Lung Cancer
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Lung cancer is one of the most common types of cancer. The lungs are a pair of cone-shaped organs situated inside the chest, they bring oxygen into the body and take out waste carbon dioxide. There is a strong link between smoking and lung cancer. There are two main categories of lung cancer; Small Cell Lung Cancer (SCLC) , and Non-Small Cell Lung Cancer (NSCLC). World-wide over 1 million people are diagnosed with lung cancer each year.

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Information for Patients and the Public
Information for Health Professionals / Researchers
Latest Research Publications
Non-Small Cell Lung Cancer
Small Cell Lung Cancer
Risk Factors and Prevention of Lung Cancer

Information Patients and the Public (19 links)

Information for Health Professionals / Researchers (17 links)

Latest Research Publications

This list of publications is regularly updated (Source: PubMed).

Zhang J, Fujimoto J, Zhang J, et al.
Intratumor heterogeneity in localized lung adenocarcinomas delineated by multiregion sequencing.
Science. 2014; 346(6206):256-9 [PubMed] Related Publications
Cancers are composed of populations of cells with distinct molecular and phenotypic features, a phenomenon termed intratumor heterogeneity (ITH). ITH in lung cancers has not been well studied. We applied multiregion whole-exome sequencing (WES) on 11 localized lung adenocarcinomas. All tumors showed clear evidence of ITH. On average, 76% of all mutations and 20 out of 21 known cancer gene mutations were identified in all regions of individual tumors, which suggested that single-region sequencing may be adequate to identify the majority of known cancer gene mutations in localized lung adenocarcinomas. With a median follow-up of 21 months after surgery, three patients have relapsed, and all three patients had significantly larger fractions of subclonal mutations in their primary tumors than patients without relapse. These data indicate that a larger subclonal mutation fraction may be associated with increased likelihood of postsurgical relapse in patients with localized lung adenocarcinomas.

de Bruin EC, McGranahan N, Mitter R, et al.
Spatial and temporal diversity in genomic instability processes defines lung cancer evolution.
Science. 2014; 346(6206):251-6 [PubMed] Related Publications
Spatial and temporal dissection of the genomic changes occurring during the evolution of human non-small cell lung cancer (NSCLC) may help elucidate the basis for its dismal prognosis. We sequenced 25 spatially distinct regions from seven operable NSCLCs and found evidence of branched evolution, with driver mutations arising before and after subclonal diversification. There was pronounced intratumor heterogeneity in copy number alterations, translocations, and mutations associated with APOBEC cytidine deaminase activity. Despite maintained carcinogen exposure, tumors from smokers showed a relative decrease in smoking-related mutations over time, accompanied by an increase in APOBEC-associated mutations. In tumors from former smokers, genome-doubling occurred within a smoking-signature context before subclonal diversification, which suggested that a long period of tumor latency had preceded clinical detection. The regionally separated driver mutations, coupled with the relentless and heterogeneous nature of the genome instability processes, are likely to confound treatment success in NSCLC.

Related: Non-Small Cell Lung Cancer

Sun H, Gan ZC, Gao JJ, Zheng F
Non-invasive detection of EGFR deletion at exon 19 in non-small cell lung cancer by real time diagnostic.
Clin Lab. 2014; 60(9):1517-26 [PubMed] Related Publications
BACKGROUND: The non-invasive identification of epidermal growth factor receptor (EGFR) mutations is important for the institution of individualized therapy of non-small cell lung cancer (NSCLC). In this study, the feasibility of screening for EGFR exon 19 E746_A750del mutations in circulating DNA from plasma was assessed.
METHODS: Mutant-specific primers with a Taqman probe (MST-PCR) were designed. The ability of this method to accurately detect decreasing concentrations of E746_A750del mutant within a wild type DNA background that mimics the situation of a plasma sample from patients with acquired mutations is verified. To verify the clinical applicability of this method, 55 plasma samples from NSCLC patients were tested, and the sensitivity of MST-PCR was compared to that of direct sequencing.
RESULTS: The results showed that MST-PCR could detect 10 to 50 copies/microL of E746_A750del, representing 0.1% of the wild type EGFR allelic population. Among the 55 cases of NSCLC, 10 cases of E746_A750del were detected by MST-PCR, while only 1 case was revealed by direct sequencing.
CONCLUSIONS: These findings demonstrate that MST-PCR provides superior sensitivity for the detection of the E746_A750del mutation, suggesting its potential application in the noninvasive detection of E746_A750del mutations in plasma samples from NSCLC patients.

Related: Non-Small Cell Lung Cancer EGFR

Pan JB, Hou YH, Zhang GJ
Correlation between efficacy of the EGFR tyrosine kinase inhibitor and serum tumor markers in lung adenocarcinoma patients.
Clin Lab. 2014; 60(9):1439-47 [PubMed] Related Publications
BACKGROUND: The mutation at epidermal growth factor receptor (EGFR) is a clinical predictor of EGFR tyrosine kinase inhibitors (TKI) in patients with non-small cell lung cancer (NSCLC). The serum carcinoembryonic antigen (CEA) level was regarded as a predictive factor for the EGFR-TKI efficacy. Are there any other serum markers? This study analysed the correlation between the EGFR-TKI treatment effect and multiple serum tumor markers only in lung adenocarcinoma to find serum predictive markers for the EGFR-TKI efficacy.
METHODS: Clinical features, survival time, and serum tumor marker levels before EGFR-TKI treatment were analysed, retrospectively, in 48 advanced lung adenocarcinoma patients treated with EGFR-TKI.
RESULTS: With EGFR-TKI treatment, the response rate was 58.3% and disease control rate was 65.6% in lung adenocarcinoma; median survival time was 13.2 months. The efficiency of EGFR-TKI significantly correlated with smoking history and the serum level of CEA and CA199 (p < 0.05). Patients with a higher level of serum CEA and CA199 had a higher disease control rate and longer survival time (p < 0.05).
CONCLUSIONS: Serum CA199 and CEA levels can predict the response of EGFR-TKI in lung adenocarcinoma patients.

