A phase II study of amrubicin combined with carboplatin for elderly patients with small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0405.

BACKGROUND: Amrubicin, a new anthracycline agent, has shown high activity for small-cell lung cancer (SCLC) in previous studies. However, a combination regimen with amrubicin and platinum has been investigated little. On the basis of previous phase I study, we conducted this study to evaluate the efficacy and the safety of amrubicin and carboplatin for elderly patients with SCLC. METHODS: Chemotherapy-naive elderly patients with SCLC received amrubicin (35 mg/m(2), days 1-3) and carboplatin [area under the curve (AUC) 4.0, day1] every 3 weeks. The primary end point was overall response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival and toxicity profile. RESULTS: From January 2005 to November 2007, 36 patients were enrolled [median age 76 (range 70-83); ECOG performance status of zero and one in 17 and 19 patients, respectively]. One complete response and 31 partial responses were observed (ORR 89%). Median PFS was 5.8 months and median survival time was 18.6 months. Grade 3-4 neutropenia was observed in 97% of the patients and six patients (17%) suffered from grade 3-4 febrile neutropenia. Other toxic effects were moderate and treatment-related death was not observed. CONCLUSIONS: Amrubicin combined with carboplatin is quite effective for SCLC with acceptable toxic effects even for the elderly population. Further evaluation of this regimen is warranted.

Expression of alpha-amylase isozymes in human thyroid tissues.

Expression of alpha-amylase genes in thyroid tissues was studied by assaying the total amylase activity as well as by using immunohistochemical and Northern blot analysis. The amylase genes expressed were determined by a combination of the polymerase chain reaction (PCR) and blot analysis using synthetic probes specific for the three known amylase isozyme complementary DNAs. The samples consisted of tissues from 18 human thyroid carcinomas (11 well-differentiated carcinomas, 2 poorly differentiated carcinomas, 1 anaplastic carcinoma, and 4 medullary carcinomas) and 9 specimens of nonmalignant thyroid tissue (2 were from nontumorous regions of resected glands and 7 were thyroid tissue from a patient with Graves' disease). Salivary-type amylase was expressed at a relatively high level in nonmalignant thyroid tissue and well-differentiated carcinoma and could be detected by Northern blot analysis. In poorly differentiated carcinoma, it was detected only by the PCR, while in anaplastic or medullary carcinoma, it was not detected even by the PCR. Thus, the expression of salivary-type amylase was characteristic of well-differentiated follicular cells. These observations suggest that salivary-type amylase expression may be a marker for identifying the histogenesis and stage of differentiation of thyroid cancer. In addition, the AMY2B gene product was detected in all different types of cells examined, although its expression was only detectable by the PCR. Pancreatic type amylase was not detected in any of the samples.

An expression profile of active genes in human colonic mucosa.

An expression profile of genes active in the human colonic mucosa was obtained by collecting 959 partial sequences from a 3'-directed cDNA library. Seven genes were found to produce mRNA each of which comprised more than 1% of total mRNA. Four of these genes are novel, and are likely to be uniquely expressed in the colonic mucosa, and the other three have been identified as genes for fatty acid binding protein, immunoglobulin lambda chain, and carcinoma-associated antigen GA733-2. In the remaining 952 clones, 310 were composed of 118 species occurred recurrently but less than 1%, and 533 clones appeared only once. Because the 3'-directed cDNA library faithfully represents the mRNA population in the source tissue, these numbers represent the relative activities of the gene expression. Altogether 156 gene species were identified in GenBank, and a significant portion of these genes encode proteins found in Golgi apparatus and lysosomes, chromosome-encoded mitochondrial proteins, cell surface proteins, and components in the protein synthesis machinery. The types and proportions of genes identified is consistent with the known major activities of the colonic mucosa such as mucous protein production, energy-dependent water absorption, and rapid cell proliferation and turnover.

An expression profile of active genes in human lung.

