Search

Several observations indicate that protein expression analysis by immunohistochemistry (IHC) remains relevant in individuals with non-small-cell lung cancer (NSCLC) when considering targeted therapy, as an early step in diagnosis and for therapy selection. Since the advent of next-generation sequencing (NGS), the role of IHC in testing for NSCLC biomarkers has been forgotten or ignored. We discuss how protein-level investigations maintain a critical role in defining sensitivity to lung cancer therapies in oncogene- and non-oncogene-addicted cases and in patients eligible for immunotherapy, suggesting that IHC testing should be reconsidered in clinical practice. We also argue how a panel of IHC tests should be considered complementary to NGS and other genomic assays. This is relevant to current clinical diagnostic practice but with potential future roles to optimize the selection of patients for innovative therapies. At the same time, strict validation of antibodies, assays, scoring systems, and intra- and interobserver reproducibility is needed., Competing Interests: Declaration of Competing Interest Dr. Fred R. Hirsch has participated in scientific advisory boards for AstraZeneca, Bristol-Myers Squibb, Sanofi, Regeneron, Novartis, Amgen, Genentech, Novocure, NextCure, Nectin Therapeutics, Merus Therapeutics, G1-Therapeutics, and Blueprint Medicines., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Patients with thoracic malignancies who develop COVID-19 infection have a higher hospitalization rate compared to the general population and to those with other cancer types, but how this outcome differs by race and ethnicity is relatively understudied., Methods: The TERAVOLT database is an international, multi-center repository of cross-sectional and longitudinal data studying the impact of COVID-19 on individuals with thoracic malignancies. Patients from North America with thoracic malignancies and confirmed COVID-19 infection were included for this analysis of racial and ethnic disparities. Patients with missing race data or races and ethnicities with fewer than 50 patients were excluded from analysis. Multivariable analyses for endpoints of hospitalization and death were performed on these 471 patients., Results: Of the 471 patients, 73% were White and 27% were Black. The majority (90%) were non-Hispanic ethnicity, 5% were Hispanic, and 4% were missing ethnicity data. Black patients were more likely to have an Eastern Cooperative Oncology Group (ECOG) Performance Status ≥ 2 (p-value = 0.04). On multivariable analysis, Black patients were more likely than White patients to require hospitalization (Odds Ratio (OR): 1.69, 95% CI: 1.01-2.83, p-value = 0.044). These differences remained across different waves of the pandemic. However, no statistically significant difference in mortality was found between Black and White patients (OR 1.29, 95% CI: 0.69-2.40, p-value = 0.408)., Conclusions: Black patients with thoracic malignancies who acquire COVID-19 infection are at a significantly higher risk of hospitalization compared to White patients, but there is no significant difference in mortality. The underlying drivers of racial disparity among patients with thoracic malignancies and COVID-19 infection require ongoing investigation., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Objective: Small cell lung cancer (SCLC) is a systemic disease and most patients have metastases at diagnosis. Better understanding of the underlying mechanisms of SCLC metastasis may provide potential approach to improve clinical outcome., Methods: HTG Edge-seq was used to identify the differential gene expression between primary SCLC lesions and paired metastatic lymph nodes (LN). Overall survival (OS) analysis was performed in patients with different levels of plasma CCL19 concentration. Invasion, migration, proliferation, apoptosis and angiogenesis ability of SCLC cells and function of CD8 + T cells were evaluated in vitro to investigate the mechanism of CCL19 in promoting metastasis., Results: Four chemokines (CCL19, CCL21, CCL8, CCR1) were the most differentially expressed between primary lesions and metastatic LN. CCL19 was further investigated because its mRNA and protein level expression were also validated in four SCLC cell lines (H446, H69, H82, H196). Higher plasma CCL19 was associated with late lymph node (N3) metastasis (training cohort P = 0.044, validation cohort P = 0.020) and shorter OS (training cohort P = 0.040, validation cohort P = 0.047) in SCLC patients. Silencing CCL19 inhibited SCLC cell migration, invasion, proliferation and HUVECs tube formation. Furthermore, we found that CCL19 could decrease percentage of CD8 + Ki67 + and CD8 + GZMB + T cells and