Matteo Simonelli

Phase II Study of Asparagine-Glycine-Arginine–Human Tumor Necrosis Factor α, a Selective Vascular Targeting Agent, in Previously Treated Patients With Malignant Pleural Mesothelioma

PURPOSE NGR-hTNF consists of human tumor necrosis factor alpha (hTNF-alpha) fused to the tumor-homing peptide asparagine-glycine-arginine (NGR) able to selectively bind an aminopeptidase N isoform overexpressed on tumor blood vessels. Hypervascularity is a prominent and poor-prognosis feature of malignant pleural mesothelioma (MPM). Currently, there are no standard options for patients with MPM who are failing a front-line pemetrexed-based regimen. We explored safety and efficacy of NGR-hTNF in this setting. PATIENTS AND METHODS Eligible patients had radiologically documented tumor progression and performance status < or = 2. Primary study aim was progression-free survival (PFS). NGR-hTNF 0.8 microg/m(2) was given intravenously every 3 weeks. A subsequent cohort of patients received 0.8 microg/m(2) on a weekly basis. RESULTS In the triweekly cohort (n = 43), only one grade 3 drug-related toxicity was noted, and the most common grades 1 to 2 were short-lived chills (71%). The median PFS was 2.8 months (95% CI, 2.3 to 3.3 months). Nineteen patients (44%) had disease control (one had partial response, and 18 had stable diseases) and experienced a median progression-free time of 4.4 months. In the weekly cohort (n = 14), there was no higher toxicity, and median PFS was 3.0 months (95% CI, 1.9 to 4.1 months). Seven patients (50%) had disease control (all stable diseases) and had a median progression-free interval of 9.1 months. In the overall study population (N = 57), median PFS was 2.8 months. Median progression-free time was 4.7 months in twenty-six patients (46%) who achieved disease control. Median survival was 12.1 months. CONCLUSION The tolerability and disease control of NGR-hTNF 0.8 microg/m(2) weekly warrant additional evaluation in patients with advanced MPM.

Advances in the biology of malignant pleural mesothelioma.

Malignant pleural mesothelioma is a highly aggressive cancer with a very poor prognosis. Although the mechanism of carcinogenesis is not fully understood, approximately 80% of malignant pleural mesothelioma can be attributed to asbestos fiber exposure. This disease is largely unresponsive to conventional chemotherapy or radiotherapy, and most patients die within 10-17 months of their first symptoms. Currently, malignant pleural mesothelioma therapy is guided by clinical stage and patient characteristics rather than by the histological or molecular features of the tumor. Several molecular pathways involved in malignant pleural mesothelioma have been identified; these include cell cycle regulation, apoptosis, growth factor pathways, and angiogenesis. Unfortunately, several agents targeting these processes, including erlotinib, gefitinib, and imatinib, have proven ineffective in clinical trials. A greater understanding of the molecular pathways involved in malignant pleural mesothelioma is needed to develop better diagnostics, therapeutics, and preventative measures. Moreover, understanding the biological basis of mesothelioma progression may facilitate personalized treatment approaches, and early identification of poor prognostic indicators may help reduce the heterogeneity of the clinical response. This paper reviews advances in the molecular biology of malignant pleural mesothelioma in terms of pathogenesis, the major molecular pathways and the associated therapeutic strategies, and the roles of biomarkers.

Thymidylate Synthase and Excision Repair Cross-Complementing Group-1 as Predictors of Responsiveness in Mesothelioma Patients Treated with Pemetrexed/Carboplatin

Purpose: The pemetrexed/platinum agent combination represents the standard of care in first-line treatment for malignant pleural mesothelioma (MPM). However, there are no established indicators of responsiveness that can be used to optimize the treatment. This retrospective study aimed to assess the role of excision repair cross-complementing group-1 (ERCC1) and thymidylate synthase (TS) in tumors, and correlate expression levels and polymorphisms of these key determinants of drug activity with the outcome of MPM patients treated with carboplatin/pemetrexed in first-line setting. Experimental design: Analysis of TS and ERCC1 polymorphisms, mRNA and protein expression was done by PCR and immunohistochemistry [with the H-score (histologic score)] in tumor specimens from 126 MPM patients, including 99 carboplatin-/pemetrexed-treated patients. Results: A significant correlation between low TS protein expression and disease control (DC) to carboplatin/pemetrexed therapy (P = 0.027), longer progression-free survival (PFS; P = 0.017), and longer overall survival (OS; P = 0.022) was found when patients were categorized according to median H-score. However, patients with the higher tertile of TS mRNA expression correlated with higher risk of developing progressive disease (P = 0.022), shorter PFS (P < 0.001), and shorter OS (P < 0.001). At multivariate analysis, the higher tertile of TS mRNA level and TS H-score confirmed their independent prognostic role for DC, PFS, and OS. No significant associations were found among ERCC1 protein expression, TS and ERCC1 polymorphisms, and clinical outcome. Conclusions: In our series of carboplatin-/pemetrexed-treated MPM patients, low TS protein and mRNA levels were significantly associated to DC, improved PFS, and OS. Prospective trials for the validation of the prognostic/predictive role of TS in MPM patients treated with pemetrexed-based regimens are warranted. Clin Cancer Res; 17(8); 2581–90. ©2011 AACR.