An expression profile of genes active in the human lung was obtained by collecting 797 partial sequences from a 3'-directed cDNA library. Three genes were found to produce mRNA each of which comprised more than 1% of total mRNA. These three have been identified as genes for pulmonary surfactant apoprotein (PSP-A), Clara cells 10-kDa secretory protein, and HLA-E heavy chain. In the remaining 745 clones, 221 were composed of 89 species that occurred recurrently, and 524 clones appeared only once. Because the 3'-directed cDNA library faithfully represents the mRNA population in the source tissue, these numbers represent the relative activities of the gene expression. Altogether 437 gene species were novel, and 179 gene species were identified in GenBank. A significant portion of these genes encode proteins found in secretory proteins, cell surface proteins, and components in the protein synthesis machinery, representing the function of the lung.

Cloning and characterization of a third type of human alpha-amylase gene, AMY2B.

We have previously reported concerning the existence of a third type of human alpha-amylase gene, AMY3 [Emi et al., Gene 62 (1988) 229-235; Tomita et al., Gene 76 (1989) 11-18], which is expressed in a lung carcinoid tissue, and differs in nucleotide sequence from the two previously characterized human alpha-amylase genes coding for salivary and pancreatic isozymes, termed AMY1 and AMY2, respectively. Here, we rename this gene AMY2B to coincide with the designation by Gumucio et al. [Mol. Cell Biol. 8 (1988) 1197-1205] and describe its genetic properties as revealed by sequencing studies. It consists of ten major exons whose sequences are highly homologous to those of AMY1 and AMY2. Not only the exons, but also most of the introns seem to be highly conserved, as judged from physical mapping data. The AMY2B gene identified from mRNA in a lung carcinoid tissue has at least two additional untranslated exons in its 5' region; hence the promoter lies far upstream relative to the other two AMY genes.

A novel sperm-specific hypomethylation sequence is a demethylation hotspot in human hepatocellular carcinomas.

Certain human DNA regions are strikingly undermethylated at CpG sites in sperm compared to adult somatic tissues. These sperm-specific hypomethylation sequences are thought to function early in embryogenesis or gametogenesis. By using the restriction landmark genomic scanning (RLGS) cloning method, we have isolated a novel sperm-specific hypomethylation sequence, the status of which changes during spermatogenesis, embryonal growth and differentiation. This sequence is a part of a new 'NotI repeat' consisting of a 1.4 kb repetitive unit sequence named DE-1. The sequence is GC-rich and has high homology to a CpG DNA clone that was isolated by a methyl CpG protein binding column, indicating that it was normally highly methylated. We investigated the methylation status of this sequence. In the normal genome the sequence was methylated, but in the human hepatocellular carcinoma (HCC) genome, the target sequence was demethylated at the cytosine residue of the CpG dinucleotides with high frequency (75% in the previous study). These data suggest that this regional DNA hypomethylation may play a role in both cell differentiation and hepatocarcinogenesis.

A novel type of human alpha-amylase produced in lung carcinoid tumor.

A novel type of alpha-amylase was detected in a lung carcinoid tissue after surveying the cDNA library constructed from this tumor mRNA. Nucleotide sequence analysis showed that the amylase expressed in this carcinoid tumor has 13 and 6 amino acid substitutions when compared with salivary amylase (Amy1) and pancreatic amylase (Amy2), respectively. The nucleotide sequence homologies of cDNAs between this carcinoid amylase and amy1, amy2 are 97.5% and 98.2%, respectively. The nucleotide sequence comparison strongly suggests that this new amylase is the product of the amy3 gene that has been detected in human genome [Emi et al., Gene 62 (1988) 229-235]

Prognostic significance of pS2 protein expression in pulmonary adenocarcinoma.

In the present study, pS2 protein expression in pulmonary adenocarcinoma was investigated on paraffin-embedded sections obtained from 170 patients. 28 (16%) patients showed varying degrees of pS2 protein expression in the cytoplasm of tumour cells, as detected by immunohistochemical staining with anti-pS2 protein antibody. There was a significant association between pS2 protein expression and larger tumour size, and the acinar or bronchiolo-alveolar subtype. However, no significant correlations between pS2 protein status and the other clinicopathological factors, i.e. T-factor, N-factor, stage and histological differentiation, were shown. In contrast to breast cancer, patients with pS2-positive pulmonary adenocarcinomas had a significantly worse prognosis than those with pS2-negative pulmonary adenocarcinomas; this was true for stage I patients, as well as for all patients. Multivariate analysis showed that pS2 protein expression was a discriminating variable in overall survival. These findings suggest that pS2 protein status is a possible prognostic indicator in pulmonary adenocarcinoma.

p53-regulated GML gene expression in non-small cell lung cancer. a promising relationship to cisplatin chemosensitivity.