Related: EGFR

Deppen SA, Blume JD, Kensinger CD, et al.
Accuracy of FDG-PET to diagnose lung cancer in areas with infectious lung disease: a meta-analysis.
JAMA. 2014; 312(12):1227-36 [PubMed] Related Publications
IMPORTANCE: Positron emission tomography (PET) combined with fludeoxyglucose F 18 (FDG) is recommended for the noninvasive diagnosis of pulmonary nodules suspicious for lung cancer. In populations with endemic infectious lung disease, FDG-PET may not accurately identify malignant lesions.
OBJECTIVES: To estimate the diagnostic accuracy of FDG-PET for pulmonary nodules suspicious for lung cancer in regions where infectious lung disease is endemic and compare the test accuracy in regions where infectious lung disease is rare.
DATA SOURCES AND STUDY SELECTION: Databases of MEDLINE, EMBASE, and the Web of Science were searched from October 1, 2000, through April 28, 2014. Articles reporting information sufficient to calculate sensitivity and specificity of FDG-PET to diagnose lung cancer were included. Only studies that enrolled more than 10 participants with benign and malignant lesions were included. Database searches yielded 1923 articles, of which 257 were assessed for eligibility. Seventy studies were included in the analysis. Studies reported on a total of 8511 nodules; 5105 (60%) were malignant.
DATA EXTRACTION AND SYNTHESIS: Abstracts meeting eligibility criteria were collected by a research librarian and reviewed by 2 independent reviewers. Hierarchical summary receiver operating characteristic curves were constructed. A random-effects logistic regression model was used to summarize and assess the effect of endemic infectious lung disease on test performance.
MAIN OUTCOME AND MEASURES: The sensitivity and specificity for FDG-PET test performance.
RESULTS: Heterogeneity for sensitivity (I2 = 87%) and specificity (I2 = 82%) was observed across studies. The pooled (unadjusted) sensitivity was 89% (95% CI, 86%-91%) and specificity was 75% (95% CI, 71%-79%). There was a 16% lower average adjusted specificity in regions with endemic infectious lung disease (61% [95% CI, 49%-72%]) compared with nonendemic regions (77% [95% CI, 73%-80%]). Lower specificity was observed when the analysis was limited to rigorously conducted and well-controlled studies. In general, sensitivity did not change appreciably by endemic infection status, even after adjusting for relevant factors.
CONCLUSIONS AND RELEVANCE: The accuracy of FDG-PET for diagnosing lung nodules was extremely heterogeneous. Use of FDG-PET combined with computed tomography was less specific in diagnosing malignancy in populations with endemic infectious lung disease compared with nonendemic regions. These data do not support the use of FDG-PET to diagnose lung cancer in endemic regions unless an institution achieves test performance accuracy similar to that found in nonendemic regions.

Grant WB
Solar ultraviolet irradiance and cancer incidence and mortality.
Adv Exp Med Biol. 2014; 810:52-68 [PubMed] Related Publications
The solar ultraviolet-B (UVB)/vitamin D/cancer hypothesis was proposed by the brothers Cedric and Frank Garland in 1980. In 2002, the list was increased to 15 types of cancer using data in the 1999 version of the atlas of cancer mortality rates in the United States. Ecological studies of cancer incidence and/or mortality rates with respect to indices of solar UVB doses have also been reported for Australia, China, France, Japan, and Spain with largely similar findings. In addition, several studies using nonmelanoma skin cancer as the index of solar UVB dose have found reduced internal cancer incidence and/or mortality rates, especially in sunny countries. A study of cancer incidence with respect to 54 categories of occupation in five Nordic countries, using lip cancer less lung cancer as the UVB index, found this index inversely correlated with 14 types of internal cancers for males and four for females. Observational studies with respect to UVB doses and serum 25-hydroxyvitamin D [25(OH)D] concentrations also support the hypothesis. Hill's criteria for causality in a biological system to assess whether solar UVB and vitamin D can be considered causal in reducing risk of cancer. The primary criteria for this analysis include strength of association, consistent findings in different populations, biological gradient, plausibility (e.g., mechanisms), and experimental verification (e.g., randomized controlled trials). The totality of evidence is judged to satisfy the criteria very well for breast and colorectal cancer, and moderately well for several other types of cancer.