increase proportion of CD8 + PD1 + T cells., Conclusion: CCL19 was associated with LN metastasis and poor prognosis in patients with SCLC. Its expression promoted tumor progression and metastasis and impaired the function of CD8 + T cells, suggesting CCL19 might be a potential target for SCLC., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Optimal second-line chemotherapy for patients with relapsed small-cell lung cancer remains debatable. In addition to topotecan or amrubicin monotherapy, re-challenge with first-line platinum-doublets have been commonly used. In this study, we investigated whether platinum-doublets are suitable as second-line treatment for relapsed small-cell lung cancer., Materials and Methods: Studies that enrolled relapsed small-cell lung cancer and compared platinum-doublets with non-platinum-based regimens for second-line treatment were identified using PubMed and EMBASE. A meta-analysis was conducted to calculate the relative risk of objective response rate and disease control rate of the second-line chemotherapy. Subgroup analyses were conducted to focus on comparison with standard second-line regimens and sensitive relapse. Progression-free and overall survival, and adverse events were systematically reviewed., Results: Ten studies published between 2011 and 2020 were included in our analysis with a total of 1222 patients: 438 treated with platinum-doublets and 784 with non-platinum-based regimens. The objective response rates for second-line platinum-doublet and non-platinum regimens were 47.3 % [95 % CI: 40.5-54.0] and 31.5 % [95 % CI: 22.2-40.8], respectively.　Patients treated with platinum-doublets had a significantly higher objective response rate than patients with non-platinum-based regimens (RR [95 % CI]: 1.527 [1.100-2.121], p = 0.011), as well as disease control rate (RR [95 % CI]: 1.152 [1.052-1.262], p = 0.002). In a subgroup analysis comparing platinum-doublets with topotecan or amrubicin, patients treated with platinum-doublets had significantly higher objective response rate and disease control rate (RR [95 % CI]: 1.663 [1.055-2.619], p = 0.028 and 1.170 [1.021-1.340], p = 0.023 respectively). Progression-free and overall survival appeared consistent with the tumor responses. Adverse events associated with platinum-doublets appeared acceptable compared with the monotherapies., Conclusion: Platinum-doublet chemotherapy as second-line treatment for patients with relapsed small-cell lung cancer can be considered as a reasonable option in comparison with non-platinum regimens., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Radiation therapy (RT) plays an important role in the curative treatment of a variety of thoracic malignancies. However, delivery of tumoricidal doses with conventional photon-based RT to thoracic tumors often presents unique challenges. Extraneous dose deposited along the entrance and exit paths of the photon beam increases the likelihood of significant acute and delayed toxicities in cardiac, pulmonary, and gastrointestinal structures. Furthermore, safe dose-escalation, delivery of concomitant systemic therapy, or reirradiation of a recurrent disease are frequently not feasible with photon RT. In contrast, protons have distinct physical properties that allow them to deposit a high irradiation dose in the target, while leaving a negligible exit dose in the adjacent organs at risk. Proton beam therapy (PBT), therefore, can reduce toxicities with similar antitumor effect or allow for dose escalation and enhanced antitumor effect with the same or even lower risk of adverse events, thus potentially improving the therapeutic ratio of the treatment. For thoracic malignancies, this favorable dose distribution can translate to decreases in treatment-related morbidities, provide more durable disease control, and potentially prolong survival. This review examines the evolving role of PBT in the treatment of thoracic malignancies and evaluates the data supporting its use., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objectives: Lung cancer has the highest incidence and fatality among all cancers. Our research analyzed the expression of galectin-9 on non-small cell lung cancer (NSCLC) tumor cells and tumor infiltrating lymphocytes (TILs)., Materials and Methods: We analyzed the expression level of galectin-9 protein in 136 NSCLC primary tumor samples by immunohistochemistry (IHC)., Results: We tested 136 surgical resected primary NSCLC tumor tissues for galectin-9 from Medical University of Gdansk, Poland. We found that on tumor cells, galectin-9 level only had correlation with T cell immunoglobulin and mucin-domain containing-3 (TIM-3) level (Correlation Coefficient = 0.360, p < 0.001). On