Retreatment with pemetrexed-based chemotherapy in patients with malignant pleural mesothelioma

The role of second-line therapy in patients with malignant pleural mesothelioma (MPM) progressing after first-line pemetrexed-based chemotherapy (PBC) is currently undefined. Recent case series have suggested a possible role of re-treatment with PBC. In this observational study, the activity and safety of this therapeutic option was assessed in a consecutive series of cases. Patients with complete response (CR), partial response (PR) or stable disease (SD) lasting for at least 3 months after first-line PBC were retreated with PBC, either as second-line (2L) or further-line (>2L) therapy. Descriptive analyses of progression-free survival (PFS), overall survival (OS), response rate and toxicity are reported. Between October 2004 and July 2009, 31 patients (21 males and 10 females) received re-treatment with PBC as 2L (18 patients) or beyond 2L therapy (13 patients). Median age was 65 years (range 37-81). Fifteen patients were re-treated with pemetrexed alone, and 16 with a pemetrexed/platinum combination. An objective response was achieved in 6 patients (one CR and 5 PRs), for a response rate of 19%. Nine patients (29%) had SD after treatment. Overall, the disease control rate (DCR) was 48%. Median PFS and overall survival (OS) after re-treatment with PBC were 3.8 months and 10.5 months, respectively. PFS and OS after re-treatment with PBC were correlated with PFS achieved after first-line PBC (FL-PFS). Patients with a FL-PFS >12 months had a median PFS after re-treatment of 5.5 months, while patients with a FL-PFS ≤12 months had a median PFS after re-treatment of 2.5 months; no patient in this group was progression-free at 1 year. Toxicity was mild, with grade 3 or 4 hematological toxicity occurring in 9.7% of patients. In conclusion, re-treatment with PBC should be considered as second-line therapy in MPM patients achieving a durable (>12 months) disease control with first-line PBC. Further prospective evaluation of this therapeutic option is warranted.

Insulin-like growth factor-1 receptor and phosphorylated AKT-serine 473 expression in 132 resected thymomas and thymic carcinomas.

Thymic malignancies are rare tumors. The insulin‐like growth factor‐1 (IGF‐1)/IGF‐1 receptor (IGF‐1R) system is involved in the development of the thymus. IGF‐1R expression in thymic epithelial malignancies is unknown.

Investigation on the role of integrated PET/MRI for target volume definition and radiotherapy planning in patients with high grade glioma

PURPOSE To evaluate the impact of fluid-attenuated-inversion-recovery MRI (FLAIR/MRI) and Carbon-11-labeled-methionine PET (11C-MET-PET) on high grade glioma (HGG) tumor volume delineation for radiotherapy planning. MATERIAL AND METHODS Sixty-nine patients with HGG were evaluated. The clinical target volumes (CTV1, generated by adding a 10mm margin to FLAIRMRI area, CTV2 by adding a 20mm margin to enhanced T1MRI) and biological target volume (BTV) were delineated on pre-operative MRI images and 11CMETPET respectively. RESULTS The overlap between CTV1 and CTV2 showed a low correlation between the two volumes with CTV1 not always fully included into the CTV2. In all cases the whole BTV was included into the CTV1, while in 35/69 patients (50%) part of BTV was outside the CTV2 despite larger margins were added. In all cases recurrences were within the CTV1 volume and in 19/38 (50%) partially outside the CTV2. In all patients relapse corresponded to the BTV area. CONCLUSIONS Our data suggest that the target volume definition using FLAIR-MRI is more adequate compared to enhanced T1MRI. 11C-METPET uptake could help identify microscopic residual areas.

