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Background: Lung cancer (LC), with the high incidence in malignant tumors in the world, and seriously affects people's lives and brings a great economic burden. Previous clinical studies on Shen-Ling-Bai-Zhu-San (SLBZS) combined with chemotherapy for the treatment of lung cancer have been increasing, but there are no systematic reviews. This study aims to systematically study the efficacy and safety of SLBZS combined with chemotherapy in the treatment of LC., Methods: The Chinese and English databases will be searched by us for related documents, and the search time limit is January 2021. Databases including PubMed, Embase, Web of Science, the Cochrane Library, Chinese databases include China National Knowledge Infrastructure, Wanfang Data, ChongqingVIP Information Resource Integration Service Platform, China Biomedical Literature. The international clinical trial registration platform and the Chinese clinical trial registration platform will be searched by us to find ongoing or unpublished trials. After screening the literature based on inclusion and exclusion criteria, 2 researchers independently extracted data. The primary outcomes were the treatment efficiency. RevMan 5.3.5 software will be used for statistical analysis. The Recommendation, Assessment, Development, and Evaluation (GRADE) system will be used to evaluate the quality evidence of each result., Results: This study will provide the latest evidence for the SLBZS combined with chemotherapy for LC., Conclusion: The efficacy and safety of SLBZS combined with chemotherapy for LC will be evaluated., Unique Inplasy Number: INPLASY202110025., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Competing Interests: The authors declare that they have no conflict of interest.

Background: Bronchogenic carcinoma (lung cancer) is one of the leading causes of death. Although many compounds isolated from natural products have been used to treat it, drug resistance is a serious problem, and alternative anti-cancer drugs are required. Here, melittin from Apis mellifera venom was used, and its effects on bronchogenic carcinoma cell proliferation and tumour-associated macrophage differentiation were evaluated. Methods: The half maximal inhibitory concentration (IC50) of melittin was measured by MTT. Cell death was observed by annexin V and propidium iodide (PI) co-staining followed by flow cytometry. Cell cycle arrest was revealed by PI staining and flow cytometry. To investigate the tumour microenvironment, differentiation of circulating monocytes (THP-1) into tumour-associated macrophages (TAMs) was assayed by sandwich-ELISA and interleukin (IL)-10 levels were determined. Cell proliferation and migration was observed by flat plate colony formation. Secretion of vascular endothelial growth factor (VEGF) was detected by ELISA. The change in expression levels of CatS, Bcl-2, and MADD was measured by quantitative RT-PCR. Results: Melittin was significantly more cytotoxic (p < 0.01) to human bronchogenic carcinoma cells (ChaGo-K1) than to the control human lung fibroblasts (Wi-38) cells. At 2.5 μM, melittin caused ChaGo-K1 cells to undergo apoptosis and cell cycle arrest at the G1 phase. The IL-10 levels showed that melittin significantly inhibited the differentiation of THP-1 cells into TAMs (p < 0.05) and reduced the number of colonies formed in the treated ChaGo-K1 cells compared to the untreated cells. However, melittin did not affect angiogenesis in ChaGo-K1 cells. Unlike MADD, Bcl-2 was up-regulated significantly (p < 0.05) in melittin-treated ChaGo-K1 cells. Conclusion: Melittin can be used as an alternative agent for lung cancer treatment because of its cytotoxicity against ChaGo-K1 cells and the inhibition of differentiation of THP-1 cells into TAMs., (Creative Commons Attribution License)

Soluble Triggering Receptor Expressed on Myeloid Cells 1 (sTREM-1) can be found in the sera of patients with infectious, autoimmune and malignant diseases. The primary objective of this study was to investigate the prognostic significance of sTREM-1 in lung cancer patients. We analyzed the sera of 164 patients with lung cancer of all histologies and all stages at the time of diagnosis. We employed an ELISA using the anti-TREM-1 clone 6B1.1G12 mAb and recombinant human TREM-1. Patient data was collected retrospectively by chart review. In ROC-analysis, a sTREM-1 serum level of 163.1 pg/ml showed the highest Youden-Index. At this cut-off value sTREM-1 was a marker of short survival in patients with NSCLC (median survival 8.5 vs. 13.3 months, p = 0.04). A Cox regression model showed stage (p < 0.001) and sTREM-1 (p = 0.011) to indicate short survival. There were no differences in sTREM-1 serum values among patients with or without infection, pleural effusion or COPD. sTREM-1 was not associated with metastasis at the time of diagnosis and was not a predictor of subsequent metastasis. In SCLC patients sTREM-1 levels were lower than in NSCLC patients (p = 0.001) and did not predict survival. sTREM-1 did not correlate with CRP or the number of neutrophils. In non-small cell lung cancer patients, sTREM-1 in serum has prognostic significance.

Immune-related adverse events (IRAEs) are rare but serious adverse events that may be associated with inhibitors of few immune control points. The purpose here is to report the case of an inflammatory ocular disease, potentially linked to the immunity and use of nivolumab, a new immunological agent used for the treatment of a solid tumor. In spite of the involvement of this treatment in the onset of inflammation, we must always seek another cause. It is possible to continue this treatment by considering the benefit/risk balance for each patient. Close collaboration between oncologists and ophthalmologists is necessary in the diagnosis and rapid management of these IRAE ocular related to these new emerging therapies., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

