Non small Cell Lung Cancer

Introduction: The objective of this study was to identify and characterize echinoderm microtubule-associated protein-like 4 anaplastic lymphoma kinase fusion (EML4-ALK+) cancers by variant-specific, quantitative reverse transcription polymerase chain reaction (RT-PCR) assays in a large cohort of North American non-small-cell lung cancer (NSCLC) patients. Methods: We developed a panel of single and multiplex RT-PCR assays suitable for rapid and accurate detection of the eight most common EML4-ALK+ variants and ALK gene expression in archival formalin-fixed, paraffin-embedded NSCLC specimens. EGFR and KRAS genotyping and thymidylate synthase RNA level by RT-PCR assays were available in a subset of patients. Results: Between December 2009 and September 2012, 7344 NSCLC specimens were tested. An EML4-ALK+ transcript was detected in 200 cases (2.7%), including 109 V1 (54.5%), 20 V2 (10.0%), 68 V3 (34.0%), and three V5a (1.5%) variants. Median age was 54.5 years (range, 23-89), and 104 patients (52.0%) were women. The great majority (n=188, 94.0%) of EML4-ALK+ NSCLC tumors had adenocarcinoma histology. ALK expression level varied significantly among different EML4-ALK+ variants and individual tumors. Only one case each of concurrent EGFR or KRAS mutation was detected. The median thymidylate synthase RNA level from 85 EML4-ALK+ cancers was significantly lower compared with that of EML4-ALK-negative lung adenocarcinomas (2.02 versus 3.29, respectively, p<0.001). Conclusions: This panel of variant-specific, quantitative RT-PCR assays detects common EML4-ALK+ variants as well as ALK gene expression level in archival formalin-fixed paraffin-embedded NSCLC specimens. These RT-PCR assays may be useful as an adjunct to the standard fluorescence in situ hybridization assay to better understand biologic variability and response patterns to anaplastic lymphoma kinase inhibitors.

Lung cancer contributes a great percentage to the number of cancer-related deaths globally, which mandates science to find ways to improve its approaches to lung cancer diagnosis and treatment. Artificial Intelligence (AI) has emerged in recent times as one of the best solutions to lung cancer diagnosis and treatment. In this essay, attention will be paid to the current roles AIs are performing in lung cancer detection and treatment. Huge successes have been recorded in the use of radiomics, deep learning, and machine learning in lung cancer screening, diagnosis, and treatment. AI has assisted healthcare professionals to better characterize cancer cells and enable them to make better choices regarding treatment procedures. AI has contributed tremendously to the improvement in imaging modalities, including PET-CT imaging, Chest radiography, low-dose CT scans, etc. It also enables healthcare professionals to detect tumor markers and biomarkers in affected patients for a better treatment procedure. However, there is room for improvement. Further studies into the field of AI in lung cancer treatment can help reduce morbidity, mortality, and other potential outcomes.

The ability of monoclonal antibody (mAb) alR-3 to interact with non-small cell lung cancer (NSCLC) cells was investigated. MAb alR-3 inhibited specific binding of 1251-IGF-I and 1251-alR-3 to a panel of 8 NSCLC cell lines with high affinity (IC50 = 200 and 50 ng/ml, respectively). 1251-alR-3 bound with high affinity (Kd = 40 ng/ml) to a single class of sites (Bmax = 8,00O/cell) using NCLH838 cells. 1251-alR-3 was internalized when exposed to N O H 8 3 8 or H I 2 9 9 cells at 37°C but not 4°C. alR-3 irnmunoprecipitated major 9 0 and 130 kD proteins. IGF-I stimulated and alR-3 inhibited the clonal growth of NCI-HI299 cells. aIR-3 slowed the growth of NCI-HI57 and H838 xenografts in nude mice. In a biodistribution study 1251-alR-3 was preferentially localized to the tumor as opposed to other organs. These data suggest that IGF-I may be a regulatory agent in NSCLC.

Previously, GRP receptors were characterized in small cell lung cancer cells and here non-small cell lung cancer (NSCLC) cells were investigated: (1251-Tyr4) bombesin (BN) or lZ51-GRP bound with high affinity to NCLH720 (lung carcinoid) and NCI-HI 299 (large cell carcinoma) cells. Binding was specific, time dependent, and saturable. Specific (1251-Tyr4)BN binding to NCI-HI299 cells was inhibited with high affinity by GRP, BN, CRP'"27, (D-Phe6)BNG13methyl ester, moderate affinity by NMB, and low affinity by GRP1-I6. BN (10 nM) transiently elevated cytosolic calcium in a dose dependent manner. BN caused translocation of protein kinase C from the cytosol to the membrane and the translocation caused by BN was reversed by (D-Phe6)BN613methylester. BN stimulated arachidonic acid release and the increase caused by BN was reversed by (D-Phe6)BNG13methylester. Using a clonogenic assay, BN stimulated the growth of NCLH720 cells, and the number of colonies was reduced using (D-Phe6)BNG13methylester. These data suggest that GRP receptors that are present in lung carcinoid and NSCLC cells may regulate proliferation.