TILs, galectin-9 level had broad connections with other checkpoints including programmed cell death protein-1 (PD-1) (Correlation Coefficient = 0.332, p < 0.001), programmed cell death-ligand 1 (PD-L1) (Correlation Coefficient = 0.247, p = 0.004) and TIM-3 (Correlation Coefficient = 0.350, p < 0.001). Interestingly, galectin-9 level on TILs also had positive relation with PD-L1 level on tumor cells (Correlation Coefficient = 0.278, p = 0.001), galectin-9 level on tumor cells (Correlation Coefficient = 0.181, p = 0.035) and TIL percentage (Correlation Coefficient = 0.236, p = 0.006). High level of galectin-9 on TILs indicated shorter RFS (recurrence-free survival) (RFS 1.82 years, 95% CI 0.795-2.845 vs. 0.67 years, 95% CI 0.086-1.254, P = 0.033). Patients with galectin-9 positive tumor cells display longer overall survival (OS) (1.76 years, 95% CI 0.222-3.298 vs. 3.10 years, 95% CI 2.662-3.538, P = 0.039) CONCLUSIONS: We found galectin-9 expression on both NSCLC tumor cells and TILs. Galectin-9 expression was found in all NSCLC pathological type. Galectin-9 level on TILs had correlation with TIM-3, PD-1 and PD-L1 level. On tumor cells, galectin-9 level had correlation with TIM-3 level. Patients with low galectin-9 level on tumor cells or high galectin-9 level on TILs were more likely to have poor prognosis., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: c-MET protein overexpression has been proposed as a biomarker in non-small cell lung cancer (NSCLC), albeit its role in the clinical setting has not been firmly established yet., Patients and Methods: We designed a retrospective cohort study, consisting of 725 patients with surgically removed NSCLC. Immunohistochemistry (IHC) was conducted in tissue microarrays (TMA) from lung tumors and healthy tissue. IHC staining was quantified using H-scores (range 0-300). Association between c-MET H-score and overall survival (OS) as well as progression-free survival (PFS) was explored., Results: c-MET H-score ≥20 had a significant positive impact on OS in the multivariate analysis in the whole study population, HR = 0.79 (95%CI: 0.64-0.97). The prognostic effect of c-MET H-score ≥20 was even stronger in patients who received adjuvant treatment with a HR = 0.61 (95% CI: 0.40-0.93). In the subgroup of adenocarcinoma and squamous cell carcinoma patients with stage IIA-IIIB disease, the prognostic impact of c-MET was significant in the univariate analysis (HR = 0.60, 95% CI: 0.43-0.83)., Conclusion: c-MET H-score ≥20 is a positive prognostic biomarker for OS in early stage NSCLC. This benefit seems to be strongly correlated to adjuvant chemotherapy, therefore rendering c-MET H-score ≥20 a possible predictive biomarker for platinum-based adjuvant chemotherapy in early stage NSCLC., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Herpes Virus Entry Mediator (HVEM) is an important immune checkpoint in cancer recognition. HVEM expressed on tumor cell membranes activates immune cell signaling pathways leading to either inhibition of activity (B- and T-lymphocyte attenuator, BTLA) or activation of immune activity (LIGHT). The aim of this study is to investigate the prevalence of HVEM expression and its association with PDL1 expression in NSCLC., Methods: A TMA of 527 resected NSCLC samples and 56 NSCLC cell lines were evaluated for HVEM and PD-L1 expression. The IHC assay for HVEM was optimized on the Dako Link48 autostainer using a polyclonal antibody from R&D Systems(AF356). PD-L1 IHC was performed on the Dako Link48 autostainer using the PD-L1 28-8 pharmDx kit. Scoring HVEM employed the H-score system while for PD-L1 the tumor proportion score (TPS) was used., Results: HVEM expression in the NSCLC resected samples and cell lines revealed a positive H-score more than 1 was 18.6% (77/415) and 48.2% (27/56) respectively. HVEM expression was significantly higher in patients with lymph node N2 metastasis (25.5% vs 7.9% vs 17.5%, p = 0.046) when comparing with N1 or no lymph node metastasis, and was marginally significantly higher in patients with stage III/IV disease (24.5% vs 16.4%, p = 0.059). Subgroup analysis showed that HVEM (median 45 vs 36 months, p = 0.706) and PD-L1 expression (median 45 vs 48 months, p = 0.178) status was not predictive of overall survival. HVEM was found to have a significant negative correlation with PD-L1 expression (r=-0.274, p < 0.001) in patients with NSCLC and also a weak negative correlation in NSCLC cell lines (r=-0.162, p = 0.352)., Conclusion: HVEM was found to be overexpressed in NSCLC patients of N2 lymph node metastasis or later stage and has a negative co-relationship with PD-L1 expression. HVEM was not prognostic for NSCLC patients., (Copyright © 2018. Published by Elsevier B.V.)