Related: Breast Cancer Colorectal (Bowel) Cancer Skin Cancer

Sugarbaker DJ, Richards WG, Bueno R
Extrapleural pneumonectomy in the treatment of epithelioid malignant pleural mesothelioma: novel prognostic implications of combined N1 and N2 nodal involvement based on experience in 529 patients.
Ann Surg. 2014; 260(4):577-80; discussion 580-2 [PubMed] Related Publications
OBJECTIVE: We review our 24-year experience with extrapleural pneumonectomy (EPP) in the treatment of epithelioid malignant pleural mesothelioma (MPM).
BACKGROUND: Recent publications, particularly the MARS (Mesothelioma and Radical Surgery) feasibility study by Treasure et al, have questioned the safety and efficacy of EPP for MPM.
METHODS: An institutional review board-approved, prospective, single-center database was retrospectively reviewed. Descriptive statistics and Kaplan-Meier analysis of overall survival are reported.
RESULTS: From 1988 to 2011, a total of 529 patients with epithelioid MPM underwent complete resection by EPP as part of a multimodality strategy. Among these, 131 (25%) were women, and the median age was 59 (range, 17-79) years. Median postoperative hospital stay was 10 (range, 1-101) days. Twenty-six patients (5%) experienced 30-day or in-hospital mortality. Median overall survival was 18 months, with 1-, 3-, 5-, and 10-year survival rates of 67%, 28%, 14%, and 4%, respectively. Outcome by pathologic lymph node status (N, median overall survival) was N0: 224, 26 months; N1: 118, 17 months; N2: 181, 13 months; N3: 5, 7 months; Nx: 1, not evaluable.
CONCLUSIONS: EPP has evolved as an effective method for macroscopic complete resection. This study confirms that lymph node status is significantly correlated with overall survival in patients with epithelioid MPM undergoing EPP and suggests that those with simultaneous involvement of N1 and N2 stations are at increased risk. This observation underscores the need for thorough staging of both N1 and N2 stations and has implications for revision of MPM staging criteria.

Related: Mesothelioma

Wong J, Xu B, Yeung HN, et al.
Age disparity in palliative radiation therapy among patients with advanced cancer.
Int J Radiat Oncol Biol Phys. 2014; 90(1):224-30 [PubMed] Article available free on PMC after 01/09/2015 Related Publications
PURPOSE/OBJECTIVE: Palliative radiation therapy represents an important treatment option among patients with advanced cancer, although research shows decreased use among older patients. This study evaluated age-related patterns of palliative radiation use among an elderly Medicare population.
METHODS AND MATERIALS: We identified 63,221 patients with metastatic lung, breast, prostate, or colorectal cancer diagnosed between 2000 and 2007 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. Receipt of palliative radiation therapy was extracted from Medicare claims. Multivariate Poisson regression analysis determined residual age-related disparity in the receipt of palliative radiation therapy after controlling for confounding covariates including age-related differences in patient and demographic covariates, length of life, and patient preferences for aggressive cancer therapy.
RESULTS: The use of radiation decreased steadily with increasing patient age. Forty-two percent of patients aged 66 to 69 received palliative radiation therapy. Rates of palliative radiation decreased to 38%, 32%, 24%, and 14% among patients aged 70 to 74, 75 to 79, 80 to 84, and over 85, respectively. Multivariate analysis found that confounding covariates attenuated these findings, although the decreased relative rate of palliative radiation therapy among the elderly remained clinically and statistically significant. On multivariate analysis, compared to patients 66 to 69 years old, those aged 70 to 74, 75 to 79, 80 to 84, and over 85 had a 7%, 15%, 25%, and 44% decreased rate of receiving palliative radiation, respectively (all P<.0001).
CONCLUSIONS: Age disparity with palliative radiation therapy exists among older cancer patients. Further research should strive to identify barriers to palliative radiation among the elderly, and extra effort should be made to give older patients the opportunity to receive this quality of life-enhancing treatment at the end of life.

Related: Breast Cancer Colorectal (Bowel) Cancer Prostate Cancer USA

Noyes AM, Lonial K, Siegel RD
Tumor lysis syndrome in a nonsmall cell lung cancer.
Conn Med. 2014; 78(7):421-3 [PubMed] Related Publications
Tumor lysis syndrome (TLS) is an oncologic emergency caused by intense tumor cell destruction resulting in profound electrolyte abnormalities. It is generally recognized as a consequence of cytotoxic therapy in particularly chemotherapy-sensitive tumors such as hematologic cancers. Despite having been primarily recognized in hematologic malignancies, TLS has been reported in solid tumors as well. We present a case of a 72-year-old female who developed TLS after receiving etoposide and carboplatin for a poorly-differentiated carcinoma with areas of small-cell differentiation metastatic to her liver. She had previously undergone a thoracotomy and resection for a poorly differentiated squamous cell cancer of the lung.

Related: Carboplatin Non-Small Cell Lung Cancer Etoposide

Jethava A, Codreanu I, Thayer J, et al.
Operated bronchial carcinoids: clinical outcomes and long-term follow-up of a single institution series of 30 patients.
Conn Med. 2014; 78(7):409-15 [PubMed] Related Publications
BACKGROUND: Bronchial carcinoids (BCs) are infrequent neoplasms that account for only 1% to 2% of all lung tumors. We reviewed the outcomes and long-term follow-up data of all patients diagnosed with BC and treated surgically at our institution between the years 2002-2009.
PATIENTS AND METHODS: We analyzed the records of all patients with BC treated between January 1, 2002 and December 31st, 2009. The results were subsequently compared with the previously published data.
RESULTS: Our records identified a total of 28 patients with typical carcinoids (TC) and two patients with atypical carcinoids (AC). Of these, 22 were women and eight were men with a median age of 62 (range, 23-91 years). About two-thirds of patients were symptomatic at presentation. Central and peripheral tumor location was encountered with equal frequency, with 63.3% of tumors being located in the right lung. Bronchoscopic biopsy revealed the diagnosis in 92.3% of cases. Twenty percent of patients underwent lung sparing procedures, 73.3% underwent lobectomies, and 6.7% had pneumonectomies. Mediastinal lymphadenectomy was performed in all patients. Two patients had positive nodal metastases, one of whom survived for only 10 months. Tumor recurrence was noted in two patients with TC (7.14%) and in one patient with AC. The overall five-year survival was 90% (27/30) for the entire cohort.
CONCLUSIONS: Histological characteristics and nodal status probably represent the most important prognostic factors in persons with operated BCs. The female prevalence recorded in our cohort appears to contrast with previously reported almost equal gender distribution. The slightly lower percentage of lung-sparing procedures in our patients could be explained by their more advanced disease state, with tumor extension to more than one lung lobe.