Introduction: We report a phase I trial of photodynamic therapy (PDT) of carcinoma in situ (CIS) and microinvasive cancer (MIC) of the central airways with the photosensitizer (PS) 2-[1-hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH). HPPH has the advantage of minimal general phototoxicity over the commonly used photosensitizer porfimer sodium (Photofrin; Pinnacle Biologics, Chicago, IL)., Methods: The objectives of this study were (1) to determine the maximally tolerated light dose at a fixed photosensitizer dose and (2) to gain initial insight into the effectiveness of this treatment approach. Seventeen patients with 21 CIS/MIC lesions were treated with HPPH with light dose escalation starting from 75 J/cm2 and increasing to 85, 95,125, and 150 J/cm2 respectively. Follow-up bronchoscopy for response assessment was performed at 1 and 6 months, respectively., Results: The rate of pathological complete response (CR) was 82.4% (14 of 17 evaluable lesions; 14 patients) at 1 month and 72.7% (8/11 evaluable lesions; 8 patients) at 6 months. Only four patients developed mild skin erythema. One of the three patients in the 150 J/cm2 light dose group experienced a serious adverse event. This patient had respiratory distress caused by mucus plugging, which precipitated cardiac ischemia. Two additional patients treated subsequently at this light dose had no adverse events. The sixth patient in this dose group was not recruited and the study was terminated because of delays in HPPH supply. However, given the observed serious adverse event, it is recommended that the light dose does not exceed 125 J/cm2., Conclusions: PDT with HPPH can be safely used for the treatment of CIS/MIC of the airways, with potential effectiveness comparable to that reported for porfimer sodium in earlier studies., (Copyright © 2015 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Lung cancer is a dreadful disease which claims to be more life threatening as compared to total sum up of colon, prostate and breast cancers. Thus, there is an urgent need to develop an effective delivery approach for its management. Paclitaxel (PTX) is one of the well-known choice as antineoplasitic agent used for the treatment of different types of human cancers such as non-small-cell lung, head and neck cancers, leukemia, breast, ovarian and melanoma. Lactoferrin (Lf), a "multifunctional protein" is crucial for natural immunity which is secreted by exocrine glands. Lf receptors are expressed on the apical surface on bronchial epithelial cells. These over-expressed LF receptors can be utilized for the transportation of Lf-conjugated drug or nanocarrier devices. The present study was aimed to develop PTX-loaded Lf-coupled solid lipid nanoparticles (SLNs) for the treatment of lung cancer. PTX-loaded SLNs were prepared, characterized and then coupled with Lf using carbodiimide chemistry. The formulations were characterized by transmission electron microscopy, particle size, polydispersity index and zeta potential, whereas Lf conjugation was confirmed by FT-IR and ¹H NMR and efficiency of prepared system was evaluated by in vitro, ex vivo and in vivo evaluations. The ex vivo cytotoxicity studies on human bronchial epithelial cell lines, BEAS-2B, revealed superior anticancer activity of Lf-coupled SLNs than plain SLNs and free PTX. In vivo biodistribution studies showed higher concentrations of PTX accumulated in lungs via Lf-coupled SLNs than plain SLNs and free PTX. These studies suggested that Lf-coupled PTX-loaded SLNs could be used as potential targeting carrier for delivering anticancer drug to the lungs with the minimal side effects.

Immunotherapy is becoming another possible alternative in the treatment of lung cancer. It is a completely different method of treating cancer which is not directed to the tumor itself, but to the immune system. Surface antigens present on tumor cells may be an effective and specific therapeutic targets and strategies based on antibodies inhibiting immune check-points significantly improves the antitumor immune response. Monoclonal antibody blocking CTLA 4 (cytotoxic T-lymphocyte antigen) and PD 1 receptor (protein programmed cell death) and its ligand PD L1 showed clinical efficacy and nivolumab (antiPD 1) was approved in 2nd line treatment squamous nonsmall cell lung cancer.

We present the case of a patient with rapidly accelerated fibrosarcoma gene F (BRAF) mutated adenocarcinoma of the lung, responding to BRAF inhibitor dabrafenib after progressing on vemurafenib followed by docetaxel. The present case illustrates the potential benefit of successful rechallenge with a BRAF inhibitor, a well known phenomenon observed in other oncogenic driven molecular subtypes of non-small cell lung cancer (NSCLC) such as epidermal growth factor receptor mutation. Rechallenge with a BRAF inhibitor in BRAF mutated NSCLC should be considered, particularly in the absence of alternative therpateutic options., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

A diagnosis of asbestosis, lung fibrosis due to asbestos exposure, was proposed in 2003 in a 64-year-old woman on the basis of the history, computed tomography appearances, lung function studies, and biometric data. This diagnosis was confirmed by the pathological examination of a lung lobe resected surgically for bronchial carcinoma in 2010. The diagnosis of asbestosis is now rarely made as a result of a substantial decrease in dust exposure over the past decades and mainly because of the interdiction of asbestos use in western countries. Currently, the most frequent thoracic manifestations of asbestos exposure are benign pleural lesions and mesothelioma. It has also become exceptional to have pathological confirmation of the diagnosis, obtained in this woman thanks to the surgical treatment of another complication of her occupational exposure., (Copyright © 2012 SPLF. Published by Elsevier Masson SAS. All rights reserved.)

