Disparity in age at lung cancer diagnosis between current and former smokers.

PURPOSE: In a previous study of smoking cessation in veterans with lung cancer, we noted as an incidental finding that current smokers were much younger than former smokers at diagnosis. To confirm and extend this observation, we analyzed the association of smoking status with age at diagnosis and survival of lung cancer patients. METHODS: The Jefferson Cancer Registry collects information on all cancer patients registered at this hospital. Information on smoking status has been recorded since 1995. We determined age at diagnosis and survival of current and former smokers with lung cancer. RESULTS: 5111 lung cancer cases were identified in the registry from 1995 to 2011 inclusive. Smoking status was recorded in 4687 cases (91.7%). Of these, 1859 (39.7%) were current, 2423 (51.7%) were former, and 405 (8.6%) were never smokers. There was a 6-year difference in median age at lung cancer diagnosis between the current (63 years) and former smokers (69 years) (P < 0.0001). The median survival was 12.1 months for current versus 14.5 months for former smokers (P < 0.0001). CONCLUSIONS: These results confirm and extend our observation that among patients diagnosed with lung cancer, current smokers are younger than former smokers. The possible explanations include higher competing causes of death and increased risk of lung cancer among current smokers as well as increasing proportions of former smokers in older populations. Ongoing exposure to tobacco carcinogens may accelerate the development of lung cancer in continuing smokers. This provides more incentive for smokers to quit at the earliest age possible.

The Role of Telemedicine in Providing Thoracic Oncology Care to Remote Areas of British Columbia.

PURPOSE OF REVIEW: The purpose of this study is to review the role of telemedicine in providing oncology care; we describe our long-standing, high-volume telemedicine experience. RECENT FINDINGS: The Interior Health Thoracic Surgical Group (IHTSG) uses telemedicine, through Virtual Thoracic Surgical Clinics (VTSC), to provide service to remote patients. The IHTSG serves a population of 1.01 million people over an area of 807,538 km2 (1.3 persons/km2) in the Interior and North of British Columbia, Canada. Between 2003 and 2015, the IHTSG conducted 15,073 telemedicine patient encounters at 63 geographic sites. Telemedicine saved these patients a total travel distance of 11.5 million km-an average of 766 km per patient. VTSC supports and strengthens the Hub and Spoke model of healthcare delivery-patients residing remotely can easily access centrally delivered service. Telemedicine makes specialized care available to all patients by overcoming a major impediment to access, namely distance.

Mitochondrial Metabolism as a Treatment Target in Anaplastic Thyroid Cancer.

Anaplastic thyroid cancer (ATC) is one of the most aggressive human cancers. Key signal transduction pathways that regulate mitochondrial metabolism are frequently altered in ATC. Our goal was to determine the mitochondrial metabolic phenotype of ATC by studying markers of mitochondrial metabolism, specifically monocarboxylate transporter 1 (MCT1) and translocase of the outer mitochondrial membrane member 20 (TOMM20). Staining patterns of MCT1 and TOMM20 in 35 human thyroid samples (15 ATC, 12 papillary thyroid cancer [PTC], and eight non-cancerous thyroid) and nine ATC mouse orthotopic xenografts were assessed by visual and Aperio digital scoring. Staining patterns of areas involved with cancer versus areas with no evidence of cancer were evaluated independently where available. MCT1 is highly expressed in human anaplastic thyroid cancer when compared to both non-cancerous thyroid tissues and papillary thyroid cancers (P<.001 for both). TOMM20 is also highly expressed in both ATC and PTC compared to non-cancerous thyroid tissue (P<.01 for both). High MCT1 and TOMM20 expression is also found in ATC mouse xenograft tumors compared to non-cancerous thyroid tissue (P<.001). These xenograft tumors have high (13)C- pyruvate uptake. ATC has metabolic features that distinguish it from PTC and non-cancerous thyroid tissue, including high expression of MCT1 and TOMM20. PTC has low expression of MCT1 and non-cancerous thyroid tissue has low expression of both MCT1 and TOMM20. This work suggests that MCT1 blockade may specifically target ATC cells presenting an opportunity for a new drug target.