Correlation of microvascular fractal dimension with positron emission tomography [11C]-methionine uptake in glioblastoma multiforme: Preliminary findings

Neuroradiological and metabolic imaging is a fundamental diagnostic procedure in the assessment of patients with primary and metastatic brain tumors. The correlation between objective parameters capable of quantifying the neoplastic angioarchitecture and imaging data may improve our understanding of the underlying physiopathology and make it possible to evaluate treatment efficacy in brain tumors. Only a few studies have so far correlated the quantitative parameters measuring the neovascularity of brain tumors with the metabolic profiles measured by means of amino acid uptake in positron emission tomography (PET) scans. Fractal geometry offers new mathematical tools for the description and quantification of complex anatomical systems, including microvascularity. In this study, we evaluated the microvascular network complexity of six cases of human glioblastoma multiforme quantifying the surface fractal dimension on CD34 immunostained specimens. The microvascular fractal dimension was estimated by applying the box-counting algorithm. As the fractal dimension depends on the density, size and shape of the vessels, and their distribution pattern, we defined it as an index of the whole complexity of microvascular architecture and compared it with the uptake of (11)C-methionine (MET) assessed by PET. The different fractal dimension values observed showed that the same histological category of brain tumor had different microvascular network architectures. Fractal dimension ranged between 1.19 and 1.77 (mean: 1.415+/-0.225), and the uptake of (11)C-methionine ranged between 1.30 and 5.30. A statistically significant direct correlation between the microvascular fractal dimension and the uptake of (11)C-methionine (p=0.02) was found. Our preliminary findings indicate that that vascularity (estimated on the histologic specimens by means of the fractal dimension) and (11)C-methionine uptake (assessed by PET) closely correlate in glioblastoma multiforme and that microvascular fractal dimension can be a useful parameter to objectively describe and quantify the geometrical complexity of the microangioarchitecture in glioblastoma multiforme.

Future developments in the management of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is an aggressive tumor with a poor prognosis and an increasing incidence as a result of widespread exposure to asbestos. In the past few years, there have been several developments in the management of patients with MPM, including more accurate staging and patient selection, improvements in surgical techniques and postoperative care, novel chemotherapy regimens and new radiotherapy techniques. However, chemotherapy remains the mainstay of treatment, considering that surgery and radiotherapy have a limited role in highly selected patients, and its results are still modest, with a median survival of approximately 1 year. The principal goals of this review are to summarize the improvements in the management of MPM that have been achieved recently and to outline the therapeutic approaches in development.

Expression of the transcription factor HEY1 in glioblastoma: a preliminary clinical study.

AIMS AND BACKGROUND The hairy/enhancer of split (E(spl))-related family of transcription factors (HES and HEY) are established targets of the notch signaling pathway, which has been implicated in different developmental processes, tumor formation and the self-renewal of neural stem cells. We determined the expression of HEY1 in human malignant gliomas to investigate whether its expression might be related to prognosis. METHODS The expression of HEY1 was studied by in situ hybridization on 62 cases of glioblastoma. Patients were treated with surgery followed by chemotherapy and radiotherapy. We considered as end points of the study the overall survival time and progression-free interval. Correlations between HEY1 expression and tumor grade/patient overall survival and free interval before recurrence were analyzed using univariate analysis. RESULTS Based on the in situ hybridization results, HEY1 expression rate was reported as negative staining in 13 cases (20.6%), as weak staining in 11 cases (17.3%), as moderate staining in 21 cases (33.3%), and as strong staining in 17 cases. We considered in the analysis the cumulative expression of HEY1 at in situ hybridization (Hey Index) as negative in 13 cases and positive in 49 cases (77.78%). The overall survival (P = 0.002) and the free-interval (P = 0.012) were significantly longer in patients who were negative for HEY1 expression. CONCLUSIONS Our data suggest that expression of HEY1 might be used as a marker to distinguish glioblastoma patients with a relatively good prognosis from those at high-risk, and that, in the future, HEY1 might represent a therapeutic target.

Thymoma associated with myasthenia and autonomic anti-Hu paraneoplastic neuropathy

Along with myasthenia, other paraneoplastic neurological syndromes (PNS) may occur in thymoma. Anti-Hu antibodies and a clinical “anti-Hu syndrome” characterized by encephalitis and/or painful neuropathies have been reported in only three patients at the time of the diagnosis of thymoma. We describe a severe anti-Hu-related autonomic neuropathy with gastrointestinal paresis and intestinal pseudo-obstruction with malabsorption that occurred concomitantly with the worsening of myasthenic symptoms long after the initial diagnosis of thymoma in a young patient. The clinical anti-Hu syndrome preceded the radiological diagnosis of thymoma recurrence. Treatment with plasma exchange led to a transient improvement of neurological symptoms.