Background. Although early-stage non-small-cell lung cancer (NSCLC) is considered a potentially curable disease following complete resection, patients have a wide spectrum of survival according to stage (IB, II, IIIA). Within each stage, gene expression profiles can identify patients with a higher risk of recurrence. We hypothesized that altered mRNA expression in nine genes could help to predict disease outcome: excision repair cross-complementing 1 (ERCC1), myeloid zinc finger 1 (MZF1) and Twist1 (which regulate N-cadherin expression), ribonucleotide reductase subunit M1 (RRM1), thioredoxin-1 (TRX1), tyrosyl-DNA phosphodiesterase (Tdp1), nuclear factor of activated T cells (NFAT), BRCA1, and the human homolog of yeast budding uninhibited by benzimidazole (BubR1). Methodology and Principal Findings. We performed real-time quantitative polymerase chain reaction (RT-QPCR) in frozen lung cancer tissue specimens from 126 chemonaive NSCLC patients who had undergone surgical resection and evaluated the association between gene expression levels and survival. For validation, we used paraffin-embedded specimens from 58 other NSCLC patients. A strong inter-gene correlation was observed between expression levels of all genes except NFAT. A Cox proportional hazards model indicated that along with disease stage, BRCA1 mRNA expression significantly correlated with overall survival (hazard ratio [HR], 1.98 [95% confidence interval (CI), 1.11-6]; P = 0.02). In the independent cohort of 58 patients, BRCA1 mRNA expression also significantly correlated with survival (HR, 2.4 [95%CI, 1.01-5.92]; P = 0.04). Conclusions. Overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients, and the validation of this finding in an independent data set further strengthened this association. Since BRCA1 mRNA expression has previously been linked to differential sensitivity to cisplatin and antimicrotubule drugs, BRCA1 mRNA expression may provide additional information for customizing adjuvant antimicrotubule-based chemotherapy, especially in stage IB, where the role of adjuvant chemotherapy has not been clearly demonstrated.

The integration of chemotherapy, radiation therapy (RT), and surgery in the management of patients with stage IIIA (N2) nonsmall-cell lung carcinoma is challenging. The American College of Radiology (ACR) Appropriateness Criteria Lung Cancer Panel was charged to update management recommendations for this clinical scenario. The 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 peerreviewed journals and the application of a well-established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances where evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. There is limited level I evidence to guide patient selection for induction, postoperative RT (PORT), or definitive RT. Literature interpretation is complicated by inconsistent diagnostic procedures for N2 disease, disease heterogeneity, and pooled analysis with other stages. PORT is an appropriate therapy following adjuvant chemotherapy in patients with incidental pN2 disease. In patients with clinical N2 disease who are potential candidates for a lobectomy, both definitive and induction concurrent chemotherapy/RT are appropriate treatments. In N2 patients who require a pneumonectomy, definitive concurrent chemotherapy/RT is most appropriate although induction concurrent chemotherapy/RT may be considered in expert hands. Induction chemotherapy followed by surgery + / À PORT may also be an option in N2 patients. For preoperative RT and PORT, 3-dimensional conformal techniques and intensity-modulated RT are most appropriate.

Phosphatase and tensin homologue deleted from chromosome 10 (Pten) is expressed aberrantly in non–small cell lung cancer cells, but the role of Pten in lung neoplasia has not been fully elucidated. In this study, we used a genetic approach to inactivate Pten in the bronchial epithelium of mice. Although, by itself, Pten inactivation had no discernible effect on bronchial epithelial histology, it accelerated lung tumorigenesis initiated by oncogenic K-ras, causing more rapid lethality than that induced by oncogenic K-ras alone (8 weeks versus 24 weeks of median duration of survival, respectively). Lung tumors arose in K-ras mutant, Pten-deficient mice that rapidly obstructed bronchial lumina and replaced alveolar spaces. Relative to K-ras mutant tumors, the K-ras mutant, Pten-deficient tumors exhibited more advanced histologic severity and more prominent inflammation and vascularity. Thus, Pten inactivation cooperated with oncogenic K-ras in promoting lung tumorigenesis. [Cancer Res ...