Modeling the overall survival of patients with advanced-stage non-small cell lung cancer using data of routine laboratory tests.

Cancer patients undergo routine clinical monitoring with an array of blood tests that may carry long-term prognostic information. We aimed to develop a new prognostic model predicting survival for patients with advanced non-small cell lung cancer (NSCLC), based on laboratory tests commonly performed in clinical practice. A cohort of 1,161 stage IIIB or IV NSCLC patients was divided into training (n = 773) and testing (n = 388) cohorts. We analyzed the associations of 32 commonly tested laboratory variables with patient survival in the training cohort. We developed a model based on those significant laboratory variables, together with important clinical variables. The model was then evaluated in the testing cohort. Five variables, including albumin, total protein, alkaline phosphatase, blood urea nitrogen and international normalized ratio, were significantly associated with patient survival after stepwise selection. A model incorporating these variables classified patients into low-, medium- and high-risk groups with median survival of 16.9, 7.2 and 2.1 months, respectively (p < 0.0001). Compared with low-risk group, patients in the medium- and high-risk groups had a significantly higher risk of death at 1 year, with hazard ratio (HR) of 1.95 (95% CI 1.62-2.36) and 5.22 (4.30-6.34), respectively. These results were validated in the testing cohort. Overall, we developed a prognostic model relying entirely on readily available variables, with similar predictive power to those which depend on more specialized and expensive molecular assays. Further study is necessary to validate and further refine this model, and compare its performance to models based on more specialized and expensive testing.

Current management of locally advanced head and neck cancer: the combination of chemotherapy with locoregional treatments.

This review will discuss the evolution of the role of chemotherapy in the treatment of locally advanced head and neck cancer (HNC), over the last few decades. Studies were identified by searching PubMed electronic databases. Surgery followed by radiotherapy (RT) or definitive RT are potentially curative approaches for locally advanced HNC. While chemotherapy itself is not curative, it can improve cure rates when given as an adjunct to RT. The benefit of combining chemotherapy with RT is related to the timing of the chemotherapy. Several prospective randomized trials have demonstrated that concurrent delivery of chemotherapy and RT (CRT) is the most promising approach, given that locoregional recurrence is the leading pattern of failure for patients with locally advanced HNC. Induction chemotherapy before CRT has not been shown to be superior to CRT alone and the added toxicity may negatively impact the compliance with CRT. Sequential chemotherapy administration, in the form of induction chemotherapy followed by RT or CRT, has been successful as a strategy for organ preservation in patients with potentially resectable laryngeal and hypopharyngeal cancer. Systemic chemotherapy delivered concurrently with RT is used as a standard treatment for locally advanced HNC.

Treatment-related acute esophagitis for patients with locoregionally advanced non-small cell lung cancer treated with involved-field radiotherapy and concurrent chemotherapy.

