Randomized phase II study of concurrent versus sequential alternating gefitinib and chemotherapy in previously untreated non-small cell lung cancer with sensitive EGFR mutations: NEJ005/TCOG0902.

BACKGROUND: The first-line combination of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) and platinum-based doublet chemotherapy has not been sufficiently evaluated for patients with EGFR-mutant non-small cell lung cancer (NSCLC). This randomized phase II study was designed to select a combination regimen for phase III evaluation. PATIENTS AND METHODS: Chemotherapy-naïve patients with advanced non-squamous, EGFR-mutant NSCLC were randomly assigned to receive either a concurrent or a sequential alternating regimen with gefitinib (250 mg) and carboplatin/pemetrexed [area under the curve (AUC) = 6 and 500 mg/m(2); 3-weekly]. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), response, and safety. RESULTS: All 80 patients enrolled were eligible and assessable for efficacy (41 and 39 patients in the concurrent and sequential alternating regimen groups, respectively). Median PFS was 18.3 months for the concurrent regimen and 15.3 months for the sequential alternating regimen [hazard ratio (HR) 0.71 (0.42-1.20), P = 0.20]. Although OS data are immature (16 and 24 death events), median survival times were 41.9 and 30.7 months in the concurrent and sequential alternating regimen groups, respectively [HR 0.51 (0.26-0.99); P = 0.042]. Response rates were similar in both groups (87.8% and 84.6%). Hematological and non-hematological adverse events were common and reversible; interstitial lung disease was neither frequent nor fatal (two cases in each group; 5% of all patients). CONCLUSION: This is the first randomized study to investigate the efficacy of combinational EGFR-TKI and chemotherapy in the EGFR-mutated setting. Both regimens had promising efficacy with predictable toxicities, although concurrent regimens might provide better OS. The concurrent regimen was chosen to compare with gefitinib monotherapy in our ongoing phase III study. CLINICAL TRIALS REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN C000002789).

Updated overall survival results from a randomized phase III trial comparing gefitinib with carboplatin-paclitaxel for chemo-naïve non-small cell lung cancer with sensitive EGFR gene mutations (NEJ002).

BACKGROUND: NEJ002 study, comparing gefitinib with carboplatin (CBDCA) and paclitaxel (PTX; Taxol) as the first-line treatment for advanced non-small cell lung cancer (NSCLC) harboring an epidermal growth factor receptor (EGFR) mutation, previously reported superiority of gefitinib over CBDCA/PTX on progression-free survival (PFS). Subsequent analysis was carried out mainly regarding overall survival (OS). MATERIALS AND METHODS: For all 228 patients in NEJ002, survival data were updated in December, 2010. Detailed information regarding subsequent chemotherapy after the protocol treatment was also assessed retrospectively and the impact of some key drugs on OS was evaluated. RESULTS: The median survival time (MST) was 27.7 months for the gefitinib group, and was 26.6 months for the CBDCA/PTX group (HR, 0.887; P=0.483). The OS of patients who received platinum throughout their treatment (n=186) was not statistically different from that of patients who never received platinum (n=40). The MST of patients treated with gefitinib, platinum, and pemetrexed (PEM) or docetaxel (DOC, Taxotere; n=76) was around 3 years. CONCLUSIONS: No significant difference in OS was observed between gefitinib and CBDCA/PTX in the NEJ002 study, probably due to a high crossover use of gefitinib in the CBDCA/PTX group. Considering the many benefits and the risk of missing an opportunity to use the most effective agent for EGFR-mutated NSCLC, the first-line gefitinib is strongly recommended.

Carcinoembryonic antigen-related cell adhesion molecules as surrogate markers for EGFR inhibitor sensitivity in human lung adenocarcinoma.

