduced in LCNEC. Moreover, the antibody 34 β E12 recognizing a set of large-sized keratin gave a different staining pattern between LCNEC and LCCNM. The immunohistochemical data suggested that LCNEC has a similar biological marker profile to SCLC and different from LCCNM. However, a loss of heterozygosity (LOH) analysis using microsatellite markers showed a high frequency of LOH at 3p in both LCNEC and LCCNM as well as in SCLC. Morphological neuroendocrine differentiation might not be identical to biological neuroendocrine differentiation in large cell carcinoma of the lung. [Copyright &y& Elsevier]

Background: The presence of residual N2 disease following induction therapy for locally advanced non-small cell lung cancer (NSCLC) has been proposed as a contraindication to surgery. However, single level N2 metastases found in the operative specimens of patients with clinical N0 NSCLC who did not receive induction therapy is associated with prolonged survival. In order to investigate whether residual single level N2 disease following induction therapy was similarly associated with prolonged survival, we conducted a retrospective review of patients with stages IIIa and IIIb NSCLC who had undergone induction therapy followed by surgery. Methods: A retrospective review was performed of the hospital records of patients with stages IIIa and IIIb NSCLC who had undergone induction therapy consisting of chemotherapy and/or radiotherapy followed by tumor resection and mediastinal lymph node dissection at 11 Japanese national referral hospitals. Survival was analyzed by the Kaplan–Meier method and prognostic factors were determined by the log-rank and Cox regression methods. Results: One hundred thirty-one patients underwent induction therapy of NSCLC stages IIIa (n=95) and IIIb (n=36) followed by complete tumor resection during a 12-year interval. Clinical N2 disease was present in 114 (87%) patients and N3 disease in 17 (13%) patients. Median follow up was 48 months. Eighteen patients had residual single level N2 disease and 25 patients had multiple residual N2 level metastases. The 5-year survival was 54% for patients with pathologic single level N2 disease and 11% for patients with multiple N2 level disease (P<0.01). In a multivariate analysis, only the pathologic N status significantly influenced survival. Conclusion: Patents who have multiple levels of N2 disease have a much worse prognosis than patients who have single level of N2. [Copyright &y& Elsevier]