PURPOSE: To explore the incidence and risk factors for treatment-related acute esophagitis associated with involved-field radiation therapy (RT) delivered concurrently with chemotherapy for patients with locoregionally advanced non-small cell lung cancer. MATERIALS AND METHODS: Forty-nine consecutive patients diagnosed with locoregionally advanced non-small cell lung cancer were treated using involved-field RT. Radiotherapy target volumes included the primary lung tumor and involved mediastinal lymphadenopathy as defined on imaging studies including computed tomography of the chest and fluorodeoxyglucose-positron emission tomography/computed tomography. The patients were treated to a median total dose of 63 Gy (range, 55.8 to 74 Gy) using daily fractions of 1.8 or 2.0 Gy. No elective radiotherapy of mediastinal lymph nodes was used. Concurrent platinum-based chemotherapy was delivered to all patients. Treatment-related toxicity was evaluated during the course of RT and subsequent follow-up visits. RESULTS: Thirty-one (63%) patients were female and 18 (37%) were male. Median age at the time of diagnosis was 68 years (range, 36 to 83 y). Thirty-one patients (63%) developed treatment-related acute esophagitis: 24 patients (49%) grade 2 and 7 (14%) patients grade 3 esophagitis, with the peak occurring during the seventh week of radiotherapy. No grade ≥ 4 esophagitis was seen in this cohort. Eighteen patients (37%) did not develop radiation-induced esophagitis associated with their course of chemoradiotherapy. In the univariate analysis, age at the time of diagnosis, radiation dose per fraction, and total volume of the esophagus were significantly associated with the risk of acute esophagitis. Increasing age reduced the risk of acute esophagitis (odds ratio [OR] for 10-y increase = 0.40) as did increasing total esophagus volume (OR for 10-U increase = 0.27). Dose per fraction of 1.8 Gy was associated with lower risk of acute esophagitis when compared with dose per fraction of 2 Gy (OR = 0.19). Marginal associations were observed for all of the volume variables. Higher volume variable values had a nonsignificant association with an increase in risk of acute esophagitis. However, only the total volume of the esophagus (P = 0.0032) and larger dose per fraction (2 vs. 1.8 Gy) (P = 0.011) remained significantly associated with higher risk of developing grade ≥ 2 acute esophagitis in the multivariate analysis. CONCLUSIONS: Higher risk of grade ≥ 2 treatment-related esophagitis was associated with lower total esophageal volume and higher radiotherapy dose per fraction and should be taken into consideration during patient treatment planning. Inclusion of total esophageal volume and dose per fraction into future clinical protocols may further help our understanding of treatment-related esophagitis and enable the development of novel preventative approaches.

Acute activation, desensitization and smoldering activation of human acetylcholine receptors.

The behavioral effects of nicotine and other nicotinic agonists are mediated by AChRs in the brain. The relative contribution of acute activation versus chronic desensitization of AChRs is unknown. Sustained "smoldering activation" occurs over a range of agonist concentrations at which activated and desensitized AChRs are present in equilibrium. We used a fluorescent dye sensitive to changes in membrane potential to examine the effects of acute activation and chronic desensitization by nicotinic AChR agonists on cell lines expressing human α4ß2, α3ß4 and α7 AChRs. We examined the effects of acute and prolonged application of nicotine and the partial agonists varenicline, cytisine and sazetidine-A on these AChRs. The range of concentrations over which nicotine causes smoldering activation of α4ß2 AChRs was centered at 0.13 µM, a level found in smokers. However, nicotine produced smoldering activation of α3ß4 and α7 AChRs at concentrations well above levels found in smokers. The α4ß2 expressing cell line contains a mixture of two stoichiometries, namely (α4ß2)2ß2 and (α4ß2)2α4. The (α4ß2)2ß2 stoichiometry is more sensitive to activation by nicotine. Sazetidine-A activates and desensitizes only this stoichiometry. Varenicline, cytisine and sazetidine-A were partial agonists on this mixture of α4ß2 AChRs, but full agonists on α3ß4 and α7 AChRs. It has been reported that cytisine and varenicline are most efficacious on the (α4ß2)2α4 stoichiometry. In this study, we distinguish the dual effects of activation and desensitization of AChRs by these nicotinic agonists and define the range of concentrations over which smoldering activation can be sustained.

Identification of a KRAS mutation in a patient with non-small cell lung cancer treated with chemoradiotherapy and panitumumab.

RTOG 0839 is a Phase II study of pre-operative chemoradiotherapy with or without panitumumab in potentially operable locally advanced non-small cell lung cancer (NSCLC). The investigational agent, panitumumab, is an anti-epithelial growth factor receptor (EGFR) antibody that improves progression-free survival in chemorefractory metastatic colorectal cancer (mCRC). Recently, both KRAS mutational status (i.e., mutated or not) and subtype (i.e., activating or inactivating) have been shown to be predictive of response to anti-EGFR therapy in mCRC. However, in NSCLC, it is unknown if KRAS mutational status or subtype predict benefit to anti-EGFR therapies because of unique genetic and epigenetic factors unique to each cancer. We present a patient with stage III NSCLC containing a KRAS G12D activating mutation who had a partial pathologic response, with disappearance of a minor KRAS mutant clone. This case suggests possible eradication of the G12D KRAS lung cancer clones by concurrent chemoradiation with panitumumab.