Objective: The prognosis of non-small cell lung cancer (NSCLC) with brain metastasis is very poor, with median survival rate below 6 months, even if treated with palliative radio and/or chemotherapy. To assess the effectiveness of surgical treatment for this kind of patients we reviewed our experience. Methods: From January 1989 to October 1999, 30 patients (26 males and four females; mean age: 58.7 years) with NSCLC and single brain metastasis underwent surgical treatment of both primary lung cancer and secondary cerebral lesion. Patients (pts) were divided into two major groups. In group 1 (G1) 20 pts (18 males and two females) presented a synchronous brain metastasis. In group 2 (G2) 10 pts (eight males and two females) presented a metachronous brain metastasis during the follow-up period (range 3±24 months since the primary tumor). Patients selected in G1 had T1±2, N0±1 clinical staging, good`performance status' (ECOG:0±1; Karnofsky index .70%), age , 75 years. Craniotomy has always been the ®rst approach. In G2 also patients with locally advanced tumors (T3 and/or N2) were included. Whole brain radiotherapy and/or chemotherapy was the post-operative choice treatment. Results: Histologic ®ndings have shown: adenocarcinoma in 17 cases (12 in G1; ®ve in G2), squamous cell carcinoma in 10 cases (six in G1; four in G2), large cell carcinoma in 2 (one in G1; one in G2) and large cell neuroendocrine carcinoma in one (G1). Survival analysis (Kaplan±Meier method) has shown an overall value of 80% at 1 year (95% in G1; 50% in G2), 41% at 2 years (47% in G1; 30% in G2) and 17% at 3 years (14% in G1; 20% in G2). Overall median survival is 23 months (23 in G1; 11 in G2); mean survival 27.8 months (30.3 months in G1; 22.8 months in G2). According to univariate analysis prognosis is de®nitively better in N0 tumors compared to N1±2 tumors and in adenocarcinoma cases compared to other histotypes (P , 0:05). Conclusions: We can conclude that combined surgical therapy is, nowadays, the choice treatment for this kind of patients, even though restricted to selected cases. The knowledge of prognostic factors may optimize indications for surgery.

tube-like structures in the cytoplasm. Raising the temperature could reverse this process. When the vaulttubes were formed, there were fewer or no VPARP-rods present in the cytoplasm, suggesting an incorporation of the VPARP into the vault-tubes. MVP molecules have to interact with each other via their coiled-coil domain in order to form vault-tubes. Furthermore, the stability of microtubules influenced the efficiency of vault-tube formation at 21°C. The dynamics and structure of the tubes were examined using confocal microscopy. Our data indicate a direct and dynamic relationship between vaults and VPARP, providing further clues to unravel the function of vaults.

Expression of insulin-like growth factor-binding protein-3, which (IGFBP-3) inhibits the proliferation of non-smallcell lung cancer (NSCLC) cells by inducing apoptosis, is lost in about half of stage I NSCLC cases. Since promoter methylation can silence gene expression, we investigated whether hypermethylation of the IGFBP-3 promoter is involved in loss of IGFBP-3 expression in NSCLC. We found the IGFBP-3 promoter to be methylated in seven of 13 NSCLC cell lines and in 16 of 23, seven of 9, eight of 11, and six of six tumor specimens from patients with stage I, II, III, and IV NSCLC, respectively. Methylation status correlated with IGFBP-3 mRNA and protein levels in a subset of NSCLC cell lines tested in our study. However, treatment with 5 0-aza-2 0-deoxycytidine (5 0aza-dC) restored IGFBP-3 expression in four of seven NSCLC cell lines with the methylated promoter, suggesting that multiple mechanisms regulate IGFBP-3 expression in NSCLC. Gel shift and chromatin immunoprecipitation assays showed that methylation of the Sp-1/ Sp-3-binding element in the IGFBP-3 promoter influenced the binding of Sp-1, methyl-CpG-binding protein-2 (MeCP2), and histone deacetylase (HDAC). A luciferase construct expressing IGFBP-3 promoter in which the Sp-1/Sp-3 binding element was methylated showed significantly reduced transcriptional activity. The reduction in promoter activity was further suppressed by overexpression of MeCP2, which was rescued by 5 0-aza-dC. Thus interference with Sp-1 transactivation by MeCP2 may contribute to the transcriptional defect of IGFBP-3 expression in NSCLC cells with methylated promoter.

To track moving tumor in real time, CyberKnife system imports a technique of the synchrony respiratory tracking system. The fiducial marker which are detectable in X-ray images were demand in CyberKnife Robotic radiosurgery system. It issued as reference markers to locate and track tumor location during patient alignment and treatment delivery. Fiducial marker implantation is an invasive surgical operation that carries a relatively high risk of pneumothorax. Most recently, it was developed a direct lung tumor registration method that does not require the use of fiducials. The purpose of this study is to measure the accuracy of target applying X-sight lung tracking using the Gafchromic film in dynamic moving thorax phantom. The X-sight Lung Tracking quality assurance motion phantom simulates simple respiratory motion of a lung tumor and provides Gafchromic dosimetry film-based test capability at locations inside the phantom corresponding to a typical lung tumor. The total average error for the X-sight Lung Tracking System with a moving target was 0.85±0.22 mm. The results were considered reliable and applicable for lung tumor treatment in CyberKnife radiosurgery system. Clinically, breathing patterns of patients may vary during radiation therapy. Therefore, additional studies with a set real patient data are necessary to evaluate the target accuracy for the X-sight Lung Tracking system.