Related: Gastrointestinal Carcinoid Tumours

Dhaou BB, Boussema F, Aydi Z, et al.
Renal paraneoplastic vasculitis complicating lung adenocarcinoma.
Saudi J Kidney Dis Transpl. 2014; 25(5):1065-7 [PubMed] Related Publications
Renal paraneoplastic vasculitis (RNPV) is rare. It can be revealed by glomerulonephritis, microaneurysms or renal failure. RPNV may precede the onset of the primary tumor, and treatment and prognosis depend on the etiology (primary tumor). A 54-year-old man who had a primary lung adenocarcinoma was admitted for nephrotic syndrome. The investigations revealed RNPV. The patient was treated with corticosteroids at high dose and cyclophosphamide with improvement of the renal condition; however, the patient died from worsening of his pulmonary neoplasia.

Hanaoka J, Kawaguchi Y, Hashimoto M, et al.
Superior sulcus tumor resection with multiple pulmonary arteriovenous fistulas.
Ann Thorac Surg. 2014; 98(3):e67-8 [PubMed] Related Publications
The authors present a case of a 66-year-old male presenting with a superior sulcus tumor and severe hypoxemia due to bilateral multiple pulmonary arteriovenous fistulas. The unilateral pulmonary arterial occlusion test was useful before surgery because it enabled evaluation of the feasibility and safety of intraoperative pulmonary artery clamp and one-lung ventilation during lung resection. Results facilitated safe resection of the superior sulcus tumor using the modified transmanubrial osteomuscular sparing approach, providing an excellent surgical field.

Hata A, Sekine Y, Koh E, Hiroshima K
Operative wound implantation of inflammatory sarcomatoid carcinoma of the lung.
Ann Thorac Surg. 2014; 98(3):1111-3 [PubMed] Related Publications
We describe a patient with iatrogenic chest wall implantation of inflammatory sarcomatoid carcinoma. A 43-year-old man underwent right partial lung resection for hemopneumothorax, with large bullae and an alveolar accumulation of histiocytes found on pathology. Three months later, a subcutaneous tumor appeared at a thoracoscopic port site. Needle aspiration of this tumor suggested a malignant neoplasm; therefore, a right upper lobectomy and chest wall resection were performed, and a pathologic diagnosis of sarcomatoid carcinoma was made. Pathologic reexamination of the original sample suggested that the tumor has been implanted in the patient's chest wall at the time of the first operation.

Lovly CM, McDonald NT, Chen H, et al.
Rationale for co-targeting IGF-1R and ALK in ALK fusion-positive lung cancer.
Nat Med. 2014; 20(9):1027-34 [PubMed] Article available free on PMC after 01/03/2015 Related Publications
Crizotinib, a selective tyrosine kinase inhibitor (TKI), shows marked activity in patients whose lung cancers harbor fusions in the gene encoding anaplastic lymphoma receptor tyrosine kinase (ALK), but its efficacy is limited by variable primary responses and acquired resistance. In work arising from the clinical observation of a patient with ALK fusion-positive lung cancer who had an exceptional response to an insulin-like growth factor 1 receptor (IGF-1R)-specific antibody, we define a therapeutic synergism between ALK and IGF-1R inhibitors. Similar to IGF-1R, ALK fusion proteins bind to the adaptor insulin receptor substrate 1 (IRS-1), and IRS-1 knockdown enhances the antitumor effects of ALK inhibitors. In models of ALK TKI resistance, the IGF-1R pathway is activated, and combined ALK and IGF-1R inhibition improves therapeutic efficacy. Consistent with this finding, the levels of IGF-1R and IRS-1 are increased in biopsy samples from patients progressing on crizotinib monotherapy. Collectively these data support a role for the IGF-1R-IRS-1 pathway in both ALK TKI-sensitive and ALK TKI-resistant states and provide a biological rationale for further clinical development of dual ALK and IGF-1R inhibitors.