The GML gene (glycosylphosphatidylinositol-anchored molecule-like protein gene) is a novel gene specifically induced by wild-type p53, which may participate in cell cycle control or the cell apoptotic pathway. Recent experiments suggest that the expression of this novel gene in cancer cells is closely associated with sensitivity to certain anticancer drugs. To elucidate the role of the gene expression in cisplatin (CDDP) chemosensitivity of non-small cell lung cancer (NSCLC), 30 surgically resected materials were examined by reverse transcriptase-polymerase chain reaction (RT-PCR). GML gene expression was detected in 9 (30%) samples. Its incidence was significantly higher in immunohistochemically p53-negative (P=0.040) or wild-type p53 tissues (P=0.041). On in vitro chemosensitivity testing using 29 primary tissues, six samples with GML gene expression showed good sensitivity to CDDP. In particular, in tissues with immunohistochemically p53-negative accumulation, those with GML gene expression showed significantly better in vitro sensitivity to CDDP (P=0.012). Clinically a good response to CDDP-based chemo(thermo)therapy for NSCLC patients with tumour residue or recurrence, was observed only in those with p53-negative accumulation and GML gene expression, in agreement with in vitro results. Thus, although the number of tested samples was small, GML gene expression is commonly detected in immunohistochemically p53-negative NSCLCs in close association with good sensitivity to CDDP. GML gene expression analysis may serve as a predictor of CDDP-based chemotherapy for patients with NSCLC.

Lymphoepithelioma-like carcinoma of the lung: analysis of two cases for Epstein-Barr virus infection.

Lymphoepithelioma-like carcinoma, which is an uncommon histological type of epithelial tumor, has been described as being closely associated with Epstein-Barr virus (EBV) infection in organs other than the lung. Recently, we experienced two surgically resected cases of pulmonary tumors mimicking lymphoepithelioma-like carcinoma. Both cases contained EBV DNA genomes as shown by polymerase chain reaction (PCR) using EBV DNA-specific primers, one positive for EBV DNA in virtually all cancer cells, and the other showing positive hybridization in a small number of cancer cells by in situ hybridization (ISH) using digoxigenin-labeled olignucletide probes for each of EBV DNA for EBV DNA. EBV-encoded RNA-1 (EBER-1) was typically detected in one case. These results are highly suggestive of EBV-associated tumors in one of the current cases, although in the other case, no such close association was determined. It seems that lymphoepithelioma-like pulmonary carcinoma, which seems extremely unusual, may be closely associated with EBV infection in tumorigenesis.

Intentional limited resection for selected patients with T1 N0 M0 non-small-cell lung cancer: a single-institution study.

OBJECTIVES: To comparatively evaluate lobectomy and limited resection for T1 N0 M0 non-small-cell lung cancer, we reviewed case series with concurrent nonrandomized controls. METHODS: Limited resection with curative intent was performed for 63 patients with T1 N0 M0 non-small-cell lung cancer over a 10-year period. These 63 patients included 46 patients who underwent a segmentectomy as an intentional limited resection. These patients had good pulmonary function and could tolerate a lobectomy in the management of their disease. The other 17 patients underwent wedge resection or segmentectomy as a compromised limited resection because they had poor pulmonary reserve or other limiting factors and could withstand a thoracotomy but could not tolerate a lobectomy in the management of their disease. RESULTS: The 5-year survival was 93% in the intentional resection group. The survival curve for this group was not different from that for 77 patients who underwent the standard operation (lobectomy plus complete mediastinal lymph node dissection) for T1 N0 M0 non-small-cell lung cancer during the same period. The frequency of local/regional recurrence in the intentional resection group was 8.7% (4/46); the recurrence in three patients was situated in the mediastinum. According to multivariate analysis, limited resection was not associated with poor survival. CONCLUSION: Segmentectomy with regional lymph node dissection, including the mediastinum, should be considered as an acceptable alternative treatment for selected patients with T1 N0 M0 disease.