Materials/Methods: Intra-fractional motion of 30 lung tumors acquired using the Real-time Tumor Tracking Radiotherapy (RTRT) were studied. The 3D motion is acquired by fluoroscopic imaging of the implanted gold seed in or near the tumor. The raw data is smoothed using a digital low pass Butterworth filter. A mean value based differentiation algorithm was used to retrieve the normalized differentiated values. Tumor motion in a breathing cycle is then modeled using curve fitting toolbox in MATLAB. Hysteresis is analyzed quantitatively by checking the direction which maximizes hysteresis. Curves for different breathing states, such as exhale and inhale, are also separated to investigate state-related hysteresis. Results: Hysteresis in a breathing cycle varies according to different direction, from almost no hysteresis in one view to a few millimeters in another view. The 3D trajectory of tumor motion in a breathing cycle can be visualized from different directions. The changing hysteresis at different angle is compared and summarized. Even for the directions with the largest hysteresis, hysteresis also changes in real-time as treatment goes inside one fraction. Our initial results showed that both intra-fractional and interfractional variations of hysteresis can change up to 5mm. The temporal changes of intra-and inter-fractional hysteresis are visualized to study its stability and the changing patterns. The aggregated hysteresis for each tumor and among tumors will be quantified and compared. Conclusions: Hysteresis is very common to most patients although it is patient specific. Hysteresis of tumor motion at different breathing states creates extra challenge for real-time motion prediction. Understanding, characterizing and predicting tumor motion behavior including hysteresis are of great importance to precision radiation treatment delivery.

Background: Reduction in visual acuity combined with blurred vision is rarely the first sign of lung cancer and very few cases have been announced globally. Case presentation: A case of a 46-year-old man who admitted with blurred vision is presented. His medical history, apart from a mild gastritis under treatment was negative. Ocular examination revealed a decrease in visual acuity due to a choroidal tumor. Further image body scans demonstrated a right lung lesion with dissemination to other organs. Diagnosis of a non-small cell lung cancer established after a VATS biopsy carried out. Conclusion: Blurred vision due to choroidal metastasis as the primary symptom of lung cancer is very uncommon. A great index of suspicion is essential when a choroidal lesion appears.

Purpose of review The aim of this review is to analyze recent evidence for optimal treatment of elderly patients with non-small cell lung cancer, focusing on surgery, and possibly to foresee the future strategies to apply in these patients. Recent findings Surgery in elderly patients affected by non-small cell lung cancer is safe and feasible when careful preoperative respiratory and cardiac studies have been carried out and the disease has been properly staged. The surgical treatment is not to be denied in elderly patients due to age per se, but when a major contraindication to surgery has been recognized. Long term survival for elderly patients with early stage lung cancer treated by anatomical pulmonary resection is comparable to the survival rate of younger patients. Pneumonectomy, extended surgical procedure or preoperative induction chemotherapy are major risk factors for an increased postoperative morbidity and mortality rate. When co-morbidities are present or a patient is 80 years or older, there is evidence that a non-anatomical resection can be performed without affecting long-term results. Summary Due to the aging of the general population, elderly patients will become a large percentage of the cases of non-small cell lung cancer to be treated. Implementing preoperative cardiologic studies and redefining selective respiratory criteria specifically could dramatically improve results.

Objective: Pneumonectomy is not always sufficient for the radical resection of cancer. In the present study, pneumonectomy may be associated with an extended resection of mediastinal or parietal structures. The postoperative risk and the oncologic benefits of such an extended procedure have not been sufficiently demonstrated. Methods: We have defined "extended" pneumonectomy (EP) as the removal of the entire lung, associated with one or more of the following structures: superior vena cava, tracheal carina, left atrium, aorta, chest wall, or diaphragm. Our clinical database was retrospectively reviewed to identify patients who underwent EP to assess their postoperative morbidity, mortality, and long-term survival. Results: Between 1998 and 2005, 47 EPs were performed. The "extended" procedure included left atrium resection in 15 patients, combined SVC and carinal resection in 9 patients, aortic resection in 8 patients (in 3 patients with prosthetic replacement), chest wall or diaphragmatic resection in 6 patients, SVC resection in 4 patients, and carinal resection in 4 patients. A partial esophageal muscular resection was performed in 1 patient. Overall 60-day mortality was 8.5%. Major postoperative complications occurred in 8 patients (17%). The 2-and 5-year survival rates for the overall population were 42% and 22.8%, respectively. Interestingly, long-term survivors were recorded only in the group of patients who received induction treatment. Conclusions: Extended pneumonectomy is a feasible procedure with an acceptable risk factor. To improve the selection of patients, all candidates should undergo preoperative mediastinoscopy and induction chemotherapy. In patients with positive response to chemotherapy or stable disease, extended pneumonectomy may afford a radical resection in more than 80% of cases and may result in a permanent cure in some instances. C omplete tumor removal is the objective of any surgical resection when treating lung cancer. 1 A tumor may infiltrate contiguous structures such as the superior vena cava (SVC), tracheal carina, left atrium, diaphragm, or chest wall. It has been demonstrated that in all of these situations, a radical resection can be achieved by combining an "extended" procedure such as SVC

Innovative therapeutic agents have significantly improved outcomes, with an acceptable safety profile, in a substantial proportion of non-small cell lung cancer (NSCLC) patients in whom the malignant phenotype of the disease is determined by oncogenic molecular alterations. However, the benefit seen with these treatment models has not translated well to NSCLCs with KRAS mutations or squamous cell histology. Although efforts have been made to develop precision medicine approaches, KRAS mutant NSCLC and lung squamous cell carcinoma (LSCC) continue to display resistance to therapy. Recently, based on the results of the Phase III SQUIRE trial, the EGFR monoclonal antibody necitumumab received FDA authorization in combination with cisplatin and gemcitabine for first line treatment of patients with metastatic LSCC.

