Oral vinorelbine and cisplatin with concomitant radiotherapy in stage III non-small cell lung cancer (NSCLC): A feasibility study

Background: Concurrent chemoradiotherapy has improved survival in inoperable stage III non-small cell lung cancer (NSCLC). This phase I trial was performed in order to establish a dose recommendation for oral vinorelbine in combination with cisplatin and simultaneous radiotherapy. Patients and Methods: Previously untreated patients with stage IIIB NSCLC received concurrent chemoradiotherapy with 66 Gy and 2 cycles of cisplatin and oral vinorelbine which was administered at 3 different levels (40, 50 and 60 mg/m(2)). This was to be followed by 2 cycles of cisplatin/vinorelbine oral consolidation chemotherapy. The study goal was to determine the maximal recommended dose of oral vinorelbine during concurrent treatment. Results: 11 stage IIIB patients were entered into the study. The median radiotherapy dose was 66 Gy. Grade 3-4 toxicity included neutropenia, esophagitis, gastritis and febrile neutropenia. The dose-limiting toxicity for concurrent chemoradiotherapy was esophagitis. 9 patients received consolidation chemotherapy, with neutropenia and anemia/thrombocytopenia grade 3 being the only toxicities. The overall response was 73%. Conclusion: Oral vinorelbine 50 mg/m(2) (days 1, 8, 15 over 4 weeks) in combination with cisplatin 20 mg/m2 (days 1-4) is the recommended dose in combination with radiotherapy (66 Gy) and will be used for concurrent chemoradiotherapy in a forthcoming phase III trial testing the efficacy of consolidation chemotherapy in patients not progressing after chemoradiotherapy

J/Psi and Psi' total cross sections and formation times from data for charmonium suppression in pApA collisions

The recent data for E866 experiment on the x_F dependence for charmonium suppression in pA collisions at 800 GeV are analyzed using a time- and energy-dependent preformed charmonium absorption cross section \sigma_{abs}^\psi(\tau,\sqrt{s}). For \sqrt{s}=10 GeV the initially (\tau=0) produced premeson has an absorption cross section of \sigma_{pr}~3mb. At the same energy but for \tau -> \infty one deduces for the total cross sections \sigma_{tot}^{J/Psi N}=(2.8\pm 0.3)mb, \sigma_{tot}^{J/Psi N}= (10.5\pm 3.6)mb. The date are compatible with a formation time \tau_{1/2}=0.6 fm/c.Comment: 13 pages of Latex including 2 figures; typos in the abstract are correcte

Early toxicity predicts long-term survival in high-grade glioma

BACKGROUND: Patients with high-grade gliomas are treated with surgery followed by chemoradiation. The risk factors and implications of neurological side effects are not known. METHODS: Acute and late ≥ grade 3 neurological toxicities (NTs) were analysed among 2761 patients from 14 RTOG trials accrued from 1983 to 2003. The association between acute and late toxicity was analysed using a stepwise logistic regression model. The association between the occurrence of acute NT and survival was analysed as an independent variable. RESULTS: There were 2610 analysable patients (86% glioblastoma, 10% anaplastic astrocytoma). All received a systemic agent during radiation (83% chemotherapy, 17% biological agents). Median radiation dose was 60 Gy. There were 182 acute and 83 late NT events. On univariate analysis, older age, poor performance status, aggressive surgery, pre-existing neurological dysfunction, poor mental status and twice-daily radiation were associated with increased acute NT. In a stepwise logistic regression model the occurrence of acute NT was significantly associated with late NT (OR=2.40; 95% CI=1.2-4.8; P=0.014). The occurrence of acute NT predicted poorer overall survival, independent of recursive partitioning analysis class (median 7.8 vs 11.8 months). INTERPRETATION: Acute NT is significantly associated with both late NT and overall survival

Radiotherapy and temozolomide for newly diagnosed glioblastoma and anaplastic astrocytoma: validation of Radiation Therapy Oncology Group-Recursive Partitioning Analysis in the IMRT and temozolomide era