Background: Non-small-cell lung cancer (NSCLC) patients with both epidermal growth factor receptor (EGFR) positive mutation and B-cell chronic lymphocytic leukemia/lymphoma-like 11 (BIM) deletion polymorphism had a poor clinical response to EGFR-tyrosine kinase inhibitors (TKIs). The current study aimed to investigate the clinical efficacy and tolerability of EGFR-TKIs plus chemotherapy versus EGFR-TKIs alone as first-line treatment in advanced NSCLC patients with EGFR mutations and BIM deletion polymorphism., Methods: A retrospective, non-randomized analysis was conducted. BIM deletion polymorphism was detected using polymerase chain reaction (PCR) analysis and direct sequencing of DNA from peripheral blood cells. Clinical characteristics, overall survival (OS), progress-free-survival (PFS), objective response rate (ORR) and treatment-related adverse events were compared between EGFR-TKIs alone versus EGFR-TKIs plus chemotherapy group., Results: 65 patients were enrolled. 36 of them received EGFR-TKIs and 29 received EGFR-TKIs plus chemotherapy. EGFR-TKIs plus chemotherapy had significantly higher ORR than TKIs alone (65.5% vs. 38.9%, P = 0.046). Median PFS was significantly longer in EGFR-TKIs plus chemotherapy group than in TKIs group (7.2 vs 4.7 m; P = 0.008). Median OS was numerically longer in EGFR-TKIs plus chemotherapy group than in TKIs alone (18.5 vs 14.2 m; P = 0.107). EGFR-TKIs plus chemotherapy was associated with more grade 3 or 4 hematological toxic effects than EGFR-TKIs alone., Conclusion: EGFR-TKIs plus chemotherapy conferred a significantly higher ORR, prolonged PFS and numerically longer OS in advanced NSCLC patients with EGFR mutation and BIM deletion polymorphism. Further prospective studies are needed to validate these findings., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Immunotherapy is an exciting development in lung cancer research. In this study we described major histocompatibility complex (MHC) Class II protein expression in lung cancer cell lines and patient tissues., Methods: We studied MHC Class II (DP, DQ, DR) (CR3/43, Abcam) protein expression in 55 non-small cell lung cancer (NSCLC) cell lines, 42 small cell lung cancer (SCLC) cell lines and 278 lung cancer patient tissues by immunohistochemistry (IHC)., Results: Seven (12.7%) NSCLC cell lines were positive for MHC Class II. No SCLC cell lines were found to be MHC Class II positive. We assessed 139 lung cancer samples available in the Hirsch Lab for MHC Class II. There was no positive MHC Class II staining on SCLC tumor cells. MHC Class II expression on TILs in SCLC was significantly lower than that on TILs in NSCLC (P＜0.001). MHC Class II was also assessed in an additional 139 NSCLC tumor tissues from Medical University of Gdansk, Poland. Patients with positive staining of MHC Class II on TILs had longer regression-free survival (RFS) and overall survival (OS) than those whose TILs were MHC Class II negative (2.980 years, 95% CI 1.628-4.332 vs. 1.050 years, 95% CI 0.556-1.554, P=0.028) (3.230 years, 95% CI 2.617-3.843 vs. 1.390 years, 95% CI 0.629-2.151, P=0.014)., Conclusions: MHC Class II was expressed both in NSCLC cell lines and tissues. However, MHC Class II was not detected in SCLC cell lines or tissue tumor cells. MHC Class II expression was lower on SCLC TILs than on NSCLC TILs. Loss of expression of MHC Class II on SCLC tumor cells and reduced expression on SCLC TILs may be a means of escaping anti-cancer immunity. Higher MHC Class II expression on TILs was correlated with better prognosis in patients with NSCLC., (Copyright © 2017. Published by Elsevier B.V.)