BIM is a proapoptotic protein that initiates apoptosis triggered by EGFR tyrosine kinase inhibitors (TKI). mTOR negatively regulates apoptosis and may influence response to EGFR TKI. We examined mRNA expression of BIM and MTOR in 57 patients with EGFR-mutant NSCLC from the EURTAC trial. Risk of mortality and disease progression was lower in patients with high BIM compared with low/intermediate BIM mRNA levels. Analysis of MTOR further divided patients with high BIM expression into two groups, with those having both high BIM and MTOR experiencing shorter overall and progression-free survival to erlotinib. Validation of our results was performed in an independent cohort of 19 patients with EGFR-mutant NSCLC treated with EGFR TKIs. In EGFR-mutant lung adenocarcinoma cell lines with high BIM expression, concomitant high mTOR expression increased IC50 of gefitinib for cell proliferation. We next sought to analyse the signalling pattern in cell lines with strong activation of mTOR and its...

Lung cancer is the most common cause of cancer-related death worldwide. Non-small-cell lung cancer (NSCLC) represents approximately 80% of lung cancer and has a 5-year survival rate of only 16%. 1 Patients with early-stage disease are treated primarily by surgical resection with curative intent. However, 30%-70% of these patients develop recurrence and die from their disease, indicating that a subgroup of these patients might benefit from adjuvant chemotherapy. A recent meta-analysis of adjuvant cisplatin-based chemotherapy in NSCLC from 5 trials with a total of 4584 patients found an absolute 5-year survival benefit for chemotherapy of 5.4%. 2 This poor outcome indicates the need to identify genetic markers that will help to improve survival in patients with completely resected stage IB-IIIA disease. Currently, tumor stage remains the most accurate prognostic factor for survival in patients with NSCLC. 3 Only recently have molecular markers become integrated into decisions about the treatment of patients with lung cancer, largely based on muta

Background: Median survival is 10 months and 2-year survival is 20% in metastatic non-small-cell lung cancer (NSCLC) treated with platinum-based chemotherapy. A small fraction of non-squamous cell lung cancers harbor EGFR mutations, with improved outcome to gefitinib and erlotinib. Experimental evidence suggests that BRCA1 overexpression enhances sensitivity to docetaxel and resistance to cisplatin. RAP80 and Abraxas are interacting proteins that form complexes with BRCA1 and could modulate the effect of BRCA1. In order to further examine the effect of EGFR mutations and BRCA1 mRNA levels on outcome in advanced NSCLC, we performed a prospective non-randomized phase II clinical trial, testing the hypothesis that customized therapy would confer improved outcome over non-customized therapy. In an exploratory analysis, we also examined the effect of RAP80 and Abraxas mRNA levels. Methodology/Principal Findings: We treated 123 metastatic non-squamous cell lung carcinoma patients using a customized approach. RNA and DNA were isolated from microdissected specimens from paraffin-embedded tumor tissue. Patients with EGFR mutations received erlotinib, and those without EGFR mutations received chemotherapy with or without cisplatin based on their BRCA1 mRNA levels: low, cisplatin plus gemcitabine; intermediate, cisplatin plus docetaxel; high, docetaxel alone. An exploratory analysis examined RAP80 and Abraxas expression. Median survival exceeded 28 months for 12 patients with EGFR mutations, and was 11 months for 38 patients with low BRCA1, 9 months for 40 patients with intermediate BRCA1, and 11 months for 33 patients with high BRCA1. Two-year survival was 73.3%, 41.2%, 15.6% and 0%, respectively. Median survival was influenced by RAP80 expression in the three BRCA1 groups. For example, for patients with both low BRCA1 and low RAP80, median survival exceeded 26 months. RAP80 was a significant factor for survival in patients treated according to BRCA1 levels (hazard ratio, 1.3 [95% CI, 1-1.7]; P = 0.05). Conclusions/Significance: Chemotherapy customized according to BRCA1 expression levels is associated with excellent median and 2-year survival for some subsets of NSCLC patients , and RAP80 could play a crucial modulating effect on this model of customized chemotherapy.

Background: There is still a sore need for better characterization of factors influencing survival in specific subgroups and in individual patients with NSCLC. RRM1 is involved in DNA repair, Tdp1 is implicated in the repair of CPT-induced topoisomerase damage, and NFAT promotes cancer invasion. BubR1 is a key spindle checkpoint gene, and altered BubR1 mRNA levels are associated with lymph node metastasis and chromosome instability. Methods: The expression of these four genes was identified in frozen resected tumors from 126 resected NSCLC p by real-time quantitative PCR. Gene expression was normalized using a-actin expression as internal reference.