Since the development of the Radiation Therapy Oncology Group-Recursive Partitioning Analysis (RTOG-RPA) risk classes for high-grade glioma, radiation therapy in combination with temozolomide (TMZ) has become standard care. While this combination has improved survival, the prognosis remains poor in the majority of patients. Therefore, strong interest in high-grade gliomas from basic research to clinical trials persists. We sought to evaluate whether the current RTOG-RPA retains prognostic significance in the TMZ era or alternatively, if modifications better prognosticate the optimal selection of patients with similar baseline prognosis for future clinical protocols. The records of 159 patients with newly-diagnosed glioblastoma (GBM, WHO grade IV) or anaplastic astrocytoma (AA, WHO grade III) were reviewed. Patients were treated with intensity-modulated radiation therapy (IMRT) and concurrent followed by adjuvant TMZ (n = 154) or adjuvant TMZ only (n = 5). The primary endpoint was overall survival. Three separate analyses were performed: (1) application of RTOG-RPA to the study cohort and calculation of subsequent survival curves, (2) fit a new tree model with the same predictors in RTOG-RPA, and (3) fit a new tree model with an expanded predictor set. All analyses used a regression tree analysis with a survival outcome fit to formulate new risk classes. Overall median survival was 14.9 months. Using the RTOG-RPA, the six classes retained their relative prognostic significance and overall ordering, with the corresponding survival distributions significantly different from each other (P < 0.01, χ2 statistic = 70). New recursive partitioning limited to the predictors in RTOG-RPA defined four risk groups based on Karnofsky Performance Status (KPS), histology, age, length of neurologic symptoms, and mental status. Analysis across the expanded predictors defined six risk classes, including the same five variables plus tumor location, tobacco use, and hospitalization during radiation therapy. Patients with excellent functional status, AA, and frontal lobe tumors had the best prognosis. For patients with newly-diagnosed high-grade gliomas, RTOG-RPA classes retained prognostic significance in patients treated with TMZ and IMRT. In contrast to RTOG-RPA, in our modified RPA model, KPS rather than age represented the initial split. New recursive partitioning identified potential modifications to RTOG-RPA that should be further explored with a larger data set

Prospective single-arm study of 72 Gy hyperfractionated radiation therapy and combination chemotherapy for anaplastic astrocytomas

<p>Abstract</p> <p>Background</p> <p>Despite intensive multimodal treatment, outcome of patients with malignant glioma remains poor, and a standard dose of radiotherapy for anaplastic astrocytoma has not been defined. In the past RTOG study (83-02), the arm of 72 Gy hyperfractionated radiotherapy (HFRT) for malignant gliomas showed better outcome than the arms of higher doses (76.8 – 81.6 Gy) and the arms of lower doses (48 – 54.4 Gy). The purpose of this study is to verify the efficacy of this protocol.</p> <p>Methods</p> <p>From July 1995, 44 consecutive eligible patients with histologically proven anaplastic astrocytoma were enrolled in this study (HFRT group). The standard regimen in this protocol was post-operative radiotherapy of 72 Gy in 60 fractions (1.2 Gy/fraction, 2 fractions/day) with concurrent chemotherapy (weekly ACNU). The primary endpoint was local control rate (LCR), and the secondary endpoints were overall survival (OS), progression-free survival (PFS) and late toxicity.</p> <p>Results</p> <p>Three-year OS of the HFRT group was 64.8% (95% confidence interval; 48.4–81.3%). Three-year PFS rate and LCR were 64.4% (95%CI: 48.4–80.3%) and 81.6% (95%CI: 69.2–94.8%), respectively.</p> <p>The number of failures at 5 years in the HFRT group were 14 (32%). The number of failures inside the irradiation field was only about half (50%) of all failures. One (2%) of the patients clinically diagnosed as brain necrosis due to radiation therapy.</p> <p>Conclusion</p> <p>The results of this study suggested that 72 Gy HFRT seemed to show favorable outcome for patients with anaplastic astrocytoma with tolerable toxicity.</p

The c-Met receptor tyrosine kinase inhibitor MP470 radiosensitizes glioblastoma cells

