Phase III Study of Surgery Versus Definitive Concurrent Chemoradiotherapy Boost in Patients With Resectable Stage IIIA(N2) and Selected IIIB Non-Small-Cell Lung Cancer After Induction Chemotherapy and Concurrent Chemoradiotherapy (ESPATUE).

PURPOSE: Concurrent chemoradiotherapy with or without surgery are options for stage IIIA(N2) non-small-cell lung cancer. Our previous phase II study had shown the efficacy of induction chemotherapy followed by chemoradiotherapy and surgery in patients with IIIA(N2) disease and with selected IIIB disease. Here, we compared surgery with definitive chemoradiotherapy in resectable stage III disease after induction. PATIENTS AND METHODS: Patients with pathologically proven IIIA(N2) and selected patients with IIIB disease that had medical/functional operability received induction chemotherapy, which consisted of three cycles of cisplatin 50 mg/m(2) on days 1 and 8 and paclitaxel 175 mg/m(2) on day 1 every 21 days, as well as concurrent chemoradiotherapy to 45 Gy given as 1.5 Gy twice daily, concurrent cisplatin 50 mg/m(2) on days 2 and 9, and concurrent vinorelbine 20 mg/m(2) on days 2 and 9. Those patients whose tumors were reevaluated and deemed resectable in the last week of radiotherapy were randomly assigned to receive a chemoradiotherapy boost that was risk adapted to between 65 and 71 Gy in arm A or to undergo surgery (arm B). The primary end point was overall survival (OS). RESULTS: After 246 of 500 planned patients were enrolled, the trial was closed after the second scheduled interim analysis because of slow accrual and the end of funding, which left the study underpowered relative to its primary study end point. Seventy-five patients had stage IIIA disease and 171 had stage IIIB disease according to the Union for International Cancer Control TNM classification, sixth edition. The median age was 59 years (range, 33 to 74 years). After induction, 161 (65.4%) of 246 patients with resectable tumors were randomly assigned; strata were tumor-node group, prophylactic cranial irradiation policy, and region. Patient characteristics were balanced between arms, in which 81 were assigned to surgery and 80 were assigned to a chemoradiotherapy boost. In arm B, 81% underwent R0 resection. With a median follow-up after random assignment of 78 months, 5-year OS and progression-free survival (PFS) did not differ between arms. Results were OS rates of 44% for arm B and 40% for arm A (log-rank P = .34) and PFS rates of 32% for arm B and 35% for arm A (log-rank P = .75). OS at 5 years was 34.1% (95% CI, 27.6% to 40.8%) in all 246 patients, and 216 patients (87.8%) received definitive local treatment. CONCLUSION: The 5-year OS and PFS rates in randomly assigned patients with resectable stage III non-small-cell lung cancer were excellent with both treatments. Both are acceptable strategies for this good-prognosis group.

Dynamic contrast-enhanced MRI parameters as biomarkers for the effect of vatalanib in patients with non-small-cell lung cancer.

AIMS: To assess the utility of dynamic contrast-enhanced MRI parameters in the demonstration of early antiangiogenic effects and as prognostic biomarkers in second-line treatment of advanced-stage non-small-cell lung cancer with vatalanib. PATIENTS & METHODS: The transfer constant (K(trans)) and the initial area under the contrast concentration-time curve at 60 s (AUC60) were assessed in 46 patients. Changes were compared with response evaluation from computed tomography imaging and Response Evaluation Criteria In Solid Tumors guidelines. RESULTS: Statistically significant mean reductions in K(trans) (38.4%; p < 0.0001) and AUC60 (24.9%; p < 0.0001) were found at day 2. After 12 weeks, 16 patients (35%) demonstrated stable disease and 30 (65%) demonstrated progressive disease. No statistically significant differences in day 2 K(trans) and AUC60 reductions between stable disease and progressive disease patients were found. CONCLUSION: Dynamic contrast-enhanced MRI can demonstrate a statistically significant reduction in vascular parameters of non-small-cell lung cancer, but does not predict patient outcome.