Contexte Le plan Hôpital 2007 a favorisé le développement de l'hospitalisation à domicile (HAD). L'objectif de ce travail était de comparer les coûts en HAD d'une chimiothérapie dans le cancer du poumon non à petites cellules (CBP NAPC) à la prise en charge habituelle. Méthodes 10 patients ont reçu le J 8 de leur cycle de chimiothérapie en HAD versus une administration en hôpital de jour. L'analyse a porté sur les tarifs d'administration de cette chimiothérapie. Résultats 30 injections dites « classiques » ont été comparées aux 24 injections en HAD. Le coût d'un cycle classique est de 2 829,51 € [2 560,74-3 147,02]. Pour l'HAD le coût par cycle est de 2 372,50 € [1 962,75-2 792,88]. Cette différence est de-457,01 € par cycle en faveur de l'HAD [-919,74 ; 26,82]. Le tarif d'une injection en HAD est de 699,89 € [643,64 ; 750,23] alors que le coût réel s'élève à 484,42 € [424,18 ; 540,32]. Il n'y a pas plus d'effets secondaires dans le groupe HAD. Conclusion La réalisation d'une chimiothérapie en HAD est possible avec un coût inférieur de 16 %. Les résultats de cette étude, non randomisée, doivent être confirmés dans le cadre d'essais cliniques ultérieurs.

Recently we identi®ed FUS1 as a candidate tumor suppressor gene (TSG) in the 120 kb 3p21.3 critical region contained in nested lung and breast cancer homozygous deletions. Mutation of FUS1 is infrequent in lung cancers which we have con®rmed in 40 other primary lung cancers. In addition, we found no evidence for FUS1 promoter region methylation. Because haploinsuciency or low expression of Fus1 may play a role in lung tumorigenesis, we tested the eect of exogenously induced overexpression of Fus1 protein and found 60 ± 80% inhibition of colony formation for non-small cell lung cancer lines NCI-H1299 (showing allele loss for FUS1) and NCI-H322 (containing only a mutated FUS1 allele) in vitro. By contrast, a similar level of expression of a tumor-acquired mutant form of FUS1 protein did not signi®cantly suppress colony formation. Also, induced expression of Fus1 under the control of an Ecdysone regulated promoter decreased colony formation 75%, increased the doubling time twofold, and arrested H1299 cells in G1. In conclusion, our data are consistent with the hypothesis that FUS1 may function as a 3p21.3 TSG, warranting further studies of its function in the pathogenesis of human cancers. Oncogene (2001) 20, 6258 ± 6262.

A gastro-oesophagealis reflux betegség (GORB) optimalis kezelése, szövődményei valamint az aero-digestiv rendszer kapcsolódó pathológiáinak vizsgálata, sebészi megoldások kidolgozása képezték kutatásunk tárgyát. A 20 cikk (IF 17.299) :, 4 könyvfejezet és 3 PhD dolgozat cumulativ IF-a 31.376 . A GORB diagnosisát új módszerrel, a sebészi kezelést új technikával gazdagítottuk. A gastro-oesophagealis junctio (GOJ) adenocarcinomák javuló túléléseit a pontosabb betegkiválasztás és a rezekabilitást biztosan javító neoadjuváns therápia okozta. A süllyesztett oesophago-gastricus anasztomózissal az epés reflux bizonyítottan szignifikánsan csökkent. A trachea sebészetben új megfigyeléseink finomították a revascularisatio nyomonkövetését. A pótlás sikeres állatkísérletei emberi alkalmazás nélkül zárultak. Az ultrahangos vágókés tüdőmintavételi technikáját a világon előszőr publikáltuk, alkalmazhatóságát kísérletes, majd klinikai anyagon igazoltuk. Bár nem sikerült egyértelműen bizonyítani a GOR...

Objectives Stereotactic body radiotherapy (SBRT) is a definitive local treatment option for patients with stage I non-small cell lung cancer (NSCLC) who are not surgical candidates and patients who refuse surgery. The purpose of this study was to assess the impact of SBRT on T1-T2 NSCLC from a national registry, reflecting practices and outcomes in a real-world setting. Methods The RSSearch® Patient Registry was screened for T1-T2N0M0 NSCLC patients treated from May 2004 to May 2013 with SBRT. Descriptive analyses were used for patient, tumor, and treatment characteristics. Overall survival (OS) and local control (LC) were calculated using the Kaplan-Meier method. Results In total, 723 patients with 517 T1 and 224 T2 lesions were treated with SBRT. Median follow-up was 12 months (1-87 months) with a median age of 76 years. Median SBRT dose was 54 Gy (range 10-80 Gy) delivered in a median of 3 fractions (range 1-5), and median biological equivalent dose (BED 10) was 151.2 Gy (range 20-240 Gy). Median OS was 30 and 26 months for T1 and T2 tumors, respectively (p= 0.019). LC was associated with higher BED 10 for T2 tumors, but not in T1 tumors at a median follow-up of 17 months. Seventeen-month LC for T2 tumors treated with BED 10 < 105 Gy, BED 10 105-149, and BED 10 ≥150 Gy was 43, 74, and 95 %, respectively (p=0.011). Local failure rates for T2 tumors treated with BED 10 < 105 Gy, 105-149 Gy, and ≥150 Gy were 32, 21, and 8 % (p=0.029), respectively.