Objectives: Immunotherapy that targets the programmed death-1/programmed death-ligand 1 (PD-L1) axis has been approved for treatment of non-small cell lung cancer (NSCLC) patients in many countries. However, our current understanding of the role of immunotherapies on NSCLC patients with epidermal growth factor receptor (EGFR) mutation, following acquisition of resistance to EGFR tyrosine kinase inhibitors (TKIs), is so far unclear. Especially, there is little data on if each acquired resistance mechanism to EGFR-TKIs alters PD-L1 expression status which is employed as an important predictive biomarker for PD-1/PD-L1 targeting agents., Materials and Methods: Lung cancer cell lines (HCC827, HCC4006, PC9, H1975, H358, SW900, and H647) and their daughter cells that acquired resistance to EGFR-TKIs or cytotoxic drugs (cisplatin or vinorelbine) were examined. PD-L1 expression was analyzed by immunohistochemistry, immunoblotting, and/or fluorescent imaging. Published microarray data were also employed to evaluate our findings., Results and Conclusion: We found correlations between therapy-induced E-cadherin downregulation and decreased PD-L1 expression using our cell lines and published microarray data. ShRNA mediated E-cadherin knockdown decreased PD-L1 expression in parental cells, and dual immunofluorescent staining of E-cadherin and PD-L1 suggests co-localization of both molecules. We also observed marked downregulation of PD-L1 in cells with E-cadherin downregulation after chronic treatment with vinorelbine. These results indicate a correlation between therapy-induced E-cadherin downregulation and decreased PD-L1 expression, highlighting the importance of re-biopsy after acquisition of resistance to EGFR-TKIs, not only for the evaluation of resistance mechanisms but also for the determination of PD-L1 expression status., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Objectives: Mutation in the PIK3CA gene is reported frequent in squamous cell carcinomas of the lung, but its potential prognostic role is still obscure. We have studied the prognostic importance of PIK3CA mutations as well as the relation to other markers in a large number of early stage lung cancers of squamous carcinoma subtype., Patients and Methods: Tumour tissue was obtained from 308 consecutively operated lung cancer patients with squamous cell carcinoma in the period 2003-2013. DNA was isolated according to standard procedures, and mutation analysis was done with either the SnapShot method and/or using PIK3CA specific primers in the Cobas system. PD-L1-expression was analysed with immunohistochemistry After thorough follow-up (median 67.6 months), overall survival and time to relapse was calculated., Results: Tumour tissue from 102 females and 206 males were analysed. 167 (54.2%) were in stage I, 96 (31.2%) in stage II and 45 (14.6%) in stage III. PIK3CA mutation was found in 35 (11.4%) patients, most frequently in exon 20. There were no differences in sex, stage or smoking behaviour between mutated and non-mutated cases. Patients with PIK3CA mutations had a significantly longer overall survival (p=0.042) and time to relapse (p=0.030) than non-mutated cases, and the difference in time to relapse was also retained in stage I-cases (p=0.044). PD-L1-expression was less frequent among mutated cases., Conclusion: Our results indicate that PIK3CA mutations may confer a survival advantage in early stage squamous cell lung cancers, but further work is needed to confirm this finding., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Objectives: Lung cancer accounts for a significant number of new cancer cases and deaths, with the majority of patients presenting with non-small cell lung cancer (NSCLC). Although epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors are recommended as an alternative to chemotherapy for certain patients, challenges exist for clinical utilization. The objective of this analysis was to assess the outcome and economic implications of a clinically validated serum-based proteomic test to guide treatment decisions in patients with advanced NSCLC, who are EGFR-negative or status unknown, and have progressed following at least one chemotherapy regimen., Methods: This analysis was conducted from a US payer perspective. Clinical outcomes were evaluated over the lifetime of a patient, based on data from randomized trials and clinical studies. The clinical endpoints included treatment utilization, adverse events, survival, and a composite measure of length and quality of life, referred to as the quality-adjusted life year (QALY). Costs for testing, treatment, surveillance, and management of adverse events were analyzed based on publicly available costs of the related procedures. The economic endpoints were cumulative lifetime direct medical costs and cost per QALY gained., Results: In the base case, treatment recommendation for 27.3% of the patient population changed from erlotinib to chemotherapy after using the proteomic test. Overall survival increased by 0.091 year and QALYs increased by 0.050 year. The total lifetime direct medical cost per patient decreased by $135 with test-guided treatment. The findings were robust over a wide range of variation in the input parameters., Conclusion: The serum-based proteomic test informed treatment selection for patients with advanced NSCLC who failed previous chemotherapy regimen(s), improving QALYs and saving costs., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Purpose: We investigated whether expression of epidermal growth factor receptor (EGFR) was associated with survival and disease control in this secondary analysis of a phase II trial of cetuximab+chemoradiation for stage III non-small cell lung cancer., Methods: Patients received cetuximab weekly before and during radiation (63 Gy/35 fractions/7 weeks) with weekly carboplatin + paclitaxel. We analyzed EGFR expression by immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) in pretreatment biopsy specimens and compared findings with overall and progression-free survival (OS, PFS) and time to progression (TTP)., Results: Specimens for IHC and FISH were collected from 51 and 45 of 87 evaluable patients. Pretreatment characteristics did not differ for patients with (n = 51) or without (n= 36) EGFR IHC data, or with (n = 45) or without (n = 42) FISH data. However, patients without IHC data had worse OS (HR = 1.63, P = 0.05), worse PFS (HR = 1.88, P = 0.008), and worse TTP [HR = 1.99, P = 0.01] than those with IHC data. EGFR protein expression was not related to pretreatment characteristics or OS; FISH-positive disease was associated with better performance status but not with OS, PFS, or TTP., Conclusions: Surprisingly, outcomes differed not by EGFR expression but by the availability of samples for analysis, underscoring the importance of obtaining biopsy samples in such trials., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Early stage radiographically occult lung cancer has a high cure rate, but comprises a small fraction of all lung cancer. Abnormal sputum cytology is one indication for bronchoscopy in patients with chest imaging that is not suspicious for lung cancer. While there is good evidence that sputum cytologic findings of carcinoma, carcinoma in situ or severe atypia predict high rates of diagnosis of lung cancer, less is known of the frequency in which lung cancer is diagnosed in bronchoscopies carried out for the indication of moderate sputum atypia. One small series, published in abstract form only, reported an 8% rate of diagnosis of lung cancer in subjects bronchoscoped for moderate atypia. We tested the hypothesis that moderate sputum atypia is an indicator of occult central airway cancer in a retrospective analysis of a group of high risk subjects, defined as current or former smokers with >30 pack-years tobacco smoking and airflow obstruction with moderate atypia sputum cytology. Seventy-nine such subjects with no evidence of malignancy on chest radiograph at the time bronchoscopy was scheduled underwent white light and autofluorescence bronchoscopy. Lung cancer was found in five subjects; three had invasive squamous cell carcinomas and two had carcinoma in situ. Seven additional subjects had severe dysplasia found on endobronchial biopsy. Moderate sputum atypia may be an important marker of risk for occult endobronchial malignancy in high risk subjects.