Related: IGF1R Crizotinib (Xalkori)

Zhao Q, Cao Y, Wang Y, et al.
Plasma and tissue free amino acid profiles and their concentration correlation in patients with lung cancer.
Asia Pac J Clin Nutr. 2014; 23(3):429-36 [PubMed] Related Publications
Variation of plasma free amino acids (PFAAs) is an essential feature of protein metabolic abnormalities in cancer patients. But there still little data about the cancer tissue free amino acid (TFAAs) profiles, including their patterns and correlations with PFAAs. To evaluate the variation in PFAAs and cancer TFAAs in patients with lung cancer, including their patterns and correlations, we investigated the concentrations of free amino acids in lung cancer tissues (n=27), paired lung paracarcinomous tissues (n=27) and plasma (n=27) using an automatic amino acid analyzer after pre-treatment. Within the PFAAs, the concentrations of five amino acids (tryptophan, glycine, citrulline, ornithine and proline) were significantly decreased, while that of phenylalanine was markedly increased compared with control subjects. Within the TFAAs, the concentrations of three amino acids (taurine, glutamic acid and glycine) were increased, while the concentrations of two amino acids (lysine and ornithine) were decreased significantly in lung cancer tissues compared with the paracarcinomous tissues. The amino acid patterns in PFAAs and TFAAs had similar trends, but percentage variations were diverse. Additionally, the concentrations of five amino acids (lysine, phenylalanine, threonine, serine, and alanine) in PFAAs correlated with those in lung cancer TFAAs, but no amino acids in PFAAs were correlated with those in lung paracarcinomous TFAAs. Thus, PFAA profiles may reflect the status of cancer tissues, which may provide more information about the metabolic statuses and prognoses of patients with lung cancer.

Alerić I, Mosler D, Seiwerth S, et al.
Pulmonary tumorlets with surrounding fibrous tissue--suspected carcinoma: case report and review of the literature.
Acta Clin Croat. 2014; 53(2):226-32 [PubMed] Related Publications
Pulmonary tumorlets are small, often multiple nodular proliferations of pulmonary neuroendocrine cells. They are common incidental findings in chronic inflammatory pulmonary diseases. They can also be found in normal lung parenchyma and as one part of the continuum known as diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. In many cases, they are incidental histologic findings of no importance or clinical consequences, or they can be associated with a very slow progression of either obstructive or mixed obstructive/restrictive impairment with good prognosis. Only rarely, they metastasize to an adjacent lymph node or produce ectopic neuroendocrine products. When found during diagnostic examination, they represent a doubt to be a malignant tumor until proven otherwise, which is often impossible without biopsy or surgical removal of the adjacent lung lobe. Hereby, we present a patient with a persistent nodular lung structure after being treated for nonspecific symptoms, cough with non purulent sputum and pain among the scapulae, for a period of one month. He had otherwise normal clinical and laboratory findings, except for a mild mixed obstructive/restrictive pattern of impairment that was shown by lung spirometry. After 8 months, he underwent lobectomy of the medial lobe of the lung with partial lymphadenectomy, since the diagnostic methods applied could not define the nature of lung nodular infiltration. Histologic examination showed a few tumorlets surrounded by the fibrous tissue with a very dense lymphocyte infiltration. We present a review of the literature and emphasize the necessity to include tumorlets with adjacent fibrosis as part of the differential diagnosis of a solitary nodular lung structure.

Related: Gastrointestinal Carcinoid Tumours

Shimoda M, Principe S, Jackson HW, et al.
Loss of the Timp gene family is sufficient for the acquisition of the CAF-like cell state.
Nat Cell Biol. 2014; 16(9):889-901 [PubMed] Related Publications
Cancer-associated fibroblasts (CAFs) drive tumour progression, but the emergence of this cell state is poorly understood. A broad spectrum of metalloproteinases, controlled by the Timp gene family, influence the tumour microenvironment in human cancers. Here, we generate quadruple TIMP knockout (TIMPless) fibroblasts to unleash metalloproteinase activity within the tumour-stromal compartment and show that complete Timp loss is sufficient for the acquisition of hallmark CAF functions. Exosomes produced by TIMPless fibroblasts induce cancer cell motility and cancer stem cell markers. The proteome of these exosomes is enriched in extracellular matrix proteins and the metalloproteinase ADAM10. Exosomal ADAM10 increases aldehyde dehydrogenase expression in breast cancer cells through Notch receptor activation and enhances motility through the GTPase RhoA. Moreover, ADAM10 knockdown in TIMPless fibroblasts abrogates their CAF function. Importantly, human CAFs secrete ADAM10-rich exosomes that promote cell motility and activate RhoA and Notch signalling in cancer cells. Thus, Timps suppress cancer stroma where activated-fibroblast-secreted exosomes impact tumour progression.

Related: Signal Transduction

Milicić V, Prvulović I, Misić M, et al.
Value of cytology in small cell lung carcinoma diagnostic--single-center study.
Coll Antropol. 2014; 38(2):611-6 [PubMed] Related Publications
Small cell carcinoma of the lung (SCLC) together with the large cell neuroendocrine carcinoma (LCNEC), typical carcinoid (TC), and atypical carcinoid (AC) make a group of morphologically identifiable neuroendocrine tumors. The differential diagnosis of SCLC includes, first of all, other neuroendocrine tumors, and primary or metastatic non-small cell carcinomas. Although the criteria for the morphologic separation from other tumors of the lung are defined, in everyday practice it can be a problem, both in cytology and with histological samples. Accurate and early differentiation of the SCLC is important because it exhibits aggressive behavior, rapid growth, early spread to distant sites, but also exquisite sensitivity to chemotherapy and radiation. The study included 127 patients who underwent bronchoscopic examination or percutaneous transthoracic fine-needle aspiration (PTTFNA) during the period from early 2003 to 2007 in University Hospital Center Osijek whose cytological diagnosis was SCLC. The value of cytological diagnosis was determined by comparing it with histological findings obtained from a biopsy sample during bronchoscopy or on a resection specimen in 50 patients. In the remaining 77 patients, histological verification of cytological diagnosis was not made and the patients were treated based on cytological diagnosis of small cell carcinoma. In 76% of cases (38/50) cytological diagnosis of small cell lung carcinoma was also confirmed histologically. In 8% of cases (4/50) adenocarcinoma was histologically confirmed, in 10% (5/50) of the cases the squamous carcinoma was confirmed, and there was one case of urothelial carcinoma, one case of sarcoma and one undifferentiated carcinoma. Cytological diagnosis of SCLC was made in all cases in a brush smear while the catheter aspirate was positive in only 32 cases (25.8%). Median survival in the group of patients with histologically confirmed small cell cancer was 238 days, for women 250 days, and for men 237 days. Cumulative survival was 63.2% for 6 months, 26.3% for 12 months, 13.2% for 18 months and 7.9% for two years. In conclusion, cytology is a reliable and relatively non-invasive method for patients. Our results confirm that there is a good correlation between cytology and histology diagnoses, especially when it comes to malignant lesions. In determining the type of tumor cytology must be supported with additional methods, especially in cases when it is not possible to take samples for histological verification.