BACKGROUND: Lung adenocarcinoma (LADCA) patients with epidermal growth factor receptor (EGFR) mutations are in general associated with relatively high clinical response rate to EGFR-tyrosine kinase inhibitors (TKIs) but not all responded to TKI. It has therefore become important to identify the additional surrogate markers regarding EGFR-TKI sensitivity. METHODS: We first examined the effects of EGFR-TKIs, gefitinib and erlotinib, upon cell proliferation of lung adenocarcinoma cell lines. We then evaluated the gene profiles related to EGFR-TKI sensitivity using a microarray analysis. Results of microarray analysis led us to focus on carcinoembryonic antigen-related cell adhesion molecule (CEACAM) family, CEACAM 3, 5, 6, 7, and 19, as potential further surrogate markers of EGFR-TKI sensitivity. We then examined the correlation between the status of CEACAM 3, 5, 6, 7, and 19 immunoreactivity in LADCA and clinicopathological parameters of individual cases. RESULTS: In the cases with EGFR mutations, the status of all CEACAMs examined was significantly higher than that in EGFR wild-type patients, but there were no significant differences in the status of CEACAMs between TKI responder and nonresponder among 22 patients who received gefitinib therapy. However, among 115 EGFR mutation-negative LADCA patients, both CEACAM6 and CEACAM3 were significantly associated with adverse clinical outcome (CEACAM6) and better clinical outcome (CEACAM3). CONCLUSION: CEACAMs examined in this study could be related to the presence of EGFR mutation in adenocarcinoma cells but not represent the effective surrogate marker of EGFR-TKI in LADCA patients. However, immunohistochemical evaluation of CEACAM3/6 in LADCA patients could provide important information on their clinical outcome.

Mycobacterial hypersensitivity pneumonitis requires TLR9-MyD88 in lung CD11b+ CD11c+ cells.

Mycobacteria are among the most common causes of hypersensitivity pneumonitis (HP), but controversy persists with regard to the involvement of the infectious potency of the organism in mycobacterial HP (hot tub lung). This study aimed to establish a mouse model of hot tub lung to clarify its pathophysiology. Mice were exposed intranasally to formalin-killed Mycobacterium avium from a patient with hot tub lung (HP strain) or chronic pulmonary infection (non-HP strain), and bronchoalveolar lavage fluids and lung tissues were evaluated for allergic inflammation. Dead M. avium HP strain, but not non-HP strain, elicited marked HP-like pulmonary inflammation in wild-type mice. Although the inflammation was induced in mice lacking CD4 or CD8, the induction of HP-like responses was prevented in mice lacking myeloid differentiation factor (MyD)88 or Toll-like receptor (TLR)9. Cultured lung CD11c+ cells responded to M. avium in a TLR9-dependent manner, and reconstitution of TLR9-/- mice with lung CD11c+ cells from wild-type mice restored the inflammatory responses. Further investigation revealed that pulmonary exposure to M. avium HP strain increased the number of lung CD11b+ CD11c+ cells (dendritic cells) through TLR9 signalling. Our results provide evidence that hot tub lung develops via the mycobacterial engagement of TLR9-MyD88 signalling in lung CD11b+ dendritic cells independent of the mycobacterial infectious capacity.

Rapid improvement of osseous sarcoidosis after the treatment of pulmonary aspergillosis by itraconazole.

Osseous sarcoidosis is relatively uncommon, and treatment with corticosteroids is not always effective. Moreover, patients with an advanced stage of pulmonary sarcoidosis are sometimes infected with aspergillus in the cavities of the pulmonary lesions, and long-term use of corticosteroids should be prohibited to prevent the development of fatal invasive pulmonary aspergillosis. Here, we described a unique case of osseous sarcoidosis with pulmonary aspergillosis, showing a rapid improvement of the osseous symptoms just after the administration of the antifungal agent, itraconazole. Itraconazole is likely to become a candidate among new therapeutic agents for osseous sarcoidosis.

Fcgamma receptor IIB-deficient mice develop Goodpasture's syndrome upon immunization with type IV collagen: a novel murine model for autoimmune glomerular basement membrane disease.

The combination of hemorrhagic pneumonitis and rapidly progressive glomerulonephritis is a characteristic feature of Goodpasture's syndrome (GPS), an autoimmune disease resulting from the interaction of pathogenic anti-collagen type IV (C-IV) antibodies with alveolar and glomerular basement membranes. Lack of a suitable animal model for this fatal disease has hampered both a basic understanding of its etiology and the development of therapeutic strategies. We now report a novel model for GPS using mice deficient in a central regulatory receptor for immunoglobulin (Ig)G antibody expression and function, the type IIB Fc receptor for IgG (FcgammaRIIB). Mutant mice immunized with bovine C-IV reproducibly develop massive pulmonary hemorrhage with neutrophil and macrophage infiltration and crescentic glomerulonephritis. The distinctive linear, ribbon-like deposition of IgG immune complex seen in GPS was observed along the glomerular and tubulointerstitial membranes of diseased animals. These results highlight the role of FcgammaRIIB in maintaining tolerance and suggest that it may play a role in the pathogenesis of human GPS.