Introduction: Erlotinib is a small molecule inhibitor of epidermal growth factor receptor tyrosine-kinase activity that has been shown to significantly increase survival for patients with previously treated advanced non-small cell lung cancer. Here, we report safety and efficacy data from a large, global, open-label, phase IV trial of erlotinib (Tarceva Lung Cancer Survival Treatment). Methods: Patients who had previously failed on chemotherapy or radiotherapy and were unsuitable for these treatments were treated with oral erlotinib (150 mg/d) until disease progression or unacceptable toxicity. Results: The disease control rate was 69% in 5394 patients for whom best response data were available. Survival data were available for 6580 patients. Median progression-free and overall survival times were 3.25 months and 7.9 months, respectively. The 1-year survival rate was 37.7%. Among the 6580 patients included in the safety analysis, 799 (12%) experienced one or more erlotinib-related adverse events (AEs, other than prespecified AEs defined in the protocol), and only 4% experienced an erlotinib-related serious AE. Of the 6580 patients for whom data were available, dose reductions were reported in 1096 (17%), the majority (95%) due to an erlotinibrelated AE (most commonly rash 65% or diarrhea 10%). Treatment was discontinued for 337 patients (5%) because of erlotinib-related AEs. Incidence of erlotinib-related rash was investigated as a separate end point. Seventy-one percent of patients for whom data were available experienced erlotinib-related rash; of these, the majority of cases were grade 1/2 (59%). Conclusions: These data confirm the favorable efficacy and safety profile of erlotinib in a large heterogeneous non-small cell lung cancer population.

Non–small cell lung cancer (NSCLC) is a leading cause of cancer-related death worldwide. NSCLC often harbors oncogenic K-RAS mutations that lead to the aberrant activation of several intracellular networks including the phosphoinositide 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway. Oncogenic K-RAS predicts poor prognosis and resistance to treatment with ionizing radiation (IR). Oncogenic K-Ras expression in the respiratory epithelium is sufficient to initiate NSCLC tumorigenesis, which requires the catalytic subunit of PI3K. Thus, effective inhibition of the PI3K signaling should lead to significant antitumor effects. However, therapy with rapamycin analogues has yielded disappointing results due in part to compensatory up-regulation of AKT. We hypothesized that dual PI3K/mTOR blockade would overcome these limitations. We tested this hypothesis with BEZ235, a novel dual PI3K/mTOR inhibitor that has recently entered clinical development. We found that BE...

S642 palliative therapy, simple WBRT or simple chemotherapy, combined radiochemotherapy, stereotactic linac-based radiosurgery plus chemotherapy/ WBRT and neurosurgical resection plus chemotherapy/ WBRT. Ninety-two specimens of lung cancer were examined for P53, nm23 and VEGF by immunohistochemical staining. Survival analysis was compared with Kaplan-Meier method and log-rank test was used respectively. Statistical significance was defined as P<0.05. Results: The univariate analysis showed that performance status, age, the number of brain metastases, the absence or presence of extracranial metastases and metastatic symptoms had influences over survival period. The multivariate analysis showed that performance status, age and the absence or presence of extracranial metastases were related to prognosis. The median survival time of patients receiving palliative therapy, simple WBRT or simple chemotherapy, combined radiochemotherapy, stereotactic linac-based radiosurgery plus chemotherapy/ WBRT and neurosurgical resection plus chemotherapy/ WBRT was 1.7 months, 3.2 months, 9.0 months, 10.6 months and 17.1 months respectively. The median survival time of patients with P53(+)/P53(-), nm23(+)/(-) and VEGF(+)/(-)was 11.

To determine the role of lung cancer tumor imaging with monoclonal antibodies directed against high molecular weight human milk fat globule antigens, we administered i.v. mIn-KC-4G3 to 24 patients with advanced non-small cell lung cancer. One mg of '"In-KC-4G3 was mixed with 0, 9, 49, 99, or 499 mg of unlabeled KC-4G3 and infused i.v. over 1 to 5 h. The mean '"In-KC-4G3 radiochemical purity was >97% and the result ant immunoreactivity averaged 62%. Successful imaging of cancer sites was accomplished in 92% of 24 patients, and 57% of 91 total lesions were visualized. Successful localization of tumor sites related to size (/' < 0.001), with 81% of lesions >3.0 cm in diameter, 50% of lesions 1.5 to 3 cm, and 6% of lesions <1.5 cm successfully imaging, and to location (P < 0.05), with 69% of pulmonary lesions, 80% of soft tissue lesions, and only 32% of bone métastasesbeing visualized. Nonspecific reticuloendothelial uptake of radioactivity was a major problem. Approximately 35% of '"In was chelated to serum transferrin by 24 and 48 h after infusion. The mean r, ...for plasma radioisotope and immunoreactive KC-4G3 was 29 and 27 h, respectively. There was no correlation between total infused antibody dose and imaging success or between total dose and effect on '"In and KC-4G3 kinetics. Circulating free KC-4 antigen was measurable in all but one patient before study. I mum biopsy following infusion could demonstrate antibody presence but not saturable antigen binding. We conclude that (a) "'In-KC-4G3 demonstrates suc cessful tumor localization in non-small cell lung cancers bearing generally high expression of its antigen and (h) further investigations to diminish nonspecific radioactivity for imaging and utilization of high dose radiolabeled antibody for therapeutic intent are warranted.