Intrathoracic chemothermotherapy following panpleuropneumonectomy for pleural dissemination of invasive thymoma.

We report a case of pleural dissemination of invasive thymoma, which was successfully treated with intrathoracic chemothermotherapy following panpleuropneumonectomy. Intrathoracic chemothermotherapy in combination with surgery may be a hopeful adjuvant treatment to control pleural disseminated lesions of invasive thymoma.

Cystic mucinous adenocarcinoma of the lung. Two cases of cystic variant of mucus-producing lung adenocarcinoma.

Two previously unreported cases of mucus-producing lung adenocarcinoma are presented as uncommon tumors, which are clinicopathologically different from other histologic types of lung adenocarcinoma. The tumors, showing apparently rapid development on chest roentgenograms, were tightly packed with copious mucus and resembled cystic lesions. Because they contained very few cancer cells, and these were only at the periphery, it was impossible to diagnose malignant neoplasms preoperatively through cytologic examination. The present tumors, which we described as cystic mucinous adenocarcinoma, are considered to be a cystic variant of mucus-producing lung adenocarcinoma that expands grossly by storing mucus.

p53 immunostaining in combined type small cell lung cancer. Brief report.

Abnormalities of the p53 oncogene in lung cancer have recently been reported to be more frequent in small cell lung cancer (SCLC) than in non-small cell lung cancer (non-SCLC), but their status in combined type SCLC is as yet unknown. In this study, immunohistochemical analysis using a polyclonal antibody against p53 protein was performed in 12 surgically resected specimens of combined type SCLC. Immunoreactivity of the p53 protein was found in 5 (42%) of the 12 cases, and the immunostaining pattern of the p53 protein in areas of the non-small cell carcinoma type was the same as in those of the small cell carcinoma type. Thus, it seems that the incidence of p53 abnormalities in combined type SCLC is slightly lower than in ordinary type SCLC. It is also suggested that abnormalities of the p53 oncogene in this histological type may not be a specific event related to the morphological difference between small cell carcinoma and non-small cell carcinoma.

Thymidylate synthase and dihydropyrimidine dehydrogenase activities in non-small cell lung cancer tissues: relationship with in vitro sensitivity to 5-fluorouracil.

We examined enzymatic activities of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) in non-small cell lung cancer (NSCLC) tissues to determine the relationship to tumor sensitivity to 5-fluorouracil (5-FU). TS and DPD activities were measured in 60 surgically resected primary NSCLC tissues using a TS-binding assay and a radioenzyme assay, respectively. In vitro tumor sensitivity to 5-FU was assayed using a collagen gel droplet embedded culture drug test (CD-DST). DPD activities slightly correlated with in vitro sensitivity to 5-FU (r=0.402,P=0.013), such that tumors with higher DPD activity were more resistant to 5-FU. In contrast, no correlation was observed in TS activities. Thus, it was suggested that only DPD activity in NSCLC tissues is a potential indicator in predicting tumor sensitivity to 5-FU. Based on these results, further study is needed to evaluate the clinical significance of these enzymes in 5-FU-based chemotherapy for patients with NSCLC.

Prognostic value of ground-glass opacity found in small lung adenocarcinoma on high-resolution CT scanning.