Objectives: Sleeve resection is the operation of choice in patients with centrally located tumours, in order to avoid a pneumonectomy. Most surgeons protect the bronchial anastomoses with tissue to prevent insufficiencies. The purpose of this study is to report on outcome of unwrapped bronchial anastomoses, especially after neoadjuvant chemo- or chemoradiotherapy., Methods: Between 2000 and 2010, 103 patients [59 years (range 16-80), 40 females] underwent bronchial sleeve resections without coverage of the anastomosis with a tissue flap. We retrospectively reviewed the data for morbidity, mortality and survival, especially with regard to the type of resection, neoadjuvant therapy and stage., Results: Sleeve lobectomy was performed in 88, sleeve bilobectomy in 8, sleeve pneumonectomy in 4 and sleeve resection of the main bronchus in 3 patients. Twenty-seven patients had a combined vascular sleeve resection. Neoadjuvant chemotherapy was performed in 20 and radiochemotherapy in 5 patients. Non-small cell lung cancer (NSCLC) was present in 76 patients (squamous cell carcinoma in 44, adenocarcinoma in 24, large cell carcinoma in 6 and mixed cell in 2) and neuroendocrine tumour in 20 and other histological types in 7 patients. The pathologic tumour stage in NSCLC was stage I in 26, stage II in 26, stage IIIA in 16, stage IIIB in 7 and stage IV in 1 patient. There were no anastomotic complications, especially no fistulas. One patient developed narrowing of the intermediate bronchus without need for intervention. Twenty-four patients had early postoperative complications, including 11 surgery-related complications (air leakage, nerve injury, haemothorax or mediastinal emphysema). The 30-day mortality was 3% (one patient died due to heart failure and two with multiorgan failure). The 5-year survival rate was 63% in NSCLC patients and 86% in neuroendocrine tumour patients., Conclusions: Sleeve resection without wrapping the bronchial anastomoses with a tissue flap is safe even in patients who underwent neoadjuvant chemo- or chemoradiotherapy. Therefore, wrapping of the bronchial anastomoses is not routinely mandatory.

Introduction: Lung cancer (LC) is the first cause of cancer-related mortality worldwide and health-related quality of life (HRQL) is a fundamental outcome for evaluating treatment results. Our objective was to validate the Mexican-Spanish versions of the European Organisation for Research and Treatment of Cancer (EORTC) Quality-of-Life QLQ-LC13 disease-specific questionnaire module in Mexican patients with LC; and to explore the possible prognostic role of HRQL data., Methods: Translation procedures followed EORTC guidelines. Both instruments were completed by patients with LC. Tests for reliability and validity were performed. A subset of patients was administered HRQL evaluations before and after chemotherapy. HRQL was associated with prognosis in chemotherapy-naïve patients. The protocol was approved by the Institute's Ethics Committee., Results: One hundred fifty three patients (mean age, 60.3 years; 84 females and 69 males) completed both questionnaires. Compliance rates were high, and the questionnaires were well accepted. Nine of 10 multi-item scales of both questionnaires presented Cronbach's alpha coefficients > 0.7. Multi-trait scaling analysis demonstrated good convergent and discriminant validity. Patients with better Karnofsky or Eastern Cooperative Oncology Group (ECOG) performance status reported better functional HRQL scores. Different scales in the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires were accurately related with clinical characteristics. Functional as well as disease-symptom scales improved after chemotherapy, but treatment side-effects scales worsened in test-retest analysis. Better role functioning and absence of thoracic pain scales were associated with longer overall survival (OS) (p = 0.009 and p = 0.035, respectively)., Conclusion: The Mexican-Spanish versions of the EORTC QLQ-C30 and EORTC QLQ-LC13 questionnaires are reliable and valid for HRQL measurement in Mexican patients with LC and can be used in clinical trials., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Stenting of the central veins is well established for treating localized venous stenosis. The techniques regarding catheter preservation for central venous catheters in the superior vena cava have been described. We describe here a method for stent implantation in the superior vena cava and the left brachiocephalic vein, and principally via a single jugular venous puncture, while saving a left sided jugular central venous catheter in a patient suffering from central venous stenosis of the superior vena cava and the left brachiocephalic vein.

Background: and Objective Photodynamic therapy (PDT) has come to be considered as the first choice of treatment for central type early stage lung cancer (CELC). Recent advances in the ability to diagnose CELC, and in photosensitizers, as well as sophisticated clinical management, may improve the therapeutic outcome and expand the indications of PDT., Materials and Methods: We made the search for papers on PDT for lung cancer to select the most relevant articles. Based on this review and our recent data, we discussed the best available evidence for the diagnosis, the definition of indications, photosensitizers, and clinical management with regard to PDT., Results: To obtain complete response (CR) by PDT, the selection of the indications is extremely important, including the extent of the tumor on the bronchial surface and the depth of invasion in the bronchial wall. The development of autofluorescence bronchoscopy (AFB) and endobronchial ultrasonography (EBUS) have had a large impact on diagnostic bronchoscopy for CELC. CELCs less than 1 cm in diameter showed a favorable cure rate by PDT, thus this is a good indication for PDT. The relatively newer photosensitizer NPe6, which has a stronger antitumor effect than Photofrin, showed similar treatment outcome even for large tumors >1.0 cm in diameter. Furthermore, comprehensive management including photodynamic diagnosis before and after PDT should be effective to minimize the possibility of local recurrence after PDT., Conclusion: The present guidelines of PDT for CELC were established based on the data obtained from studies in the 1980's. We postulate that comprehensive diagnosis and the new generation of photosensitizers may increase the CR rate and expand the indications of PDT for larger tumors., (Copyright © 2011 Wiley-Liss, Inc.)

Smoking status is essential to know when taking care of a lung cancer patient. Never-smoking patients account for 15% of lung cancer patients, more often women and adenocarcinoma. Environmental tobacco smoke and occupational exposure could be important risk factors. Lung cancer in never-smoker appears to be a distinct entity from lung cancer in smoker, with specific molecular characteristics such as frequent EGFR mutations. New molecular targets are on investigation, such as EML4-ALK translocation. Treatment of lung cancer in never-smoker is getting different from that of smoker with more efficacy of molecular targeted therapies., (Copyright © 2011. Published by Elsevier Masson SAS.)