The still-high mortality for lung cancer urgently requires the availability of new, noninvasive diagnostic tools for use in early diagnosis and screening programs. Recently, exhaled breath condensate (EBC) has been proposed as a useful tool to obtain biological information on lung cancer disease. This study provides, for the first time, evidence that DNA alterations already described in lung cancer are detectable in EBC from patients with non-small cell lung cancer (NSCLC) and in healthy subjects. Thirty patients with histologic evidence of NSCLC and 20 healthy subjects were enrolled in the present study. All subjects had allelotyping analysis of DNA from EBC (EBC-DNA) and from whole blood (WB-DNA) of a selected panel of five microsatellites (D3S2338, D3S1266, D3S1300, D3S1304, D3S1289) located in chromosomal region 3p. Results from healthy subjects and subjects with cancer, and from EBC and WB, were compared. In addition, the relationships with smoking habit and clinicopathologic tumor features were considered. Microsatellite alterations (MAs) were found in 53% of EBC-DNA and in 10% of WB-DNA loci investigated in patients with NSCLC (p Ͻ 10 Ϫ6); conversely, MAs were present only in 13% of EBC-DNA and in 2% of WB-DNA informative loci in healthy subjects. In patients with NSCLC, a direct association between number of MAs detected in EBC-DNA and tobacco consumption was observed. We conclude that EBC-DNA is highly sensitive in detecting MA information unique to patients with lung cancer. Furthermore, MA information seems to be directly related with tobacco consumption, and is potentially applicable to screening and early diagnostic programs for patients with NSCLC.

Acquired resistance to TKIs TKIs: overcome T790M TKIs: overcome EGFR mutations Until recently, all types of Non-Small Cell Lung Cancer (NSCLC), which account for 85-90% of lung cancers, were treated with cytotoxic chemotherapy which produces great toxicities owing to the lack of selectivity for tumor cells. Further understanding of molecular alterations was vital to introduce a new approach: the targeted therapy. Some of these mutations occur in the Epidermal Growth Factor Receptor (EGFR). EGFR signalling pathway has become an encouraging targeted therapy to improve outcomes in NSCLC patients. This review will provide a fresh insight into the major progress toward the understanding of EGFR so far.

Stage IIIA non-small cell lung cancer represents a relatively heterogeneous group of patients with metastatic disease to the ipsilateral mediastinal (N2) lymph nodes and also includes T3N1 patients. Presentations of disease range from apparently resectable tumors with occult microscopic nodal metastases to unresectable, bulky multistation nodal disease. This review explores the published clinical trials to make treatment recommendations in this controversial subset of lung cancer. Design, setting, and participants: Systematic searches were made of MEDLINE, HealthStar, and Cochrane Library databases up to May 2006, focusing primarily on randomized trials, with inclusion of selected metaanalyses, practice guidelines, and reviews. Study designs and results are summarized in evidence tables. The evidence derived from the literature now appears to support routine adjuvant chemotherapy after complete resection of stage IIIA lung cancer encountered unexpectedly at surgery. However, using neoadjuvant therapy followed by surgery for known stage IIIA lung cancer as a routine therapeutic option is not supported by current published randomized trials. Combination chemoradiotherapy, especially delivered concurrently, is still the preferred treatment for prospectively recognized stage IIIA lung cancer with all degrees of mediastinal lymph node involvement. Current and future trials may modify these recommendations. Conclusions: Multimodality therapy of some type appears to be preferable in all subsets of stage IIIA patients. However, because of the relative lack of consistent randomized trial data in this subset, the following evidence-based treatment guidelines lack compelling evidence in most scenarios.

Background Liquid biopsy has the potential to monitor biological effects of treatment. KRAS represents the most commonly mutated oncogene in Caucasian non-small-cell lung cancer (NSCLC). The aim of this study was to explore association of dynamic plasma KRAS genotyping with outcome in advanced NSCLC patients. Methods Advanced NSCLC patients were prospectively enrolled. Plasma samples were collected at baseline (T1), after 3 or 4 weeks, according to treatment schedule (T2) and at first radiological restaging (T3). Patients carrying KRAS mutation in tissue were analysed in plasma with droplet digital PCR. Semi-quantitative index of fractional abundance of mutated allele (MAFA) was used. Results KRAS-mutated cohort included 58 patients, and overall 73 treatments (N = 39 chemotherapy and N = 34 immune checkpoint inhibitors) were followed with longitudinal liquid biopsy. Sensitivity of KRAS detection in plasma at baseline was 48.3% (95% confidence interval (CI): 35.0–61.8). KRAS mutation...