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.

Randomized phase II trial of weekly paclitaxel combined with carboplatin versus standard paclitaxel combined with carboplatin for elderly patients with advanced non-small-cell lung cancer.

BACKGROUND: The optimal platinum doublet regimen in elderly patients with non-small-cell lung cancer (NSCLC) is still uncertain. We conducted a randomized phase II study to compare the efficacy and safety of weekly paclitaxel combined with carboplatin with those of the standard schedule. PATIENTS AND METHODS: Elderly patients (age > or =70 years) with advanced NSCLC were randomly assigned to either the weekly arm {70 mg/m(2) paclitaxel on days 1, 8, and 15 and carboplatin [area under the curve (AUC) = 6] on day 1} or the standard arm [200 mg/m(2) paclitaxel and carboplatin (AUC = 6) on day 1]. The primary end point was the overall response rate (ORR). RESULTS: Eighty-two patients were enrolled. The ORR and median progression-free survival were 55% and 6.0 months for the weekly arm and 53% and 5.6 months for the standard arm. Grade 3/4 neutropenia and peripheral neuropathy were observed in 41% and 0% of the patients in the weekly arm and in 88% and 25% in the standard arm, respectively. CONCLUSIONS: This is the first randomized study that compares the platinum doublet designed specifically for the elderly. Regarding the safety, the weekly regimen was less toxic than the standard regimen and seems to be preferable for elderly patients with advanced NSCLC.

Pirfenidone in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease without proven effective therapy. A multicentre, double-blind, placebo-controlled, randomised phase III clinical trial was conducted in Japanese patients with well-defined IPF to determine the efficacy and safety of pirfenidone, a novel antifibrotic oral agent, over 52 weeks. Of 275 patients randomised (high-dose, 1,800 mg x day(-1); low-dose, 1,200 mg x day(-1); or placebo groups in the ratio 2:1:2), 267 patients were evaluated for the efficacy of pirfenidone. Prior to unblinding, the primary end-point was revised; the change in vital capacity (VC) was assessed at week 52. Secondary end-points included the progression-free survival (PFS) time. Significant differences were observed in VC decline (primary end-point) between the placebo group (-0.16 L) and the high-dose group (-0.09 L) (p = 0.0416); differences between the two groups (p = 0.0280) were also observed in the PFS (the secondary end-point). Although photosensitivity, a well-established side-effect of pirfenidone, was the major adverse event in this study, it was mild in severity in most of the patients. Pirfenidone was relatively well tolerated in patients with IPF. Treatment with pirfenidone may decrease the rate of decline in VC and may increase the PFS time over 52 weeks. Additional studies are needed to confirm these findings.

Massive pleural effusion and bronchopleural fistula in Wegener's granulomatosis.

Wegener's granulomatosis (WG) is characterized by systemic granulomatous necrotizing vasculitis, primarily affecting the respiratory tract and kidneys. We describe a rare case in a 28-year-old woman with WG, presenting with a massive lateral pleural effusion, accompanied by an aseptic bronchopleural fistula formed during immunosuppressive treatment. Although any organ can be involved in WG, only left pleuritis and a purpuric lesion on the neck were detected in this case. The pleural effusion and bronchopleural fistula resolved following immunosuppressive treatment for six months. Thus, WG should be considered in the differential diagnosis of a massive pleural effusion, and fistula formation is a possible complication of treatment. Moreover, immunosuppressive treatment was sufficient to resolve the massive pleural effusion and fistula formation without infection (120 words).

Association between mycobacterial genotypes and disease progression in Mycobacterium avium pulmonary infection.