Recent exciting advances have been made in identifying potential molecular markers in sputum which may soon be ready for validation trials to indicate high risk for lung cancer, especially central airway squamous cell lung cancer. Hopefully, a set of biomarkers will be identified with higher sensitivity, specificity, and enough lead-time compared to traditional cytopathology to justify endobronchial evaluation and local therapy to help reduce lung-cancer mortality in high-risk patients.

The statistics on lung cancer form a powerful argument to develop new methods to control this most deadly form of cancer. Chemoprevention is one of these new approaches. Carcinogens from cigarette smoke form the link between nicotine addiction and lung cancer. At the same time it has become increasingly clear that dietary and genetically determined factors play an important role in modulating the individual susceptibility and are linked to the chemoprevention approach. In spite of many positive pre-clinical observations, most of the experiences with potential chemopreventive agents such as retinoids and antioxidants in individuals at risk for lung cancer have been negative so far. Moreover, beta-carotene was associated with an increased lung cancer incidence in two large randomized studies, most likely due to negative interaction with cigarette smoke. The recent progress in diagnostic techniques and molecular biology has led to a new paradigm for chemoprevention and there is considerable optimism regarding the potential of new molecules and antibodies that target specific cellular receptors or mutations. This article reviews the lung cancer chemoprevention efforts of the last two decades and also gives prospects for the next coming years.

Despite therapeutic improvements and ongoing efforts to develop more efficacious therapies, the majority of lung cancer patients face a poor prognosis. Therefore, the primary goal of current treatment is palliation, improvement and maintenance of quality of life (QOL), and (modest) prolongation of survival. Anemia frequently occurs in lung cancer patients and has been associated with decreased QOL, impaired treatment outcomes, and shortened survival time. Furthermore, anemia is a causative factor of tumor hypoxia, which compromises the efficacy of chemotherapy and radiotherapy. Thus, correction of even mild anemia seems to have a beneficial effect on QOL and cancer treatment outcomes. The current article describes the basis and mechanism for the use of recombinant human erythropoietin (rHuEPO, epoetin alfa), a molecular targeted therapy, for the treatment of cancer-related anemia, with a focus on lung cancer. Epoetin alfa has proven efficacy and safety in correcting anemia and improving QOL based on numerous clinical studies and over a decade of clinical practice. In addition, emerging data show that epoetin alfa may offer potential benefits beyond treating anemia, specifically in terms of treatment outcomes and cognitive function. Future research needs to be conducted to explore the potential for epoetin alfa to improve survival time in lung cancer patients.

Vast numbers of individuals who have stopped smoking have already been exposed to critical amounts of tobacco combustion products and are at significant risk of developing lung cancer. If these individuals are diagnosed with regional or distant metastatic disease this condition is not typically curable with existing systemic therapy. The need for more effective tools to detect and intervene with early lung cancer detection is a pressing public health priority. A major challenge in this regard is the development of safe and effective lung cancer chemoprevention. The factors influencing the development of this new clinical tool are reviewed in the context of existing trends for lung cancer care. Existing pharmaceutical efforts have involved evaluation of existing treatments for advanced cancer or other disorders in early lung cancer. The paper describes approaches to tailor chemoprevention development specifically to the biological, pharmacological and anatomical realities of this most lethal cancer.