Choline transporter-like protein 4 (CTL4) links to non-neuronal acetylcholine synthesis.

Synthesis of acetylcholine (ACh) by non-neuronal cells is now well established and plays diverse physiologic roles. In neurons, the Na(+) -dependent, high affinity choline transporter (CHT1) is absolutely required for ACh synthesis. In contrast, some non-neuronal cells synthesize ACh in the absence of CHT1 indicating a fundamental difference in ACh synthesis compared to neurons. The aim of this study was to identify choline transporters, other than CHT1, that play a role in non-neuronal ACh synthesis. ACh synthesis was studied in lung and colon cancer cell lines focusing on the choline transporter-like proteins, a five gene family choline-transporter like protein (CTL)1-5. Supporting a role for CTLs in choline transport in lung cancer cells, choline transport was Na(+) -independent and CTL1-5 were expressed in all cells examined. CTL1, 2, and 5 were expressed at highest levels and knockdown of CTL1, 2, and 5 decreased choline transport in H82 lung cancer cells. Knockdowns of CTL1, 2, 3, and 5 had no effect on ACh synthesis in H82 cells. In contrast, knockdown of CTL4 significantly decreased ACh secretion by both lung and colon cancer cells. Conversely, increasing expression of CTL4 increased ACh secretion. These results indicate that CTL4 mediates ACh synthesis in non-neuronal cell lines and presents a mechanism to target non-neuronal ACh synthesis without affecting neuronal ACh synthesis.

Spontaneous smoking cessation before lung cancer diagnosis.

INTRODUCTION: We have observed that many patients with lung cancer stop smoking before diagnosis, usually before clinical symptoms, and often without difficulty. This led us to speculate that spontaneous smoking cessation may be a presenting symptom of lung cancer. METHODS: Patients from the Philadelphia Veterans Affairs Medical Center with lung cancer and for comparison, prostate cancer and myocardial infarction underwent a structured interview about their smoking habits preceding diagnosis. Severity of nicotine addiction was graded using the Fagerström Test for Nicotine Dependence. Among former smokers, dates of cessation, onset of symptoms, and diagnosis were recorded. Difficulty quitting was rated on a scale of 0 to 10. Distributions of intervals from cessation to diagnosis were compared between groups. RESULTS: All 115 patients with lung cancer had been smokers. Fifty-five (48%) quit before diagnosis, and only six of these (11%) were symptomatic at quitting. Patients with lung cancer who quit were as dependent on nicotine, when smoking the most, as those who continued to smoke, unlike the other groups. Despite this, 31% quit with no difficulty. The median interval from cessation to diagnosis was 2.7 years for lung cancer, 24.3 years for prostate cancer, and 10.0 years for patients with myocardial infarction. CONCLUSIONS: These results challenge the notion that patients with lung cancer usually quit smoking because of disease symptoms. The hypothesis that spontaneous smoking cessation may be a presenting symptom of lung cancer warrants further investigation.

The HDAC inhibitor panobinostat (LBH589) inhibits mesothelioma and lung cancer cells in vitro and in vivo with particular efficacy for small cell lung cancer.