BACKGROUND: Non-tuberculous mycobacterial lung disease, most commonly caused by Mycobacterium avium infection, tends to show variable disease progression, and significant disease predictors have not been adequately established. METHODS: Variable numbers of tandem repeats (VNTR) were evaluated in 16 mycobacterial interspersed repetitive unit (MIRU) loci from M avium isolates cultured from respiratory specimens obtained from 2005 to 2007. Specifically, the association between VNTR profiles and disease progression was assessed. RESULTS: Among the 37 subjects who provided positive respiratory cultures for M avium during the 2005-6 period, 15 subjects were treated within 10 months following a microbiological diagnosis of progressive M avium lung disease. Nine subjects underwent long-term follow-up (>24 months) without treatment for stable M avium lung disease. Based on a neighbour-joining cluster analysis used to classify M avium-positive subjects according to the VNTR profile, subjects with progressive versus stable lung disease were found to be grouped together in distinct clusters. Further analysis using logistic regression modelling showed that disease progression was significantly associated with the genetic distance of the M avium isolate from an appropriately selected reference (age-adjusted odds ratio 1.95; 95% confidence interval 1.16 to 3.30; p = 0.01 for the most significant model). A best-fit model could be used to predict the progression of M avium lung disease when subjects from the 2005-6 period were combined with those from 2007 (p = 0.003). CONCLUSION: Progressive lung disease due to M avium infection is associated with specific VNTR genotypes of M avium.

A genome-wide association study identifies an association of a common variant in TERT with susceptibility to idiopathic pulmonary fibrosis.

In order to identify a gene(s) susceptible to idiopathic pulmonary fibrosis (IPF), we conducted a genome-wide association (GWA) study by genotyping 159 patients with IPF and 934 controls for 214 508 tag single-nucleotide polymorphisms (SNPs). We further evaluated selected SNPs in a replication sample set (83 cases and 535 controls) and found a significant association of an SNP in intron 2 of the TERT gene (rs2736100), which encodes a reverse transcriptase that is a component of a telomerase, with IPF; a combination of two data sets revealed a p value of 2.9 x 10(-8) (GWA, 2.8 x 10(-6); replication, 3.6 x 10(-3)). Considering previous reports indicating that rare mutations of TERT are found in patients with familial IPF, we suggest that the common genetic variation within TERT may contribute to the risk of sporadic IFP in the Japanese population.

Epidemiology of sarcoidosis in Japan.

The present study was designed to identify recent clinical phenotypes using the National Epidemiological Survey and to compare findings with those of previous surveys in Japan. Pathologically confirmed sarcoidosis cases newly diagnosed in 2004 were eligible for the present study. Disease parameters were recorded and compared. A total of 1,027 patients were enrolled from a cluster encompassing 79.4% of the entire Japanese population. The study participants consisted of 364 males and 663 females, providing an average incidence rate of 1.01 per 100,000 inhabitants (0.73 for males and 1.28 for females). The age-specific incidence rate displayed a biphasic pattern in the whole patient population and in the females. The male incidence rates peaked in the 20-34-yr-old group. A second peak for 50-60-yr-old females showed a higher incidence than the first younger peak. Patients with abnormalities in eyes, skin and cardiac laboratory findings accounted for 54.8, 35.4 and 23.0% of cases, respectively. The female/male incidence ratio was increased, and the frequency of eye and skin involvement and cardiac abnormality was higher than in previous surveys conducted in Japan. In conclusion, the data obtained in the present study differ from those of other countries and showed changes in sarcoidosis clinical phenotypes compared with previous studies in Japan.

Hepatocyte growth factor leads to recovery from alcohol-induced fatty liver in rats.

A fatty liver is characterized by the hyperaccumulation of lipids within hepatocytes and is often caused by excessive alcohol intake. Rats fed ethanol-containing diets for 37 days showed remarkable increase in hepatic lipids and lipid droplet accumulation in the hepatocytes, indicating the onset of alcoholic fatty liver. Administration of hepatocyte growth factor (HGF) for the last seven days of ethanol treatment markedly decreased hepatic lipids to a level lower than that seen before HGF treatment. In contrast, serum levels of lipids and lipoproteins increased with HGF administration. Primary cultured hepatocytes prepared from the fatty liver retained lipid droplets during a 48-hour culture. However, when cultured in the presence of HGF, intracellular lipid concentrations decreased and lipid secretion was enhanced. Consistent with these events, HGF stimulated the rate of protein synthesis of apolipoprotein B (apoB) and enhanced subsequent mobilization of lipids into the medium. These results indicate that HGF administration induced recovery from the fatty liver, at least in part, by enhancing apoB synthesis and the subsequent mobilization of lipids from hepatocytes with fatty change. The possibility that HGF can be therapeutic for subjects with an alcohol-related fatty liver warrants further attention.

Evaluation of "at risk" alpha 1-antitrypsin genotype SZ with synthetic oligonucleotide gene probes.