Lung transplantation: a treatment option in end-stage lung disease.

BACKGROUND: Lung transplantation is the final treatment option in the end stage of certain lung diseases, once all possible conservative treatments have been exhausted. Depending on the indication for which lung transplantation is performed, it can improve the patient's quality of life (e.g., in emphysema) and/ or prolong life expectancy (e.g., in cystic fibrosis, pulmonary fibrosis, and pulmonary arterial hypertension). The main selection criteria for transplant candidates, aside from the underlying pulmonary or cardiopulmonary disease, are age, degree of mobility, nutritional and muscular condition, and concurrent extrapulmonary disease. The pool of willing organ donors is shrinking, and every sixth candidate for lung transplantation now dies while on the waiting list. METHOD: We reviewed pertinent articles (up to October 2013) retrieved by a selective search in Medline and other German and international databases, including those of the International Society for Heart and Lung Transplantation (ISHLT), Eurotransplant, the German Institute for Applied Quality Promotion and Research in Health-Care (Institut für angewandte Qualitätsförderung und Forschung im Gesundheitswesen, AQUA-Institut), and the German Foundation for Organ Transplantation (Deutsche Stiftung Organtransplantation, DSO). RESULTS: The short- and long-term results have markedly improved in recent years: the 1-year survival rate has risen from 70.9% to 82.9%, and the 5-year survival rate from 46.9% to 59.6%. The 90-day mortality is 10.0%. The postoperative complications include acute (3.4%) and chronic (29.0%) transplant rejection, infections (38.0%), transplant failure (24.7%), airway complications (15.0%), malignant tumors (15.0%), cardiovascular events (10.9%), and other secondary extrapulmonary diseases (29.8%). Bilateral lung transplantation is superior to unilateral transplantation (5-year survival rate 57.3% versus 47.4%). CONCLUSION: Seamless integration of the various components of treatment will be essential for further improvements in outcome. In particular, the follow-up care of transplant recipients should always be provided in close cooperation with the transplant center.

10-year long-term survival (LTS) of induction chemotherapy with three cycles cisplatin/paclitaxel followed by concurrent chemoradiation cisplatin/etoposide/45 Gy (1.5 Gy bid) plus surgery in locally advanced non-small-cell lung cancer (NSCLC)-a multicenter phase-II trial (CISTAXOL).

BACKGROUND: Induction chemoradiotherapy plus surgery remains an option to study in IIIA(N2) and selected IIIB NSCLC. Here we report ten-year long-term survival of a prospective multicenter German-French phase-II trial with trimodality. PATIENTS AND METHODS: Mediastinoscopically proven IIIA(N2)/selected IIIB NSCLC received three cycles cisplatin (50 mg/m(2) day 1+8) and paclitaxel (175 mg/m(2)d1) qd 22. Concurrent CTx/RTx followed: 45 Gy (1.5 Gy bid) with cisplatin 50 mg/m(2) day 2+9 and etoposide 100 mg/m(2) d 4-6. Surgery was planned three to five weeks after RTx. If evaluated inoperable/irresectable at the end of RTx, definitive RTx-boost (20 Gy; 2 Gy qd) followed. Here we report 10-year-LTS for this cohort. RESULTS: All 64 patients were accrued 3/99 to 2/02. Patients characteristics: IIIA(N2)/IIIB 25/39; m/f 48/16; adeno/squamous/large-cell/adenosquamous/NOS 15/26/18/3/2; age: median 52.5 (range 33-69). 36 operated: R0 32/36 (89%); pCR 16/36 (44%). 10-year-LTS%; all 26.0; IIIA(N2) 37.1; IIIB 17.9; relevant prognostic factors (exploratory): pretreatment - histopathology (squamous/adeno) - age (<50/≥50) - Charlson-CI: 1/>1 - BMI (≥25/<25) - pack years smoking (≥10/<10); treatment-dependent - R0/no-R0. CONCLUSIONS: This regimen achieves substantial LTS. Interestingly, adenocarcinomas, older patients, unfavorable comorbidity scores, higher BMI and light smokers demonstrate poor long-term outcome even with aggressive trimodality. This dataset defines the rationale for our ongoing randomized trial with surgery after induction therapy in IIIA(N2)/selected IIIB (ESPATÜ).