The Erb-B family of receptors plays an important role in lung carcinogenesis and tumor development, and EGFR and HER2 are highly expressed in bronchial preneoplasia. In invasive tumors, EGFR are expressed in 50-90%, and mostly in squamous cell carcinomas, but also in adenocarcinomas and large cell carcinomas, while HER2 is less frequently expressed (20-30%) and mostly expressed in adenocarcinomas. Bronchioloalveolar cell carcinomas may present a distinct EGFR profile compared to the other NSCLCs and evidence and consequences are discussed. The genetic mechanisms responsible for overexpression of EGFR and HER2 proteins might be numerous, including gene dosage (overrepresentation or amplification) as well as translational and post-translational mechanisms. However, for EGFR and HER2 there is a positive correlation between gene copy numbers and level of protein expression demonstrated by fluorescence in situ hybridization analysis and immunochemistry. Gene amplification for EGFR and HER2 is demonstrated in only 5-10% of the tumors. The treatment status and therapeutic limitation with trastuzumab (Herceptin) in lung cancer compared to breast cancer is discussed.

Lung cancer is the most frequent cause of cancer deaths in the western world. Despite some improvements in treatment results, especially by the use of combined treatment modalities, the overall prognosis is still very poor, and less than 15% of the patients survive 5-year after primary diagnosis. Through rapid developments in biotechnology and increased knowledge about important signaling pathways leading to cell proliferation, apoptosis, angiogenesis and metastases, new treatment possibilities with specific targeted therapies have emerged for chemoprevention and treatment of lung cancer. Together with developments of new technology available for early diagnosis new paradigms for management of lung cancer are under development with great promises for improvement of the overall prognosis., (Copyright 2002 Elsevier Science Ireland Ltd.)

The stagnation of therapeutic results in lung cancer over the last decade(s) is a matter of great concern, also due to the constantly increasing incidence of the disease. Among the reasons for this failing therapeutic progress is the lack of understanding of the molecular mechanisms underlying the disease. Presently molecular biology techniques contribute to the deciphering of these mechanisms. This review article gives an overview of the actual situation. The genetic changes leading to malignancy are successively considered at the DNA, RNA and protein levels. Alterations at the DNA level represent the bulk of the available data, being related to p53 mutations, alterations in the beta-tubulin gene, microsatellite alterations, methods for identifying individual and isolated aberrant cells, identification of epigenetic mechanisms such as methylation of the promoter region of tumor suppressor genes; alterations in pre-neoplastic lesions are also evoked. In all cases, the techniques are described and results presented. RNA based methods are critically considered, and the yeast functional assay described. Protein based methods are also considered. The use of cDNA microarrays opens new perspectives and brings the simultaneous identification of numerous DNA alterations at a grip, with hopefully significant improvements in treatment results and increased efficiency for early detection and prevention., (Copyright 2002 Elsevier Science Ireland Ltd.)

The purpose of this document is to provide recommendations for the selection of the optimal target population for lung cancer screening trials with Spiral Computer Tomography based on an analysis of risk factors and high-risk populations. Our recommendations are to include current or ex-smokers (<5 years) with a smoking history of at least 30 years and an average consumption of at least 20 cigarettes a day. When these selection criteria are applied there is no need for a lower age cut-off. Elderly people can be included as long as their life expectancy is more than 10 years. Participants should be fit enough to undergo thoracic surgery. They may have a history of previous cancer, provided that the cancer has been curatively treated at least 5 years ago without evidence of relapse, except for breast cancer, melanoma and hypernephroma. People with an inability to lie flat, who are unable to hold their breath for 20 s, with a body weight above 140 kg, a chest CT scan within 1 year before enrolment or a previous pneumonectomy should not be invited. The inadequacy of the unit 'Pack-Years' (PY) to estimate the individual lung cancer risk is recognised, and future initiatives to develop an appropriate lung cancer risk model are encouraged.

Pulmonary neuroendocrine tumors are currently considered to consist of three grades of malignancy, ranging from typical and atypical carcinoids to large-cell neuroendocrine carcinoma and small-cell carcinoma. The study reported here is the first population-based study of the demographics of patients with neuroendocrine tumors grouped by histological subtype. A cancer registry-based analysis of patients in Denmark in whom bronchial neuroendocrine tumor was diagnosed in 1978-97 was performed and the patients were followed up to 31 December 1999. Typical carcinoid was diagnosed in 105 patients, atypical carcinoid in 192, large-cell neuroendocrine carcinoma in 50 and small-cell carcinoma in 11,998. The recorded incidence of neuroendocrine tumors other than small-cell carcinoma increased by twofold among men (from 0.24 to 0.53 per 100,000 inhabitants per year) and by threefold in women (from 0.14 to 0.41 per 100,000 inhabitants per year) during the study period, while the incidence of small-cell carcinoma decreased among men and levelled off among women. The prognosis of patients with bronchial neuroendocrine tumors varied with the degree of malignancy; the 5-year survival rate ranged from 87% for patients with typical carcinoids, to 44, 15 and 2% for patients with atypical carcinoids, large-cell neuroendocrine carcinoma and small-cell carcinoma, respectively. In Denmark, the incidence of neuroendocrine tumours is increasing. Our findings support the pathological categorization of neuroendocrine tumors into three grades of malignancy. More research is needed to establish the etiological factors in the development of pulmonary neuroendocrine tumors.