Chang JY, Kestin LL, Barriger RB, et al.
ACR Appropriateness Criteria® nonsurgical treatment for locally advanced non-small-cell lung cancer: good performance status/definitive intent.
Oncology (Williston Park). 2014; 28(8):706-10, 712, 714 passim [PubMed] Related Publications
Concurrent chemotherapy/radiotherapy has been considered the standard treatment for patients with a good performance status and inoperable stage III non-small-cell lung cancer (NSCLC). Three-dimensional chemoradiation therapy and intensity-modulated radiation therapy have been reported to reduce toxicity and allow a dose escalation to 70 Gy and beyond. However, the Radiation Therapy Oncology Group 0617 trial recently showed that dose escalation from 60 Gy to 74 Gy with concurrent chemotherapy in stage III NSCLC was associated with higher toxicity and worse survival. A "one size fits all" treatment approach may need to be changed and adapted to each patient's particular disease and unique biologic/anatomic features, as well as the most appropriate radiotherapy modalities for that patient. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.

Related: Non-Small Cell Lung Cancer

Vijayvergia N, Mehra R
Clinical challenges in targeting anaplastic lymphoma kinase in advanced non-small cell lung cancer.
Cancer Chemother Pharmacol. 2014; 74(3):437-46 [PubMed] Related Publications
The revolution in individualized therapy for patients with advanced non-small cell lung cancer (NSCLC) has seen the emergence of a number of molecularly targeted therapies for distinct patient molecular subgroups. Activating anaplastic lymphoma kinase (ALK)-gene rearrangement has been detected in 3-7 % of NSCLC cases, and the ALK inhibitor crizotinib is now an approved treatment for patients with tumors harboring this event. However, resistance to ALK-targeted therapies is a ubiquitous problem in the management of advanced ALK-positive NSCLC and can be mediated by secondary kinase mutations or the activation of compensatory alternative oncogenic drivers. New, more potent ALK inhibitors such as ceritinib (LDK378), alectinib (CH5424802), and AP26113 are now emerging, together with an increased knowledge of the molecular basis of resistance. There is a need to evaluate the optimal clinical application of these new agents, either as sequential therapies or in combination with other targeted agents, to combat resistance and prolong survival in patients with ALK-positive NSCLC. The remarkable clinical activity of ALK inhibitors also emphasizes the importance of optimal diagnostic testing algorithms, to ensure that all eligible patients receive these breakthrough therapies.

Related: Non-Small Cell Lung Cancer Crizotinib (Xalkori)

Moghadamtousi SZ, Kadir HA, Paydar M, et al.
Annona muricata leaves induced apoptosis in A549 cells through mitochondrial-mediated pathway and involvement of NF-κB.
BMC Complement Altern Med. 2014; 14:299 [PubMed] Related Publications
BACKGROUND: Annona muricata leaves have been reported to have antiproliferative effects against various cancer cell lines. However, the detailed mechanism has yet to be defined. The current study was designed to evaluate the molecular mechanisms of A. muricata leaves ethyl acetate extract (AMEAE) against lung cancer A549 cells.
METHODS: The effect of AMEAE on cell proliferation of different cell lines was analyzed by MTT assay. High content screening (HCS) was applied to investigate the suppression of NF-κB translocation, cell membrane permeability, mitochondrial membrane potential (MMP) and cytochrome c translocation from mitochondria to cytosol. Reactive oxygen species (ROS) formation, lactate dehydrogenase (LDH) release and activation of caspase-3/7, -8 and -9 were measured while treatment. The western blot analysis also carried out to determine the protein expression of cleaved caspase-3 and -9. Flow cytometry analysis was used to determine the cell cycle distribution and phosphatidylserine externalization. Quantitative PCR analysis was performed to measure the gene expression of Bax and Bcl-2 proteins.
RESULTS: Cell viability analysis revealed the selective cytotoxic effect of AMEAE towards lung cancer cells, A549, with an IC50 value of 5.09 ± 0.41 μg/mL after 72 h of treatment. Significant LDH leakage and phosphatidylserine externalization were observed in AMEAE treated cells by fluorescence analysis. Treatment of A549 cells with AMEAE significantly elevated ROS formation, followed by attenuation of MMP via upregulation of Bax and downregulation of Bcl-2, accompanied by cytochrome c release to the cytosol. The incubation of A549 cells with superoxide dismutase and catalase significantly attenuated the cytotoxicity caused by AMEAE, indicating that intracellular ROS plays a pivotal role in cell death. The released cytochrome c triggered the activation of caspase-9 followed by caspase-3. In addition, AMEAE-induced apoptosis was accompanied by cell cycle arrest at G0/G1 phase. Moreover, AMEAE suppressed the induced translocation of NF-κB from cytoplasm to nucleus.
CONCLUSIONS: Our data showed for the first time that the ethyl acetate extract of Annona muricata inhibited the proliferation of A549 cells, leading to cell cycle arrest and programmed cell death through activation of the mitochondrial-mediated signaling pathway with the involvement of the NF-kB signalling pathway.