Background and Objective: Lung transplantation is an efficient therapeutic option for patients with end-stage pulmonary diseases, but less is known about lung cancer after lung transplantation. The aim of this study is to improve the awareness, diagnosis and treatment of bronchogenic carcinoma after lung transplantation with a case report and related literatures., Methods: We reported a 65-year-old male with idiopathic pulmonary fibrosis (IPF) who underwent right lung transplantation under extracorporeal membrane oxygenation (ECMO) support in May 2007 in our hospital. The patient recovered smoothly and discharged from the hospital 46 days after the procedure with regular follow-up. Immunosuppression therapy was triple drug maintenance regimen including tacrolimus (Tac), mycophenolate mofetil (MMF) and steroids., Results: Small cell lung cancer in the left lung with multiple osseous metastases was found 13 months after the lung transplantation. Symptoms were relieved a bit by administering chemotherapeutics (etoposide and cisplatin) for 4 cycles. However, the patient was succumbed to his illness within 11 months after the diagnosis of lung cancer., Conclusions: Lung cancer after lung transplantation has been suggested as one of causes of late mortality with the risk factors such as chronic obstructive pulmonary disease (COPD), IPF, cigarette smoking history and immunosuppression etc. Early diagnosis and treatment are very important to improve the prognosis.

A 53-year-old female patient presented with cough and hoarseness for 3 years. Based on a biopsy of a bronchial tumor, a small cell neuroendocrine tumor of the lung was diagnosed and chemotherapy with etoposide and cisplatin was initiated. As the tumor progressed under chemotherapy, the bronchial biopsy was reevaluated and further biopsies of liver and adrenal metastases were obtained. The diagnosis was corrected, and an atypical neuroendocrine bronchial carcinoma was diagnosed. Under octreotide therapy, the patient remained stable for 1 year, when a discrete progress of the primary tumor in the lung was observed. Treatment with the mTOR (mammalian target of rapamycin) inhibitor everolimus was then initiated. Based on this case, the diagnostic criteria, prognostic factors and therapeutic options of neuroendocrine bronchial carcinomas are discussed.

Purpose: Most centrally located early lung cancers (CLELC) <1.0 cm in diameter do not invade beyond the bronchial cartilage, and photodynamic therapy (PDT) with Photofrin is currently recommended as a treatment option for such lesions. NPe6 is a second-generation photosensitizer, and because it has a longer absorption band (664 nm) than Photofrin (630 nm), we hypothesized that NPe6-PDT would exert a strong antitumor effect against cancer lesions >1.0 cm in diameter, which are assumed to involve extracartilaginous invasion and to be unsuitable for treatment with Photofrin-PDT., Experimental Design: Between June 2004 and December 2008, 75 patients (91 lesions) with CLELC underwent NPe6-PDT after the extent of their tumors had been assessed by fluorescence bronchoscopy for photodynamic diagnosis and tumor depth had been assessed by optical coherence tomography., Results: Seventy cancer lesions < or =1.0 cm in diameter and 21 lesions >1.0 cm in diameter were identified, and the complete response rate was 94.0% (66 of 70) and 90.4% (19 of 21), respectively. After the mass of large tumors and deeply invasive tumors had been reduced by electrocautery, NPe6-PDT was capable of destroying the residual cancer lesions., Conclusion: NPe6-PDT has a strong antitumor effect against CLELCs >1.0 cm in diameter that have invaded beyond the bronchial cartilage, thereby enabling the destruction of residual cancer lesions after mass reduction of large nodular- or polypoid-type lung cancers by electrocautery. The PDT guidelines for lung cancers should therefore be revised because use of NPe6-PDT will enable expansion of the clinical indications for PDT., (Copyright 2010 AACR.)

Micro total analysis systems (-TAS) or labs-on-achip, have been spreading rapidly due to their desirable characteristics, including reductions in reagent consumption, space requirements and analysis time. This work aimed at establishing an integrated microfluidic system which can supply the cells with fresh medium of oxygen and nutrition continuously at a control flow rate mimicking the microenvironment in vivo. Human non-small cell lung cancer cell line SPCA1 was seeded in a microchip supplied with fresh medium at a constant rate of 15 mm/24 h controlled by a pump. The expression of P-gp for verapamil-pretreated or non-pretreated cells was assayed with immunofluorescence. Both groups cells were exposed to anticancer drug VP-16 at 30 microM for 6 h before the apoptosis analysis online. The results indicated that the cells could grow and spread well for 4 days in the microfluidic system successively furnished with fresh medium. Immunofluorescence assay showed that the intensity of the fluorescence for the verapamil-pretreated cells was obvious weak compared with that of nonpretreated cells. Apoptosis analysis demonstrated that the percentage of apoptotic cells for verapamil-pretreated group increased around twofold compared with that of nonverapamil pretreated group (26.5+/-2.5% versus 10.9+/- 0.85%, p<0.05), showing a similar results as by flow cytometry analysis. All these indicate that P-gp plays an important role in the resistance to VP-16 in SPCA1, the microfluidic system provides a suitable environment for cells survival and is valuable in long time cell culture and bioassays mimicking the microenvironment in vivo and deserved to be studied further.