Alpha 1-antitrypsin (alpha 1AT), a 52,000-mol-wt serum glycoprotein produced by hepatocytes and mononuclear phagocytes, functions as the major inhibitor of neutrophil elastase. The alpha 1AT haplotype S is associated with childhood liver disease and/or adult emphysema when inherited with the Z haplotype to give the phenotype SZ. To accurately identify the SZ phenotype at the level of genomic DNA, four 32P-labeled 19-mer synthetic oligonucleotide probes were prepared; two to identify the M and S difference in exon III, and two to identify the M and Z difference in exon V. These probes were hybridized with various cloned DNAs and genomic DNAs cut with the restriction endonucleases BgII and EcoRI; the genomic DNAs represented all six possible phenotype combinations of the M, S, and Z haplotypes (MM, MS, MZ, SS, ZZ, and SZ). Using the four probes to evaluate 42 samples of genomic DNA, the "at risk" SZ and ZZ phenotypes were correctly identified in all cases, as were the "not at risk" phenotypes SS, MS, MM, and MZ, demonstrating that both exon III and exon V directed probes are necessary to properly identify all of the major "at risk" alpha 1AT genes. However, when used to evaluate a very rare family carrying a null allele, these four oligonucleotide probes misidentified the "at risk" null-null and S null phenotypes as "not at risk" MM and SM combinations. These observations indicate that oligonucleotide gene probes yielded reliable and accurate assessment of "at risk" alpha 1AT genotypes in almost all situations, but in the context of prenatal diagnosis and genetic counseling this approach must be used with caution and in combination with family studies so as not to misidentify rare genotypes that may be associated with a risk for disease.

Alveolar macrophages release an insulin-like growth factor I-type molecule.

Human alveolar macrophages, when activated, release a progression-type growth factor for fibroblasts that signals "competent" fibroblasts to replicate. The present study demonstrates that this growth activity is an insulin-like growth factor I (IGF-I)-type molecule. Partial purification of medium conditioned by activated alveolar macrophages using ion exchange and gel filtration chromatography revealed an IGF-I molecule as detected by an anti-IGF-I polyclonal antibody and that the specific activity of the progression-type growth activity tracked with the amount of IGF-I present. In a serum-free complementation test, the increase in fibroblast proliferation by alveolar macrophage IGF-I was reduced in a dose-response manner with an anti-IGF-I monoclonal antibody. The alveolar macrophage IGF-I displaced 125I-IGF-I from its receptor in a binding assay utilizing human lung fibroblasts and it stimulated type I IGF receptors purified from human lung fibroblasts to phosphorylate a tyrosine-containing artificial substrate. In contrast to the 7.6-kD serum IGF-I, gel chromatography revealed that the alveolar macrophage IGF-I had an apparent molecular mass of 26 kD, similar to other tissue IGF-Is. Alveolar macrophages expressed IGF-I mRNA transcripts as detected by solution hybridization using a 32P-labeled riboprobe complementary to exons I-II-III of the IGF-I gene. In the context of the known functions of the family of IGF-I molecules in cell growth, IGF-I released by activated alveolar macrophages may play a role in acute and chronic inflammatory disorders.

Targeted delivery of NK4 to multiple lung tumors by bone marrow-derived mesenchymal stem cells.

Most advanced solid tumors metastasize to different organs. However, no gene therapy effective for multiple tumors has yet been developed. Since a unique characteristic of bone marrow-derived mesenchymal stem cells (MSCs) is that they migrate to tumor tissues, we wanted to determine whether MSCs could serve as a vehicle of gene therapy for targeting multiple tumors. First, we confirmed that mouse MSCs preferentially migrate to multiple tumors of the lung in the Colon-26 (C-26) lung metastasis model. Next, MSCs were efficiently transduced with NK4, an antagonist of hepatocyte growth factor (HGF), by an adenoviral vector with an RGD motif. MSCs expressing NK4 (NK4-MSCs) strongly inhibited development of lung metastases in the C-26 lung metastasis model after systemic administration via a tail vein. Treatment with NK4-MSCs significantly prolonged survival of the C-26-tumor-bearing mice by inhibiting tumor-associated angiogenesis and lymphangiogenesis and inducing apoptosis of the tumor cells. MSC-based gene therapy did not induce the severe adverse effects induced by conventional adenoviral vectors. These results indicate that MSCs can serve as a vehicle of gene therapy for targeting multiple lung metastatic tumors.