Related: Apoptosis Mitochondrial Mutations in Cancer Signal Transduction

Zhang C, Schmidt LA, Hatanaka K, et al.
Evaluation of napsin A, TTF-1, p63, p40, and CK5/6 immunohistochemical stains in pulmonary neuroendocrine tumors.
Am J Clin Pathol. 2014; 142(3):320-4 [PubMed] Related Publications
OBJECTIVE: A panel of immunohistochemical (IHC) stains frequently used to subclassify non-small cell lung cancers (NSCLCs) includes napsin A, TTF-1, CK5/6, p40, and p63. The expression profiles of these stains in neuroendocrine tumors have not been systematically evaluated.
METHOD: Sixty-eight resected pulmonary neuroendocrine tumors, including 52 typical carcinoids (TCs), eight atypical carcinoids (ACs), seven small cell carcinomas (SCLCs) and one large cell neuroendocrine carcinoma (LCNEC), were stained for napsin A, TTF-1, p63, p40, and CK5/6. Tumors were scored as positive (>1% tumor cells reactive) or negative, and percentage of reactive tumor cells was recorded.
RESULTS: Napsin A, p63, p40, and CK5/6 were consistently negative in neuroendocrine tumors. TTF-1 was positive in 17 of 52 TCs, 4 of 8 ACs, 5 of 7 SCLCs, and 0 of 1 LCNECs.
CONCLUSION: Pulmonary neuroendocrine tumors have a distinct but nonspecific profile on IHC panel commonly applied to subclassify NSCLCs. They are napsin A-/p40-/p63-/CK5/6-/TTF-1±. Recognizing this profile may have value in separating neuroendocrine tumors from NSCLCs.

Lewis DR, Check DP, Caporaso NE, et al.
US lung cancer trends by histologic type.
Cancer. 2014; 120(18):2883-92 [PubMed] Article available free on PMC after 15/09/2015 Related Publications
BACKGROUND: Lung cancer incidence rates overall are declining in the United States. This study investigated the trends by histologic type and demographic characteristics.
METHODS: Surveillance, Epidemiology, and End Results (SEER) program rates of microscopically confirmed lung cancer overall and squamous cell, small cell, adenocarcinoma, large cell, other, and unspecified carcinomas among US whites and blacks diagnosed from 1977 to 2010 and white non-Hispanics, Asian/Pacific Islanders, and white Hispanics diagnosed from 1992 to 2010 were analyzed by sex and age.
RESULTS: Squamous and small cell carcinoma rates declined since the 1990s, although less rapidly among females than males. Adenocarcinoma rates decreased among males and only through 2005, after which they then rose during 2006 to 2010 among every racial/ethnic/sex group; rates for unspecified type declined. Male/female rate ratios declined among whites and blacks more than among other groups. Recent rates among young females were higher than among males for adenocarcinoma among all racial/ethnic groups and for other specified carcinomas among whites.
CONCLUSIONS: US lung cancer trends vary by sex, histologic type, racial/ethnic group, and age, reflecting historical cigarette smoking rates, duration, cessation, cigarette composition, and exposure to other carcinogens. Substantial excesses among males have diminished and higher rates of adenocarcinoma among young females have emerged as rates among males declined more rapidly. The recognition of EGFR mutation and ALK rearrangements that occur primarily in adenocarcinomas are the primary basis for the molecular revolution that has transformed lung cancer diagnosis and treatment over the past decade, and these changes have affected recent type-specific trends.

Related: USA

Parums DV
Current status of targeted therapy in non-small cell lung cancer.
Drugs Today (Barc). 2014; 50(7):503-25 [PubMed] Related Publications
Tumor tissue biomarkers are the basis for targeted therapy in non-small cell lung cancer (NSCLC). These biomarkers either reflect the target of the specific drug or some factor that might abrogate the effect of the drug. These targeted drugs are small-molecule inhibitors of a specific tyrosine kinase or a monoclonal antibody against a specific receptor. In this review, tissue biomarkers in NSCLC and companion diagnostics will be described, followed by an overview of targeted therapy to EGF/EGFR, HER2, VEGF/VEGFR, ALK, KRAS, BRAF, MEK and MET and some of the newer potential targets. Recent initiatives include the Lung Cancer Matrix Network, the BATTLE trials and the Lung Cancer Mutation Consortium. There are a number of key clinical trials in targeted therapy in NSCLC which will be reporting during the next year.