Lung cancer is the leading cause of cancer deaths worldwide. Small cell lung cancer (SCLC), which comprises 15% of all lung cancers, is almost exclusively due to smoking and is highly aggressive due to early widespread metastasis. While combination chemotherapy has lead to modest improvements in outcome, the five-year overall survival for SCLC remains at 5%. Identifying distinct biochemical pathways of metastasis and chemotherapy resistance in SCLC may lead to novel therapeutic approaches and improve survival in SCLC patients. The chemokine receptor CXCR4 is emerging as an important target in cancer growth, metastasis, relapse and resistance to therapy. In this article, we review the structure and function of CXCR4 and its ligand, CXCL12, as well as mechanisms of CXCR4/CXCL12 signal transduction in lung cancer. We review the current preclinical and translational research involving this pathway in lung cancer and the clinical development of several novel agents targeting the CXCR4/CXCL12 pathway. Further understanding of the CXCR4/CXCL12 pathway in SCLC and NSCLC may provide a rationale for innovative research on the CXCR4 receptor as a potential novel therapeutic target in lung cancer.

Purpose: Some 85% of lung cancers are smoking related. Here, we investigate the role of serine protease HtrA3 in smoking-related lung cancer., Experimental Design: We assess HtrA3 methylation and its corresponding expression in the human bronchial cell line BEAS-2B following cigarette smoke carcinogen treatment, in lung cancer cell lines and in primary lung tumors from light, moderate, and heavy smokers. We also show the effects of HtrA3 downregulation on MTT reduction and clonogenic survival with etoposide and cisplatin treatment and the corresponding effects of HtrA3 re-expression during treatment., Results: We show for the first time that HtrA3 expression is reduced or completely lost in over 50% of lung cancer cell lines and primary lung tumors from heavy smokers. Treatment of HtrA3-deficient cell lines with 5-aza-2'-deoxycytidine resulted in a dose-dependent increase in HtrA3 transcription. Further, sequence analysis of bisulfite-modified DNA from lung cancer cell lines and from primary lung tumors showed an increased frequency of methylation within the first exon of HtrA3 with a corresponding loss of HtrA3 expression, particularly in tumors from smokers. In BEAS-2B, treatment with the cigarette smoke carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone resulted in HtrA3 downregulation with a corresponding increase in methylation. Additional studies indicate resistance to etoposide and cisplatin cytotoxicity as a functional consequence of HtrA3 loss. Finally, immunohistochemical analysis of primary lung tumors revealed a strong correlation between low HtrA3 expression and heavy smoking history., Conclusions: Collectively, these results suggest that cigarette smoke-induced methylation of HtrA3 could contribute to the etiology of chemoresistant disease in smoking-related lung cancer.

Unlabelled: The aim of this study was to investigate the apoptosis resulting from NSC 95397, brefeldin A, bortezomib and sanguinarine in neuroendocrine tumor cell lines., Materials and Methods: A multiparametric high-content screening assay for measurement of apoptosis was used. The human pancreatic carcinoid cell line, BON-1, human typical bronchial carcinoid cell line NCI-H727 and the human atypical bronchial carcinoid cell line NCI-H720 were tested. After incubation with cytotoxic drugs, the DNA-binding dye Hoechst 33342, fluorescein-tagged probes that covalently bind active caspase-3 and chloromethyl-X-rosamine to detect mitochondrial membrane potential were added. Image acquisition and quantitative measurement of fluorescence was performed using automated image capture and analysis instrument ArrayScan. In addition, nuclear morphology was examined on microscopic slides stained with May-Grunewald-Giemsa., Results: A time- and dose-dependent activation of caspase-3 and increase in nuclear fragmentation and condensation were observed for the drugs using a multiparametric apoptosis assay. These results were confirmed with nuclear morphological examination on microscopic slides., Conclusion: NSC 95397, brefeldin A, bortezomib and sanguinarine induced caspase-3 activation with modest changes in nuclear morphology.

Introduction: Bevacizumab (Avastin, Fa. Roche, Genentech) is the first anti-angiogenic agent to be approved for the routine clinical treatment of cancer. Its toxicity profile is different to that of standard chemotherapeutic substances. Despite the rarity of gastrointestinal (GI) perforation in patients treated with bevacizumab, this serious adverse event results in significant morbidity and mortality. It was the aim of this study, based on exemplary cases of the reporting clinic as well as on published experiences, to characterise the specific clinical findings, the extraordinary pathogenesis, and the therapeutic outcome of such cases of peritonitis caused by perforation after antibody treatment., Methods: Data of all patients with perforation-caused peritonitis due to bevacizumab therapy since its clinical inauguration were sought in i) the database of the reporting clinic (case series), ii) in the published literature for comparison (historical comparative group) and iii) analysed with regard to results of the surgical management (evaluated parameters: rate of anastomotic insufficiency / disturbances of wound healing, morbidity, mortality)., Results: Over a time period of 4 years (from 2 / 1 / 2004 to 1 / 31 / 2008), overall 15 patients were found in this study, among whom 4 patients came from the reporting clinic (mean age, 57 years; males : females = 2 : 2). The mean duration of antibody (Ab) treatment until occurrence of the complication was 70 days (range: 8-150 days). Thirteen patients underwent surgical intervention, 2 patients died due to severe peritonitis without any operation. The overall morbidity was 73.3 % (n = 11 / 15), the mortality was 33.3 % (n = 5 / 15). All patients with an anastomosis developed an anastomotic insufficiency (100 %). Wound healing complications occurred in 38.5 % of the subjects (n = 5 / 13)., Conclusions: Peritonitis after GI perforation due to bevacizumab-based Ab treatment needs to be considered as a rare but serious and life-threatening complication. Impairment of wound healing because of the inhibition of angiogenesis is the reason for a different management of GI perforation under these conditions compared with the standard surgical treatment of peritonitis of other causes. In particular, it is recommended to avoid primary anastomosis and to prefer application of an intestinal stoma., ((c) Georg Thieme Verlag Stuttgart-New York.)