[Lung cancer]. / Lungenkarzinom.

Since the late 1980s, lung cancer incidence in men has declined in Germany whereas in women there is still a rise. There is no approved screening program for lung cancer up to now and results from randomized trials like the National Lung Screening Trial are eagerly awaited. In stage II and IIIA non-small cell lung cancer (NSCLC), several positive trials have demonstrated the advantage of adjuvant chemotherapy which is now an established modality to improve cure rates. Epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC. Erlotinib, an EGFR tyrosine kinase inhibitor, has been approved for relapsed advanced-stage NSCLC. Bevacizumab is a monoclonal antibody against vascular endothelial growth factor, a primary mediator of angiogenesis that is commonly overexpressed in solid tumors including lung cancer. Bevacizumab, in combination with chemotherapy, has demonstrated improved outcomes in advanced NSCLC and is now approved for selected patients with advanced-stage NSCLC. Patient selection for therapeutic use of bevacizumab is crucial to optimize safety. Ongoing trials explore multitargeted agents such as sorafenib, sunitinib, and vandetanib.

Ameloblastic fibrosarcoma or odontogenic carcinosarcoma: a matter of classification?

A biphasic odontogenic tumor with aggressive clinical behaviour is reported. The tumor arose posterior to the right mandibular third molar involving the angle of the mandible and the ascending ramus. Within a 5 years period the patient suffered from two episodes of local progression and final disease generalization occurred 6 years after initial surgical therapy. On histopathologic evaluation, both recurrences and the distant metastasis preserved the biphasic pattern seen in the primary tumor with both epithelial and mesenchymal components exhibiting clear cytological features of malignancy. There was no evidence of sarcomatous overgrowth within the progression of the tumor. By contrast, the proportion of the epithelial component was even enlarged in the second recurrence. Thus, both pathologic features and clinical behaviour clearly distinguishes this tumor from ameloblastic fibrosarcoma and demonstrates the clear morphological as well as clinical characteristics of a true malignant mixed type tumor with a definite sarcomatous and carcinomatous component. Thus, even though a very rare lesion, our case supports the consideration of the odontogenic carcinosarcoma as an individual entity.

The tetrahydropyranopterin structure of the sulfur-free and metal-free molybdenum cofactor precursor.

The molybdenum cofactor (Moco), a highly conserved pterin compound coordinating molybdenum (Mo), is required for the activity of all Mo-dependent enzymes with the exception of nitrogenase. Moco is synthesized by a unique and evolutionary old multi-step pathway with two intermediates identified so far, the sulfur-free and metal-free pterin derivative precursor Z and molybdopterin, a pterin with an enedithiolate function essential for Mo ligation. The latter pterin component is believed to form a tetrahydropyranopterin similar to the one found for Moco in the crystal structure of Mo as well as tungsten (W) enzymes. Here we report the spectroscopic characterization and structure elucidation of precursor Z purified from Escherichia coli overproducing MoaA and MoaC, two proteins essential for bacterial precursor Z synthesis. We have shown that purified precursor Z is as active as precursor Z present in E. coli cell extracts, demonstrating that no modifications during the purification procedure have occurred. High resolution electrospray ionization mass spectrometry afforded a [M + H]+ ion compatible with a molecular formula of C10H15N5O8P. Consequently 1H NMR spectroscopy not allowed structural characterization of the molecule but confirmed that this intermediate undergoes direct oxidation to the previously well characterized non-productive follow-up product compound Z. The 1H chemical shift and coupling constant data are incompatible with previous structural proposals and indicate that precursor Z already is a tetrahydropyranopterin system and carries a geminal diol function in the C1' position.

c-kit expression in adenocarcinomas of the lung.