Lung cancer is the leading cause of cancer deaths in the United States. Current therapies are inadequate. Histone deacetylase inhibitors (HDACi) are a recently developed class of anticancer agents that cause increased acetylation of core histones and nonhistone proteins leading to modulation of gene expression and protein activity involved in cancer cell growth and survival pathways. We examined the efficacy of the HDACi panobinostat (LBH589) in a wide range of lung cancers and mesotheliomas. Panobinostat was cytotoxic in almost all 37 cancer cell lines tested. IC(50) and LD(50) values were in the low nmol/L range (4-470 nmol/L; median, 20 nmol/L). Small cell lung cancer (SCLC) cell lines were among the most sensitive lines, with LD(50) values consistently <25 nmol/L. In lung cancer and mesothelioma animal models, panobinostat significantly decreased tumor growth by an average of 62% when compared with vehicle control. Panobinostat was equally effective in immunocompetent and severe combined immunodeficiency mice, indicating that the inhibition of tumor growth by panobinostat was not due to direct immunologic effects. Panobinostat was, however, particularly effective in SCLC xenografts, and the addition of the chemotherapy agent etoposide augmented antitumor effects. Protein analysis of treated tumor biopsies revealed elevated amounts of cell cycle regulators such as p21 and proapoptosis factors, such as caspase 3 and 7 and cleaved poly[ADP-ribose] polymerase, coupled with decreased levels of antiapoptotic factors such as Bcl-2 and Bcl-X(L). These studies together suggest that panobinostat may be a useful adjunct in the treatment of thoracic malignancies, especially SCLC.

A population-based study of lung carcinoma in Pennsylvania: comparison of Veterans Administration and civilian populations.

BACKGROUND: Lung carcinoma remains the major cause of cancer death in North America and is even more common among military veterans. The objective of this study was to determine whether there were differences in the characteristics and survival of Pennsylvania patients with lung carcinoma in the Veterans Administration (VA) hospital system compared with patients in the rest of the state. METHODS: The Pennsylvania Cancer Registry was used to identify all patients who were diagnosed with lung carcinoma in the State of Pennsylvania from 1995 to 1999. Patients who were treated within the Veterans Administration Health Care Network were identified by hospital code. Survival from the date of diagnosis of lung carcinoma was determined by using the Pennsylvania state mortality files from 1995 to 2001. RESULTS: From 1995 to 1999, 48,994 patients were newly diagnosed with lung carcinoma in Pennsylvania (41.2% women), including 856 patients in the VA system (6 women). The current analysis was restricted to male patients (n = 28,798 men). There was no major difference in age of VA patients compared with non-VA patients, and the proportions of patients who had localized or regional stage disease were similar (49% of VA patients vs. 48% of non-VA patients). The proportion of black patients was much higher in the VA population (23%) compared with the non-VA population (9%). The median survival was 6.3 months for VA patients compared with 7.9 months for patients in the rest of the state, and the 5-year overall survival rate was 12% for VA patients compared with 15% for patients in the rest of the state. When survival was analyzed according to race, there was a significant difference in the age-adjusted survival of white patients in the VA system compared with patients in the rest of the state (P = 0.0007), but no significant difference was observed among black patients (P = 0.92). CONCLUSIONS: The overall survival of VA patients with lung carcinoma in Pennsylvania was inferior to that of patients in the remainder of the state and this was due primarily to differences in survival among the white patients. Further investigation will be necessary to determine whether this disparity was caused by differences in socioeconomic status or comorbidities or whether there are systematic differences in the diagnosis, staging, or treatment of lung carcinoma between VA patients and civilian patients.

Clinical implication of p53 mutation in lung cancer.

Lung cancer development involves multiple genetic abnormalities leading to malignant transformation of the bronchial epithelial cells, followed by invasion and metastasis. One of the most common changes is mutation of the p53 tumor suppressor gene. The frequency of p53 alterations in lung cancer is highest in small cell and squamous cell carcinomas. A genetic "signature" of the type of p53 mutations has been associated with carcinogens in cigarette smoke. The majority of clinical studies suggest that lung cancers with p53 alterations carry a worse prognosis, and may be relatively more resistant to chemotherapy and radiation. An understanding of the role of p53 in human lung cancer may lead to more rational targeted approaches for treating this disease. P53 gene replacement is currently under clinical investigation but clearly more effective means of gene deliver to the tumor cells are required. Novel approaches to lung cancer therapy are needed to improve the observed poor patient survival despite current therapies.

Clinical implications of p53 mutations in lung cancer.