Background: Photodynamic therapy (PDT) is considered a useful and minimally invasive modality for treating centrally located early lung cancer. To date, there has been limited information on the long-term outcome of patients treated with PDT, especially those who are medically operable., Methods: Beginning in 1994, patients with roentgenographically occult bronchogenic squamous cell carcinoma (ROSCC) who met our criteria underwent PDT at Tohoku University Hospital and were followed up through 2006. Our criteria were as follows: (1) ROSCC without distant metastasis; (2) medically operable by means of lobectomy or further resection; (3) longitudinal tumor length of

Purpose: The aim of this prospective study was to examine two port systems for intravenous chemotherapy, authorized for high pressure injection, with respect to implantation, complications, implementation, and patency., Materials and Methods: 40 high pressure port systems of the two available models (20 x Power Port [Bard], 20 x T-Port-Contrast [PFM]) and 20 standard port systems (X-Port [BARD]) as the control group were implanted. Both high pressure systems are authorized for injection with a maximum pressure of 300 PSI. The patient population was comprised of patients with different malignomas and liver metastases. At regular intervals following the protocol of the chemotherapy, multiphasic CT for tumor staging was carried out., Results: The intravenous port systems were implanted without complications under sonographic guidance with transjugular access. The mean implantation time was 30 min (range: 22 - 40 min). After a median follow-up time of 6 months, the port patency was 100%. No port infections and no complications during high pressure injection of contrast agent occurred during this period. The level of contrast measured in the aorta was equivalent to the level of contrast in the vessels when contrast agent is administered over a large peripheral intravenous access., Conclusion: The intravenous high pressure port systems are equivalent to standard systems with regard to implantation and implementation. Intravenous chemotherapy can be performed as usual. The advantage is the possibility of multiphasic CT with authorized flow rates of up to 5 ml/sec.

Background: Chemotherapy often leads to encouraging responses in lung cancer. But, in the course of the treatment, resistance to chemotherapy ultimately limits the life expectancy of the patient. We aimed at investigating if treatment with cisplatin alters the intracellular Ca2+-homeostasis of lung cancer cells and how this may be related to cisplatin resistance., Methods: The squamous cell lung carcinoma cell line EPLC M1 and the small cell lung cancer cell line H1339 were exposed to cisplatin analogue to the in vivo pharmacokinetics. Changes in the cytoplasmic Ca2+-concentration ([Ca2+]c) were recorded using fluorescence microscopy. Protein expression was quantified using immuno-fluorescence and Western Blot analysis. Changes in gene expression were accomplished by small-interfering (si) RNA techniques., Results: Four "cycles" of cisplatin led to low level resistance in EPLC and H1339 cells. In the low level resistant cell clones, the Ca2+-content of the endoplasmic reticulum (ER) was decreased. In low level resistant EPLC cells, this was correlated with an increased expression of the inositol-1,4,5-trisphosphate receptor (IP3R). Inhibiting the increased expression of IP3R using siRNA, the low level resistance could be reversed. In low level resistant H1339 cells, the decreased Ca2+-content of the ER was correlated with a decreased expression of sarco/endoplasmic reticulum Ca2+-ATPases (SERCA). Decreasing the expression of SERCA in naïve H1339 cells resulted in low level cisplatin resistance., Conclusion: We conclude that cisplatin therapy leads to a decreased Ca2+-content of the ER thereby inducing low level resistance. This is caused by upregulation of the IP3R in EPLC and decreased expression of SERCA in H1339 cells.

Introduction: Anorexia and cachexia are the most common symptoms in cancer patients. They increase morbidity and mortality among cancer patients as well as complications of surgery, radiotherapy and chemotherapy. The most common drugs for treatment of cancer cachexia are corticosteroids and megestrol acetate., Material and Methods: The purpose of this study was to determine the influence of dexamethasone on appetite loss and weight loss in lung cancer patients treated with chemotherapy. Group A (30 patients) was treated with cisplatin, etoposide and standard supportive therapy, while group B (30 patients) received, in addition to this treatment, dexamethasone in the dose of 8 mg intravenously per day (1-3 day of chemotherapy)., Results: There was a statistically significant difference in appetite loss between two groups after the second chemotherapy cycle favouring group A. The analysis of weight loss showed a statistically significant difference between two groups after both chemotherapy cycles, once again in favour of group A. Concerning the impovement of appetite and weight gain, there was no statistically significant difference between two groups after both chemotherapy cycles., Discussion: Many double-blind randomized controlled studies showed beneficial symptomatic effect of corticosteroids in cancer cachexia, especially on the improvement of appetite, food intake and performance status. In most of the studies the weight gain was not recorded The most effective type of corticosteroids, dose and route of administration have not been established., Conclusion: Dexamethasone significantly decreases appetite loss and weight loss in lung cancer patients treated with chemotherapy, while it has no influence on appetite impovement and weight gain.

Neuroendocrine tumours belong to a heterogeneous family of neoplasms, originating in endocrine glands (such as the pituitary, parathyroid or the neuroendocrine adrenal glands), in endocrine islets (within the thyroid or pancreas) as well as in endocrine cells dispersed between exocrine cells throughout the digestive or respiratory tracts. The clinical behaviour of neuroendocrine tumours is variable; they may be functioning or not functioning, ranging from well-differentiated slow growing neuroendocrine tumours to poorly differentiated neuroendocrine tumours, which are highly aggressive malignant tumours. The development of somatostatin analogues as important diagnostic and treatment tools have revolutionised the clinical management of patients with neuroendocrine tumours. However, although symptomatic relief and stabilisation of tumour growth for various periods of time are observed in many patients treated with somatostatin analogues, tumour regression is rare. Development of new somatostatin analogues and new drug combination therapies should further improve the clinical management of these patients.