The tyrosine-kinase receptor c-kit (CD117) and its ligand stem cell factor are considered to be co-expressed in various solid tumors, including adenocarcinomas of the lung. The frequency of c-kit expression and its association with clinical parameters has not yet been evaluated in a larger population of lung adenocarcinomas. Therefore, tumor tissue of 95 consecutive patients with adenocarcinoma of the lung was stained using a polyclonal c-kit antibody. c-kit expression was correlated with relevant clinical parameters obtained by chart review. Positive c-kit expression in tumor tissue was observed in 61 of 95 patients (64%). Univariate analysis showed a significant effect of T (p = 0.003), N (p = 0.001) and M stage (p < 0.001) as well as of performance status (p = 0.001), surgical resection (p < 0.001), and LDH serum levels (p = 0.016) on survival. In contrast, c-kit protein expression was non- significant (p = 0.913). However, multivariate Cox regression with the influential parameters revealed a significant effect of c-kit expression on survival. Forward stepwise selection showed a 1.77-fold increased risk to die (hazard ratio, HR; 95% confidence interval, CI: 1.00-3.14, p = 0.047) for patients with c-kit-positive tumors. Similar data for c-kit expression were obtained by backward stepwise selection (HR: 1.78; 95% CI: 1.00-3.16; p = 0.044). In conclusion, the receptor tyrosine kinase c-kit is frequently expressed in adenocarcinomas of the lung and has a relevant effect on patient survival. The results of this study support clinical trials targeting the c-kit receptor with specific c-kit inhibitors (e.g. imatinib).

Phase II study of imatinib in patients with small cell lung cancer.

PURPOSE: The purpose of our study was to assess the objective response to imatinib administered to patients with small cell lung cancer (SCLC). EXPERIMENTAL DESIGN: Eligible patients were those with SCLC who either had chemotherapy-naive extensive-stage or had SCLC in a sensitive relapse. Patients enrolled on the trial were treated with 600 mg of imatinib daily. The response was assessed using Southwest Oncology Group (SWOG) criteria after 3 and 6 weeks. Tumor specimens were examined by immunohistochemistry for the KIT receptor. RESULTS: Nineteen patients with SCLC entered on the study, including 16 men and 3 women. Nine patients had previously untreated extensive-stage disease and 10 patients had sensitive relapse. A central pathology review confirmed SCLC in only 14 of the 19 patients. There were no objective responses; however, one patient with sensitive-relapse disease had prolonged stabilization of disease (>3 months) while on imatinib therapy. The median time to progression was 0.8 months (range, 0.6-1.3 months) and 1.2 months (range, 0.2-4.1 months) in the previously untreated and sensitive-relapse groups, respectively. Tumor tissue samples from 4 (21%) of the 19 patients had the KIT receptor (CD117). CONCLUSIONS: There was no observed antitumor activity in this limited Phase II trial of patients with SCLC, of which only a few tumors showed expression of the imatinib target. The results of this trial are, thus, inconclusive about the antitumor activity of imatinib against SCLC with the targeted KIT receptor (CD117). Further testing of imatinib in patients with SCLC will focus on demonstration of KIT expression in the setting of confirmed SCLC histology.

Characterization of c-kit expression in small cell lung cancer: prognostic and therapeutic implications.