The process of bronchial carcinogenesis is characterized by accumulated genetic abnormalities which ultimately lead to malignant transformation of bronchial epithelial cells, followed by invasion and metastasis. One of the most common and consistent of these genetic lesions is inactivation of the p53 tumor suppressor gene by mutation or deletion. The frequency of p53 alterations in lung cancer is highest in those subtypes of bronchial carcinomas that are most consistently associated with smoking, especially SCLC and squamous cell carcinomas. The frequency is lower in adenocarcinomas, in which the association with smoking, although present, is not as strong. The frequency of p53 abnormalities is higher in patients with greater cumulative tobacco exposure. Tobacco-specific carcinogens, in particular BPDE, cause a unique spectrum of p53 mutations, quite distinct from those found in cancers that are not associated with smoking. This characteristic genetic "signature" may persist even decades following smoking cessation. The prognostic significance of p53 mutations in lung cancer is not entirely clear despite the multitude of clinical studies that have been carried out. Nevertheless, the majority of clinical studies suggest that lung cancers with p53 alterations carry a worse prognosis. Furthermore, those tumors with mutant p53 may be relatively more resistant to chemotherapy and radiation. An understanding of the role of p53 in human lung cancer may lead to more rational targeted approaches for treating this disease. For example, the observation that the introduction of wild-type p53 into lung cancer cells with mutant or deleted p53 may reverse the malignant phenotype despite the presence of multiple other genetic abnormalities (14) suggests that replacement of this gene may be an effective clinical strategy. Preclinical and early clinical studies indicate that this is a promising approach, but clearly more effective means of gene delivery to the tumor cells are required (127-129), as discussed elsewhere in this volume.

Constitutive activation of met kinase in non-small-cell lung carcinomas correlates with anchorage-independent cell survival.

Lung cancer is currently the most frequent cause of cancer death in North America. Hepatocyte growth factor (HGF) and its receptor Met are frequently over-expressed in non-small-cell lung carcinomas (NSCLC), but their potential role in tumor progression is not clearly known. To assess the role of HGF/Met signaling in lung carcinomas, we have examined the expression, activation status, and function of Met in NSCLC cell lines (n = 7), established from primary tumors or pleural fluids of cancer patients. We observed Met expression in three NSCLC cell lines, two of which exhibited constitutive tyrosine-phosphorylation of Met, and Met kinase activity. In addition, the observed constitutive activation of Met was sustained under anchorage-independent conditions, and correlated with phosphatidyl inositol 3-kinase-dependent cell survival. Immunoreactive HGF-like protein was secreted by two Met-positive and two Met-negative NSCLC cell lines. However HGF activity, as determined by the ability to induce cell scattering and tyrosine-phosphorylation of Met in reporter cell lines, was detected in conditioned medium from only one Met-negative NSCLC cell line: none of the conditioned media from Met-expressing NSCLC cell lines showed detectable HGF activity. Thus, constitutive activation of Met in NSCLC cell lines may occur at least in part through intracrine, or HGF-independent mechanisms. Interestingly, additional paracrine stimulation with exogenous recombinant HGF was required for DNA synthesis and correlated with increased activation of ERK1/2 in all Met-positive NSCLC cell lines, regardless of the basal activation status of Met. These findings indicate that a medium level of constitutive activation of Met occurs in some NSCLC cell lines, and correlates with survival of detached carcinoma cells; whereas additional paracrine stimulation by recombinant HGF is required for DNA synthesis. Thus constitutive and paracrine activation of Met may provide complementary signals that promote survival and proliferation, respectively, during tumor progression of NSCLC.

Clinical and molecular features of small cell lung cancer.

Small cell lung cancer is a common malignancy found in smokers. It has a poor long-term prognosis despite initial sensitivity to chemotherapy and radiation. The clinical features of small cell lung cancer are unique among lung cancers and other neuroendocrine tumors. In order to better understand the pathogenesis of small cell lung cancer, there has been a great effort to identify the genetic alterations involved in the development and progression of the disease, and to translate these to novel molecular strategies for treatment.