Peritumoral injection of adenovirus vector expressing NK4 combined with gemcitabine treatment suppresses growth and metastasis of human pancreatic cancer cells implanted orthotopically in nude mice and prolongs survival.

NK4 or adenovirus vector expressing NK4 (Ad-NK4) can act bifunctionally as a hepatocyte growth factor antagonist and angiogenesis inhibitor and has potential value in cancer therapy. The aim of this study was to evaluate the therapeutic efficacy of Ad-NK4 in combination with gemcitabine (GEM) against pancreatic cancer. In vitro study showed a strong antiproliferative effect of GEM and a potent anti-invasive effect of Ad-NK4 against pancreatic cancer cells. In in vivo experiments, SUIT-2 human pancreatic cancer cells were implanted into the pancreas of nude mice. Mice were treated with Ad-NK4 by injection into the peritumoral region of the pancreas on day 5 after implantation followed by weekly i.p. injections of GEM. On day 28 after implantation, pancreatic tumor volume was significantly smaller than that in mice treated with Ad-LacZ, Ad-NK4 alone, or GEM alone. Furthermore, combination therapy completely suppressed peritoneal dissemination and liver metastases, leading to significantly increased survival. Histologic and immunohistochemical assays of primary tumors indicated that combination therapy prohibited both cell proliferation and angiogenesis, resulting in high levels of apoptosis. These results suggest that peritumoral injection of Ad-NK4 plus GEM is a potent combination therapy for pancreatic cancer.

Prognostic value of nucleolar protein p120 in patients with resected lung adenocarcinoma.

PURPOSE: In this study we investigated the prognostic significance of proliferation-associated nucleolar protein p120 in primary resected lung adenocarcinoma because it reflects tumor growth fractions in vitro. PATIENTS AND METHODS: Expression levels of p120 in tumors were assessed by immunohistochemistry in 74 patients who underwent radical resection. With clinical follow-up data, the prognostic significance of p120 calculated by labeling indices was evaluated using the Cox proportional hazards model. RESULTS: p120 protein was clearly detected in nucleoli of adenocarcinoma cells. Its expression levels widely varied in each sample from 8.5% to 67. 2%, with a mean +/- SD of 35.2% +/- 15.1%. No significant correlation was found between expression levels of p120 and clinicopathologic factors. However, the expression levels of p120 were negatively correlated with the tumor doubling time calculated with retrospective chest roentgenograms. Using a cutoff value of 35% in the labeling index of p120, patients with high expression of p120 experienced early recurrence and shorter survival compared with those who had low expression of p120. Multivariate analysis showed that p120 served as an independent, as well as the strongest, prognostic factor for resected lung adenocarcinoma. CONCLUSION: This report provides the first evidence that expression levels of p120 in tumor tissues can be used as an independent and powerful prognostic marker for resected lung adenocarcinoma.

Expression of nucleolar protein p120 in human lung cancer: difference in histological types as a marker for proliferation.

The function of proliferation-associated nucleolar protein p120 is unclear. A recent report that a yeast protein, NOP2, 67% homologous to human p120, is up-regulated during the onset of growth and influences the morphology of the nucleolus supports the notion that this protein could serve as a marker for proliferation in neoplastic cells. Lung cancer is characteristic in that different histological types show different biological features. We attempted to evaluate the levels of p120 expression in resected human lung cancer tissues of different histological types and the relation of p120 expression and cell proliferation using human lung cancer cell lines. When 37 frozen specimens of human lung cancer and normal lung were stained with a p120 monoclonal antibody, the nucleoli of cancer cells were positively stained, whereas a few macrophages in normal lung revealed only weak staining. The labeling index of p120 in squamous cell carcinoma (67.7 +/- 12.4%) was significantly higher than that in adenocarcinoma (35.3 +/- 12.6%) or in large cell carcinoma (30.1 +/- 17.3%; P < 0.01). In six human lung cancer cell lines and one normal lung fibroblast cell line cultured in vitro, there was a significant correlation between S-phase fraction and p120 mRNA (r = 0.851, P < 0.02)/p120 protein (r = 0.869, P < 0.01) or between doubling time and p120 protein (r = -0.928, P < 0.01). In the context of the reports that indicate higher [3H]thymidine incorporation and shorter doubling time in the squamous cell carcinoma, these results indicate that p120 can be a marker for proliferation in human lung cancer cells in vivo and in vitro, and that it has an important function in the cell cycle of tumor proliferation.