PURPOSE: The tyrosine-kinase receptor c-kit and its ligand stem cell factor are coexpressed in many small cell lung cancer (SCLC) cell lines, leading to the hypothesis that this coexpression constitutes an autocrine growth loop. To further evaluate the frequency and pathogenic relevance of c-kit expression, tumor tissue together with the corresponding clinical data of SCLC patients was analyzed. EXPERIMENTAL DESIGN: Tumor tissue of 102 consecutive SCLC cancer patients was analyzed immunohistochemically using an affinity-purified polyclonal c-kit antibody. Immunostaining data were correlated with survival and other relevant clinical parameters. RESULTS: A positive c-kit expression was observed in 37% of patients. c-kit expression was associated with decreased survival in the likelihood-ratio-forward selection model of the Cox regression including clinically relevant risk factors (c-kit expression, age, gender, stage, tumor stage, node stage, metastasis stage, weight loss, performance status, response to chemotherapy, lactate dehydrogenase, neuronspecific enolase, hemoglobin). Only c-kit expression [hazard ratio, 2.00; confidence interval (CI), 1.17-3.41; P = 0.012], response to chemotherapy (hazard ratio, 4.49; CI, 2.36-8.55; P < 0.001), and tumor stage (hazard ratio, 2.11; CI, 1.18-3.74; P = 0.008) were explanatory prognostic factors. These factors and all possible interactions between them were further analyzed in a second Cox regression model. As expected, response to chemotherapy had the highest impact on survival (hazard ratio, 3.06; CI, 1.69-5.54; P < 0.001). In patients with extensive disease, minor response to chemotherapy, and positive c-kit expression, the risk to die increased to 8.4 (hazard ratio, 2.74; CI, 1.52-4.91; P = 0.002). In a Kaplan-Meier analysis median survival of patients with minor response to chemotherapy and extensive stage was 288 days (CI, 255-321 days) when c-kit expression was negative compared with only 71 days (CI, 0-237 days) for c-kit-positive patients (log rank test: P = 0.003). CONCLUSIONS: c-kit represents a new prognostic factor in SCLC. c-kit expression is of particular clinical relevance in patients with advanced disease and poor response to chemotherapy. Given the very limited therapeutic options and unfavorable prognosis of these patients, clinical studies aimed at targeting c-kit (e.g., STI571) are clearly warranted.

Synthesis and Characterization of an Octanuclear Mixed-Ligand Copper(II) Complex of the Immunosuppressant Thiopurine Drug Azathioprine.

An octanuclear mixed-ligand copper(II) complex of the immunosuppressant drug azathioprine (AZA) and 2,2,6,6-tetramethylheptane-3,5-dione (THD), [{Cu(4)(AZA(-))(2)(THD(-))(5)(OH(-))}(2)].2CH(3)CN, has been synthesized and characterized by X-ray crystallography and by mass spectrometric and magnetic measurements. Eight copper(II) ions, four monodeprotonated azathioprine(-) ligands, ten monodeprotonated THD(-) ligands, and two hydroxide anions are assembled to form a centrosymmetric, octanuclear molecule, where two tetranuclear moieties of the molecule are connected by four coordination bonds between copper atoms and the N(3) and N(9) atoms of two different AZA ligands. In each half of the molecule, all four copper atoms are five-coordinated with a square pyramidal geometry. Three copper atoms are bridged through a &mgr;(3)-OH(-) group to form a Cu(3)OH cluster with Cu-Cu distances of 3.213(2), 3.585(2), and 3.672(2) Å, respectively, while the fourth one is separated from the cluster by a purine base. Antiferromagnetic coupling is observed within the two OH(-)-bridged trinuclear copper clusters of the octanuclear molecule. The magnetic susceptibility data fit well with the theoretical model proposed (J = -75 cm(-)(1), g = 2.235). Three of the four purine nitrogen atoms (N(3), N(7), and N(9)) bind to copper atoms in both crystallographically independent AZA moieties. All of the 6-mercaptopurine (6-MP) fragments of AZA, a biologically active component of the drug, are buried inside the complex molecule. According to ESI-MS measurements, at least the main skeleton of the molecule is still present in solution despite partial decomposition of the complex via ligand exchange with the solvent. Crystal data: P2(1)/n, a = 21.754(4) Å, b = 16.441(3) Å, c = 25.209(5) Å, beta = 97.07(2) degrees, V = 8948(3) Å(3), Z = 2.