Background: Lung cancer is the most common cause of cancer deaths in the western world. Progress in treatment results has been limited, and the prognosis is poor with a 5-year survival less than 15%. Based on new developments in molecular biology, our knowledge about lung carcinogenesis and mechanisms for invasion and metastasis has expanded and may in the future lead to more specific targeted therapies and better prognosis. The E-cadherin-catenin complex is critical for intercellular adhesiveness and maintenance of normal and malignant tissue architecture. Reduced expression of this complex in malignant disease is associated with tumour invasion, metastasis, and unfavorable prognosis., Methods: This review is based on search in the Medline database from 1991 to 2001. We have reviewed the relevance of the E-cadherin-catenin adhesion complex in malignancy in general and lung cancer in particular. Furthermore, its role as target for specific therapy is discussed., Results: Available data indicate that alterations of proteins involved in the E-cadherin-catenin complex are early incidents in cancer development. Reduced or altered expression of one or more of the components in this complex is associated with extended invasive and progressive behavior of cancer cells. Consistently, the E-cadherin-catenin complex appears to be increasingly delicate with regard to cancer prognosis. beta-Catenin, one of the components of the adhesion complex, also plays a significant role in cell signal transduction, gene activation, apoptosis inhibition, and increased cellular proliferation and migration., Conclusion: Inactivation of the E-cadherin-catenin adhesion complex, induced by genetic and epigenetic events, plays a significant role in multistage carcinogenesis, and seems to be associated with dedifferentiation, local invasion, regional metastasis, and reduced survival in lung cancer.

This is a registry-based analysis of 97,281 lung cancer patients diagnosed in Denmark during the period 1943-1994. The development of lung cancer incidence in Denmark in the study period is described and this information is used to predict the future trends in lung cancer in Denmark. Since 1960, lung cancer has been the most frequent type of cancer in Danish men, excluding skin cancer. The incidence in men reached its maximum in 1985, when it was 100 new cases per 100,000 inhabitants, whereafter the incidence began to level off and was 83 per 100,000 inhabitants in 1994. During the study period, the incidence of lung cancer in Danish women was somewhat lower than in men. The incidence in women has been steadily increasing since 1960 by approximately 20% per each 5-year period, and was 46 per 100,000 inhabitants in 1994. Adenocarcinoma is the most frequent histological subtype in women and the only subtype increasing in incidence in men. Taking the actual development into account, the incidence of lung cancer will continue to fall among men and rise among women, leading to a reversal of the classical gender ratio in about 15 years.

During the past two decades many different treatment regimens of combination chemotherapy have been applied in extensive stage small-cell lung cancer (SCLC). This study was carried out to identify whether these modifications have resulted in an improved overall survival for extensive stage during the past two decades. In total, 1111 patients with extensive stage SCLC were included in six consecutive randomised trials in our setting from 1973 until 1992. Of these, 526 patients treated in the early period (1973-1981) were compared with 585 patients treated in the late period (1981-1992) with respect to pretreatment prognostic factors, staging, treatment and outcome. No change in the distribution of prognostic factors was detected and the frequency of patients with extensive stage was equal in the two periods, and no difference in overall response rates and survival was observed (P = 0.49). Median survival in the two periods was 208 days and 215 days, respectively. No stage migration or treatment-related improved outcome was observed in extensive disease. We suggest restricting aggressive treatment to patients with favorable prognosis and long-term survival as a realistic aim.

In a blinded cross-over design, we studied whether three pathologists were biased by clinical information when making histopathological diagnoses of adenocarcinoma of the lung and benign and malignant mesothelial tumours. Furthermore, the interobserver variation of these diagnoses was assessed. Forty-one cases of adenocarcinoma of the lung and mesothelial tumours were assessed by three pathologists in four rounds. In the first two rounds, slides stained by H&E and clinical information were available. Slides and information were matched so that a specific slide in one round was given clinical information suggesting adenocarcinoma and in the other round, the clinical information suggested mesothelial tumour. In the third and fourth rounds, a panel of immunohistochemical stains was added. The clinical information was matched in the same way as in the first and second rounds. Bias by clinical information was observed when the diagnoses were made on slides stained by H&E, while no bias could be demonstrated when immunohistochemical reactions were included. The reproducibility also improved significantly when these slides were available.