<p>Abstract</p> <p>Purpose</p> <p>Glioblastoma multiforme (GBM) is resistant to current cytotoxic therapies, in part because of enhanced DNA repair. Activation of the receptor tyrosine kinase c-Met has been shown to protect cancer cells from DNA damage. We hypothesized that inhibiting c-Met would decrease this protection and thus sensitize resistant tumor cells to the effects of radiation therapy.</p> <p>Materials and methods</p> <p>Eight human GBM cell lines were screened for radiosensitivity to the small-molecule c-Met inhibitor MP470 with colony-count assays. Double-strand (ds) DNA breaks was quantified by using antibodies to gamma H2AX. Western blotting demonstrate expression of RAD51, glycogen synthase kinase (GSK)-3β, and other proteins. A murine xenograft tumor flank model was used for <it>in vivo </it>radiosensitization studies.</p> <p>Results</p> <p>MP470 reduced c-Met phosphorylation and enhanced radiation-induced cell kill by 0.4 logs in SF767 cells. Cells pretreated with MP470 had more ds DNA damage than cells treated with radiation alone. Mechanistically, MP470 was shown to inhibit dsDNA break repair and increase apoptosis. MP470 influences various survival and DNA repair related proteins such as pAKT, RAD51 and GSK3β. <it>In vivo</it>, the addition of MP470 to radiation resulted in a tumor-growth-delay enhancement ratio of 2.9 over radiation alone and extended survival time.</p> <p>Conclusions</p> <p>GBM is a disease site where radiation is often used to address both macroscopic and microscopic disease. Despite attempts at dose escalation outcomes remain poor. MP470, a potent small-molecule tyrosine kinase inhibitor of c-Met, radiosensitized several GBM cell lines both <it>in vitro </it>and <it>in vivo</it>, and may help to improve outcomes for patients with GBM.</p

Age-related delay in information accrual for faces: Evidence from a parametric, single-trial EEG approach

Background: In this study, we quantified age-related changes in the time-course of face processing by means of an innovative single-trial ERP approach. Unlike analyses used in previous studies, our approach does not rely on peak measurements and can provide a more sensitive measure of processing delays. Young and old adults (mean ages 22 and 70 years) performed a non-speeded discrimination task between two faces. The phase spectrum of these faces was manipulated parametrically to create pictures that ranged between pure noise (0% phase information) and the undistorted signal (100% phase information), with five intermediate steps. Results: Behavioural 75% correct thresholds were on average lower, and maximum accuracy was higher, in younger than older observers. ERPs from each subject were entered into a single-trial general linear regression model to identify variations in neural activity statistically associated with changes in image structure. The earliest age-related ERP differences occurred in the time window of the N170. Older observers had a significantly stronger N170 in response to noise, but this age difference decreased with increasing phase information. Overall, manipulating image phase information had a greater effect on ERPs from younger observers, which was quantified using a hierarchical modelling approach. Importantly, visual activity was modulated by the same stimulus parameters in younger and older subjects. The fit of the model, indexed by R2, was computed at multiple post-stimulus time points. The time-course of the R2 function showed a significantly slower processing in older observers starting around 120 ms after stimulus onset. This age-related delay increased over time to reach a maximum around 190 ms, at which latency younger observers had around 50 ms time lead over older observers. Conclusion: Using a component-free ERP analysis that provides a precise timing of the visual system sensitivity to image structure, the current study demonstrates that older observers accumulate face information more slowly than younger subjects. Additionally, the N170 appears to be less face-sensitive in older observers

The role of a pseudocapsula in thymic epithelial tumors: outcome and correlation with established prognostic parameters. Results of a 20-year single centre retrospective analysis

<p>Abstract</p> <p>Background</p> <p>Treatment of thymoma is often based on observation of only a few patients. Surgical resection is considered to be the most important step. Role of a pseudocapsula for surgery, its clinical significance and outcome compared with established prognostic parameters is discussed which has not been reported so far.</p> <p>Methods</p> <p>84 patients with thymoma underwent resection and analysis was carried out for clinical features, prognostic factors and long-term survival.</p> <p>Results</p> <p>Fifteen patients were classified in WHO subgroup A, 21 in AB, 29 in B and 19 patients in C. Forty two patients were classified in Masaoka stage I, 19 stage II, 9 stage III and 14 stage IV. Encapsulated thymoma was seen in 40, incomplete or missing capsula in 44 patients. In 71 complete resections, local recurrence was 5%. 5-year survival was 88.1%. Thymomas with pseudocapsula showed a significant better survival (94.9% vs. 61.1%, respectively) (p = 0.001) and was correlated with the absence of nodal or distant metastasis (p = 0.04 and 0.001, respectively). Presence of pseudocapsula as well as the Masaoka and WHO classification, and R-status were of prognostic significance. R-status and Masaoka stage appeared to be of independent prognostic significance in multivariate analysis.</p> <p>Conclusion</p> <p>Intraoperative presence of an encapsulated tumor is a good technical marker for the surgeon to evaluate resectability and estimate prognosis. Although the presence of a capsula is of strong significance in the univariate analysis, it failed in the multivariate analysis due to its correlation with clinical Masaoka stage. Masaoka stage has a stronger relevance than WHO classification to determinate long-term outcome.</p