Related: Non-Small Cell Lung Cancer

Landi L, Cappuzzo F
Ceritinib for the treatment of non-small cell lung cancer.
Drugs Today (Barc). 2014; 50(7):465-73 [PubMed] Related Publications
Non-small cell lung cancer (NSCLC) represents the paradigm of personalized treatment in human cancer. Several oncogenic alterations with druggable potential have been identified, with ALK rearrangements representing one of the newest and most appealing. Crizotinib is now recognized as the standard of care in chemotherapy-pretreated ALK-positive NSCLC due to the positive results of a recently published trial. Unfortunately, no patient exposed to crizotinib can be cured, and after a median time of 1 year, resistance inevitably occurs. Overcoming resistance is the major challenge in clinical oncology and many molecules are currently under evaluation, including ceritinib (LDK-378). Ceritinib is an oral, potent, second-generation ALK inhibitor recently approved by the U.S. Food and Drug Administration. Preclinical data showed impressive antitumor activity against crizotinib-resistant clones, and based on available data, ceritinib could represent a suitable option in crizotinib-resistant NSCLC.

Related: Non-Small Cell Lung Cancer

D'Amato C, Rosa R, Marciano R, et al.
Inhibition of Hedgehog signalling by NVP-LDE225 (Erismodegib) interferes with growth and invasion of human renal cell carcinoma cells.
Br J Cancer. 2014; 111(6):1168-79 [PubMed] Related Publications
BACKGROUND: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth.
METHODS: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC.
RESULTS: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays.
CONCLUSIONS: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.

Related: Kidney Cancer AKT1 Signal Transduction GLI Sunitinib (Sutent) Everolimus (Afinitor)

Ural K, Jakob K, Lato S, et al.
Spinal cord ischemia resulting in paraplegia following extrapleural pneumonectomy.
Chest. 2014; 146(2):e38-40 [PubMed] Related Publications
A patient undergoing radical extrapleural pneumonectomy for epithelioid malignant mesothelioma developed acute paraplegia postoperatively related to long-segment spinal cord ischemia. The usual area of concern for this complication is the T9 to T12 area where the artery of Adamkiewicz is most likely to originate. In this patient, there was ligation of only upper thoracic, ipsilateral segmental arteries from the T3 to T6 level, yet he still developed paraplegia. Our hypothesis is variant mid-thoracic vascular anatomy. Previously unreported, to our knowledge, this should be understood as a rare complication of this surgery.

Related: Mesothelioma

Huang J, Logue AE, Ostroff JS, et al.
Comprehensive long-term care of patients with lung cancer: development of a novel thoracic survivorship program.
Ann Thorac Surg. 2014; 98(3):955-61 [PubMed] Related Publications
BACKGROUND: Recent advances have improved the likelihood of long-term survival for patients with lung cancer. However, little attention has been given to the growing need for dedicated survivorship care for these patients. To address this unmet need, we developed a unique follow-up care model.
METHODS: In 2006, we convened a multidisciplinary working group to design a thoracic survivorship program (TSP) that provides follow-up by a nurse practitioner (NP) trained in survivorship care. Patients with early-stage lung cancer who were disease free for at least 1 year after resection were eligible for the program, which incorporates a standardized approach to cancer surveillance. Data on symptoms and outcomes were prospectively collected. Real-time electronic medical documentation was developed to optimize communication with primary physicians.
RESULTS: Data were analyzed for the initial phase of the program, which comprised 655 patients. Ninety-two percent of eligible survivors who remained disease free chose to continue their care in the TSP, rather than receive follow-up with their thoracic surgeon. Clinically significant posttreatment symptoms were common, including fatigue (46%), anxiety (32%), chronic pain (25%), dyspnea (14%), and depression (12%). The majority of recurrences (72%) and second primary cancers (91%) in this cohort were identified by scheduled chest computed tomography at TSP visits.
CONCLUSIONS: Survivorship care for patients with lung cancer, delivered in our NP-led TSP, is feasible, effective, and well accepted by patients. Through the implementation of a uniform self-sustaining patient-centered system, the TSP model improves on the variation of physician-led follow-up care.

Jungraithmayr W, Delaloye-Frischknecht B, Weder W
Anthracotic intrapulmonal lymph nodes mimicking lung metastases.
Ann Thorac Surg. 2014; 98(2):704-6 [PubMed] Related Publications
Intrapulmonal round lesions show characteristic radiologic features that distinguish them from other lung pathologies. Typically, they display a sharp margin with a homogenous inner pattern. Differential diagnosis includes metastases, particularly if the patient has a history of malignancy. However, benign lesions, although less common, should also be considered. We here present the case of a 58-year-old man with a history of bladder and prostate carcinoma, showing multiple typical round lesions on chest computed tomography, mimicking metastatic disease to the lung. Subsequently, wedge-resected specimens revealed anthracotic lymph nodes, so that intrapulmonal lymph nodes should be anticipated even in patients with preceding malignant disease.

Jhuang JY, Chou YH, Hua SF, Hsieh MS
Mixed lung mucoepidermoid carcinoma and adenocarcinoma with identical mutations in an epidermal growth factor receptor gene.
Ann Thorac Surg. 2014; 98(2):695-7 [PubMed] Related Publications
Lung cancers presenting two different histologic types are relatively rare. This paper presents a case report of mixed lung cancer comprising mucoepidermoid carcinoma and conventional adenocarcinoma, a combination that has not been reported previously. These two carcinomas showed distinct morphologic and immunohistochemical features. However, gene analysis revealed identical mutations in each component, which indicates they possess a monoclonal origin. Specifically, we identified the same mutation in exon 19 of the epidermal growth factor receptor gene. Molecular analysis further substantiated a monoclonal origin with divergent differentiation, as opposed to the collision of discrete tumors.

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