OBJECTIVE: This study was undertaken to investigate the value of the ground-glass opacity (GGO) area found on high-resolution computed tomography (HRCT) scanning as a preoperative prognostic indicator. PATIENTS AND METHODS: We studied 104 patients with small-sized lung adenocarcinoma, 20 mm or less in diameter, between 1995 and 1999. Three independent radiologists semi-quantitatively scored the extent of GGO on HRCT as greater than or less than 50%. Three independent pathologists semi-quantitatively scored the extent of the bronchioloalveolar carcinoma (BAC) component of the tumor on histologic examination as greater than or less than 50%. As no relapse occurred in patients with GGO greater than 50%, multivariate analysis of this prognostic factor was not possible. RESULTS: Fifty patients were scored as having both BAC and GGO greater than 50%, 36 as both BAC and GGO less than 50%, and 16 as BAC greater than 50% and GGO less than 50%. In only two patients (1.9%), BAC less than 50% was overestimated on HRCT as GGO greater than 50%. The sensitivity and specificity of GGO to BAC were 76 and 95%, respectively. The 3 year-relapse-free survival rates in each group of 52 patients with GGO greater than and less than 50% were 100 and 72%, respectively, after a median follow-up of 24 months. Univariate analysis indicated that both GGO and BAC areas were significantly correlated with cancer relapse (P=0.005 and P=0.002). The multivariate analysis revealed an independent prognostic influence of the BAC area on relapse-free survival (P=0.015, relative risk=0.07). CONCLUSIONS: To date there has been no relapse among the 52 patients with GGO greater than 50%. This novel classification based on the semiquantitative analysis of GGO area on HRCT should become an useful independent preoperative indicator when deciding on operative procedure, and to predict the potential of relapse in patients with small adenocarcinoma arising from the peripheral lung.

Myoepithelioma of the lung: report of two cases and review of the literature.

Myoepithelial tumors occur mainly in the salivary glands, the sweat glands or the breast, but uncommonly in the lung. Herein, we describe two cases of myoepithelioma of the lung. Both patients were 58-year-old men, in whom the tumors were located in the right-upper bronchus and in the left-upper bronchus, respectively, with endobronchial growth pattern. Surgery was performed, but metastasis occurred into the forearm and hip muscles in the former case, and into the liver in the latter. Histologically, the tumor in the former was a spindle-plasmacytoid type, and that in the latter was a plasmacytoid type in part with squamous differentiation. Based on histochemical, immunohistochemical and ultrastructural analyses, both were compatible with myoepithelioma. The clinicopathological uniqueness of this neoplasm is discussed, together with a review of reports of this disease in the literature.

Cathepsin B expression in tumour cells and laminin distribution in pulmonary adenocarcinoma.

AIMS: To determine the correlation between cathepsin B expression and laminin distribution in pulmonary adenocarcinoma tissue. METHODS: The distribution of cathepsin B and laminin was examined in 28 formalin fixed, paraffin wax embedded specimens of pulmonary adenocarcinoma tissue, using a double immunostaining technique with commercially available antibodies to cathepsin B and laminin, respectively. RESULTS: Tumour cells in 23 (82%) cases reacted to cathepsin B: 13 cases were weakly positive and 10 were strongly positive. Laminin in tumour associated basement membrane produced various staining patterns: two cases had an almost continuous distribution of laminin in tumour associated basement membrane in the tumour tissues, while a moderately discontinuous laminin distribution pattern was found in 12 cases, and a highly fragmented pattern was found in 14 cases. The degree of cathepsin B expression in tumour cells was significantly correlated with the break up of laminin staining. In some cases a discontinuous pattern of tumour associated laminin was frequently observed adjacent to cathepsin B positive tumour cell nests. CONCLUSIONS: Considering that cathepsin B has the capacity to degrade basement membrane components, including laminin, the inverse correlation shown in this study between the increase in cathepsin B expression by tumour cells and the diminution of laminin in tumour associated basement membrane could reflect local progression and spread by pulmonary adenocarcinoma.

Bronchial neurofibrosarcoma.

A 56-year-old woman was seen with the clinical features of collapse of the right lower lobe. Intrabronchial extension of a tumor was demonstrated endoscopically. Sleeve bilobectomy was performed, and a diagnosis of bronchial neurofibrosarcoma was confirmed by light and electron microscopic and immunohistochemical studies.

Radical laser segmentectomy for T1 N0 lung cancer.

Over the last 40 months, 18 lung cancer patients with T1 N0 non-small cell lung carcinoma have been treated with radical laser segmentectomy. This innovative operative method consists of a combination of anatomical or nonanatomical segmentectomy by neodymium:yttrium-aluminum garnet laser parenchyma sparing with complete hilar lymph node dissection. Although the median follow-up period is too short, there is no local recurrence and no cancer deaths. There have been no major complications. Even deep-seated tumors can be resected with a clear safety margin using this method. Radical laser segmentectomy may be a useful adjunct to preserve normal lung tissue and to perform very radical resection.