Up to 10% of patients with non-small cell lung carcinoma (NSCLC) achieve an objective response to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as erlotinib or gefitinib. This rate of response is related to non-smoker status, female gender, adenocarcinoma subtype, and Asian ethnicity. Molecular analysis showed that EGFR tyrosine kinase domain somatic mutations appear to be a strong predictor of response to EGFR-TKI. The L858R point mutation and the E746-A750 deletion represent 90% of the mutations encountered in responding patients. The amplification of EGFR gene also seems to be predictive of the response to EGFR-TKI, whereas T790M point mutation induces secondary resistance to EGFR-TKI. Nevertheless, objective responses or strong long-term stabilizations are observed in patients without any EGFR abnormality. Thus, the assessment of the EGFR status in patients with NSCLC remains controversial for clinical practice. The assessment of EGFR abnormalities should be targeted to identify reliable biomarkers of the NSCLC response to EGFR-TKI. This review presents the current knowledge on predictive biomarkers of NSCLC response to EGFR-TKI and the methods available for the assessment of EGFR status.

Currently available cytotoxic chemotherapy is ineffective for treating bronchogenic carcinoma, and this is partly due to unpredictable inter-tumor variation in resistance. For example, tumors with inactivating p53 mutations or deletions are less likely to respond to certain chemotherapeutics. However, even if p53 is intact, a tumor may be unresponsive if defects in other p53 pathway genes compromise apoptosis. In an effort to identify biomarkers that better predict response to camptothecin, we investigated the association of CPT-11 (irinotecan)-induced cytotoxicity (IC50) with apoptosis or expression of genes upstream or downstream of p53 in cell lines that retain wild-type p53. CPT-11 response was greater in cell lines with higher baseline apoptosis (p<0.05). In addition, the interactive transcript abundance index (ITAI) [c-myc*p73alpha]/[p21*Bcl-2] was directly correlated with baseline apoptosis (p<0.01) and CPT-11 response (p<0.05). The ITAI was also correlated with CPT-11 response among cell lines derived from a variety of tissues that had inactivating p53 mutations or deletions, supporting its applicability for predicting response to camptothecins in other tissues regardless of p53 status.

This review highlights the numerous molecular biology findings in the field of lung cancer with potential therapeutic impact in both the near and distant future. Abundant pre-clinical and clinical data indicate that BRCA1 mRNA expression is a differential modulator of chemotherapy sensitivity. Low levels predict cisplatin sensitivity and antimicrotubule drug resistance, and the opposite occurs with high levels. The main core of recent research has centered on epidermal growth factor receptor (EGFR) mutations and gene copy numbers. For the first time, EGFR mutations have been shown to predict dramatic responses in metastatic lung adenocarcinomas, with a threefold increase in time to progression and survival in patients receiving EGFR tyrosine-kinase inhibitors. Evidence has also been accumulated on the crosstalk between estrogen and EGFR receptor pathways, paving the way for clinical trials of EGFR tyrosine-kinase inhibitors plus aromatase inhibitors. Understanding the relevance of these findings can help to change the clinical practice in oncology towards customizing chemotherapy and targeted therapies, leading to improvement both in survival and in cost-effectiveness.

The economic assessment of treatments or medical strategies has been the subject of an increasing number of publications. The elevated costs and modest efficacy of many treatments for lung cancer are an added impetus to such analyses. This review summarises the principal results of these analyses, the limitations of the methods used and discusses the evaluation of the cost of these cancers to society. The economic assessment of new chemotherapeutic drugs, and the place of cost-effectiveness analysis in randomized trials is also considered. In the final part, we outline future prospects for this area of research and the importance of such considerations for clinicians. These evaluations, which provide complementary data for clinicians when making decisions on therapeutic options, will be adopted more widely in coming years.

The development of new anticancer agents specifically targeting the molecular processes involved in carcinogenesis is a major step forward in the treatment of patients with lung cancer. Preclinical models often show a cytostatic mechanism of action and predict an improved toxicity profile compared to traditional cytostatic drugs. This means that a standard development design based upon tumour shrinkage is not appropriate for these agents. The development of targeted therapies requires a new model for clinical phase I and II trials, with careful selection of patients who might benefit from treatment and adapted endpoints to establish that growth inhibition can be translated into a clinical benefit. Some targeted agents may have been discarded because of the use of inappropriate traditional endpoints during their development. A greater investment with additional implementation of correlative translational and pharmacodynamic studies during early development is crucial before going to phase III trials.

In the last decade there have been important innovations in the treatment of lung tumors. New combined modality therapies are becoming standard and require a network of cooperating partners. New therapeutic agents are under investigation that will hopefully improve the outcome of small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). Principles of chemotherapy in non-small cell und small cell lung cancer depending on stage and combination in multimodal regimens are shown. In the second part single drugs are described with their typical effects and side effects from the viewpoint of a clinician. A following part II will discuss new "targeted" biologicals.

The primary treatment of lung cancer depends on tumor stage. Chest CT scan and bronchoscopy are used to define the TNM stage and resectability. In case of lung cancer without mediastinal lymph node enlargement or direct mediastinal involvement (clinical stage I-IIb + T3N1) surgical treatment is recommended. The use of adjuvant chemotherapy has to be defined, but will be indicated in stage II and IIIa. Expected 5-year survival achieves 40 to 80 % depending on tumor stage. Exceeds the shorter diameter of mediastinal lymph nodes in chest CT scan more than 1 cm (or in case of positive PET scan) mediastinoscopy is indicated. In case of N2-disease and after tumor response to preoperative chemotherapy (about 60 %) secondary resection of the tumor leads to higher 5-year survival rates (20-40 %) compared to patients without induction therapy (5-20 %). In these patients and after unexpected detection of solitary lymph node metastasis by primary resection adjuvant mediastinal radiotherapy should be added. If the tumor has infiltrated the mediastinum or the upper sulcus (T3/4) and/or mediastinal lymph nodes are obviously tumor burden (e. g. > 3 cm, N2 bulky, N3) radical primary resection may not be possible. In these patients combined radio- and chemotherapy induces a high percentage of tumor regression and can be used before secondary resection (5-year survival 5-20 %). Locally advanced tumors infiltrating the main bronchus close to the carina or the carina itself and tumors with metastases in the same lobe, both without mediastinal lymph node metastases (T3/4N0-1), can be resected by sleeve pneumonectomy and lobectomy with satisfactory results respectively. In patients with resectable lung cancer and no clinical sign of tumor disease (f. e. anemia, weight loss, pain) limited staging procedure with chest CT scan including upper abdomen and bronchoscopy is reasonable. In the remaining patients complete staging is necessary. We recommend an interdisciplinary approach to patients with lung cancer.

Background: It is well known that central-type early stage lung cancer < 1.0 cm in diameter shows almost 100% complete response (CR) to photodynamic therapy (PDT). However, we have encountered cases of local recurrence after CR of tumors with a surface diameter < 1.0 cm., Patients and Methods: Ninety-three patients with 114 lesions were followed up, and cases of recurrence after CR has been obtained with initial tumors that had a diameter < 1.0 cm were examined. We compared the cytologic findings of local recurrence after CR to the cytologic findings before PDT. The relationship between the cell features and the depth of bronchial tumor invasion before PDT and on recurrence was evaluated., Results: The CR and 5-year survival rates of patients with lesions < 1.0 cm were 92.8% (77 of 83 patients) and 57.9%, respectively; meanwhile, in the group of patients with lesions > or = 1.0 cm, CR and 5-year survival rates were 58.1% (18 of 31 patients) and 59.3%. There was a significant difference in efficacy between the two groups (p < 0.001). Recurrences after CR were recognized in 9 of 77 lesions (11.7%) < 1.0 cm. When the recurrent tumor cells showed type I-II (low-to-moderate atypia) at the same site initially treated, CR could be obtained by a second PDT. Type III cells (high-grade atypia) showed the characteristics of tumor cells from deeper layers of the bronchial wall. Local recurrence at the same site may be caused by residual tumor cells from deep layers because of inadequate laser irradiation and penetration., Conclusions: To reduce the recurrence rate, it is essential to accurately grasp the tumor extent and the depth of the bronchogenic carcinoma before performing PDT. Analysis of cell features of recurrent lesions after CR appears to be a useful source of information as to the depth of cancer invasion in the bronchial wall.

Improvements in conventional cytotoxic treatment have probably reached a plateau for the treatment of lung cancer; therefore, new treatment strategies that are based on a better understanding of tumour biology are required. Some progress has been made for non-small cell lung cancer, in which erlotinib (Tarceva, OSI-774; Genentech), an epidermal growth factor receptor antagonist, has demonstrated a significant clinical benefit in a Phase III randomised trial, and has been licensed for second- or third-line treatment. Other therapies under investigation include angiogenesis inhibitors, COX-2 inhibitors, retinoids, farnesyl transferase inhibitors, Bcl-2 inhibitors and c-Kit antagonists. In this article the recent and ongoing Phase II and III trials of these therapies in lung cancer are summarised, and the prospects for their further clinical development are discussed.

Introduction: In France, cancer of the bronchus is responsible for 25,000 deaths per year. Non small cell lung cancer (NSCLC) represents 80% of bronchial carcinoma of which 40-50% are mefastatic at the time of diagnosis. At present, although the therapeutic benefits are modest, it is now recognised that combination chemotherapy including platinum salts improves the survival of these patients., Methods: We analysed retrospectively a cohort of 57 patients suffering from stage IV NSCLC treated with chemotherapy combining cisplatin (80 mg/rn2 on day 1), vinorelbine (25 mg/rn2 on days 1 and 8) and ifosfamide (3000 mg/in 2 on day 1), (NIP), repeated every 21 days., Results: The population studied comprised 6 women and 51 men, of average age 59.8 +/- 9.1 years. A history tobacco use (smokers and ex-smokers) was identified in 93%. The WHO performance index was equal to or greater than 2 in 22.8%. All patients were studied in terms of toxicity and overall survival but only 40 (70%) were able to be evaluated in terms of response to treatment (on account of having received more than three cycles of NIP chemotherapy). For the group considered as a whole, the median survival was 6.7 months with a one year survival of 24.5%. Median survival without progression was 4.4 months. The most frequent toxicities were haematological and digestive. They were most common among patients over the age of 70 but had no effect on median survival. For the 40 patients for whom chemotherapy was evaluable, the objective response rate was 20%. This objective response was the only factor that was signiticantly correlated with one year survival: 62.5% in responders, 28.1% in non-responders (p < 0.05)., Conclusion: Treatment of stage IV NSCLC with NIP chemotherapy is effective and improves the survival of these patients independently of other prognostic factors such as age, the presence of cerebral metastases, performance status, histological type, the number of metastatic sites or the serum LOH level.