MITO END-3: efficacy of avelumab immunotherapy according to molecular profiling in first-line endometrial cancer therapy.

BACKGROUND: Immunotherapy combined with chemotherapy significantly improves progression-free survival (PFS) compared to first-line chemotherapy alone in advanced endometrial cancer (EC), with a much larger effect size in microsatellite instability-high (MSI-H) cases. New biomarkers might help to select patients who may have benefit among those with a microsatellite-stable (MSS) tumor. PATIENTS AND METHODS: In a pre-planned translational analysis of the MITO END-3 trial, we assessed the significance of genomic abnormalities in patients randomized to standard carboplatin/paclitaxel without or with avelumab. RESULTS: Out of 125 randomized patients, 109 had samples eligible for next-generation sequencing analysis, and 102 had MSI tested. According to The Cancer Genome Atlas (TCGA), there were 29 cases with MSI-H, 26 with MSS TP53 wild type (wt), 47 with MSS TP53 mutated (mut), and 1 case with POLE mutation. Four mutated genes were present in >30% of cases: TP53, PIK3CA, ARID1A, and PTEN. Eleven patients (10%) had a BRCA1/2 mutation (five in MSI-H and six in MSS). High tumor mutational burden (≥10 muts/Mb) was observed in all MSI-H patients, in 4 out of 47 MSS/TP53 mut, and no case in the MSS/TP53 wt category. The effect of avelumab on PFS significantly varied according to TCGA categories, being favorable in MSI-H and worst in MSS/TP53 mut (P interaction = 0.003); a similar non-significant trend was seen in survival analysis. ARID1A and PTEN also showed a statistically significant interaction with treatment effect, which was better in the presence of the mutation (ARID1A P interaction = 0.01; PTEN P interaction = 0.002). CONCLUSION: The MITO END-3 trial results suggest that TP53 mutation is associated with a poor effect of avelumab, while mutations of PTEN and ARID1A are related to a positive effect of the drug in patients with advanced EC.

Calcified coronary lesions.

The treatment of calcific coronary lesions is still a major interventional issue in haemodynamics laboratories. The prevalence of the disease is even increasing, considering the general ageing of the population undergoing coronarography, as well as the often associated comorbidities. In recent years, new devices have been developed that allow both better identification and also better treatment of these lesions. The aim of this review is to summarize both imaging modalities and dedicated techniques and materials, thus providing a kind of compendium for the treatment approach.

The impact of COVID-19 pandemic control on vaccine-preventable invasive bacterial diseases in Piedmont (Italy).

PURPOSE: The impact of SARS-CoV-2 pandemic on other pathogens is largely unknown. We aimed to compare the prevalence of vaccine-preventable invasive bacterial infections before and during the pandemic in Piedmont (Italy). METHODS: We defined the monthly incidence of S. pneumoniae, H. influenzae and N. meningitides-invasive diseases from January 2010 to June 2021. Then, we compared the mean monthly cases during the previous 5 years (2015-2019) and the monthly cases in 2020 or 2021. RESULTS: We found significant reductions for invasive pneumococcal diseases (IPDs) in adults and H. influenzae-invasive diseases in 2020 and 2021 in comparison to the previous years, but not for invasive meningococcal diseases and IPDs in children. CONCLUSIONS: Further data are needed to confirm these findings and define possible post-pandemic evolutions in the epidemiology of vaccine-preventable invasive bacterial diseases.

A multicenter validation of the revised version of the Milan system for reporting salivary gland cytology (MSRSGC).

INTRODUCTION: Fine-needle aspiration cytology (FNAC) is a basic step in the diagnosis of salivary gland tumors that have a wide variety of histological types. The recent Milan system for reporting salivary gland cytopathology (MSRSGC) can correlate the risk of malignancy with precise cytological features. A revised version was recently proposed to improve the surgical relevance and facilitate uniform management. MATERIAL AND METHODS: A multicenter study retrospectively used the original and revised MSRSGC criteria to classify a series of patients who received surgery after FNAC. RESULTS: We enrolled 503 patients from three tertiary centers. The risk of malignancy for the MSRSGC resulted 19.5% in cat. I, 14.3% in cat. II, 17.6% in cat. III, 3.6% in cat. IVa, 24.6% in cat. IVb, 66.7% in cat. V, and 96.8% in cat. VI. The results from the revised MSRSGC were consistent with the original values. CONCLUSION: The MSRSGC is a promising classification system. In our opinion, the revised version of the MSRSGC supplements FNAC with some crucial clinical information and can better identify the appropriate treatment in each category.

Radiofrequency ablation of functioning and non-functioning thyroid nodules: a single institution 12-month survey.

PURPOSE: Radiofrequency (RF) treatment has played an increasing role in the management of benign thyroid nodules in recent years. The aim of this retrospective study was to evaluate the efficacy of RF treatment on volume reduction in functioning and non-functioning thyroid nodules. PATIENTS AND METHODS: We reviewed the medical records of patients who had thyroid nodule RF ablation at our department between August 2017 and May 2018. Patients underwent a periodical follow-up with ultrasound examinations and thyroid function tests at 1, 3, 6 and 12 months from RF. Complications were assessed using the reporting standards of Interventional societies. RESULTS: 43 patients were submitted to thyroid nodule RF ablation treatment. Patients were subdivided into two groups, those with functioning (17 patients) or non-functioning nodules. At baseline (i.e. pre-RF treatment), the two groups of patients were superimposable for gender, age, BMI, nodule volume and maximum nodule diameter. The volume reduction of all 43 nodules was 69.1 ± 17.3% (range 26.0-94.5%) with no difference between functioning and non-functioning lesions (72.9 ± 18.1% vs 66.7 ± 16.7%, p = 0.254). A total energy delivered per nodule was 16.5 ± 6.8 kJ, with no difference between functioning and non-functioning lesions (14.5 ± 7.2 kJ vs. 18.2 ± 6.3 kJ, p = 0.083, respectively). No major complications were observed. CONCLUSIONS: Radiofrequency ablation is a clinically effective and safe outpatient treatment in patients with benign nodules. In particular, we showed that a single treatment is effective in restoring euthyroidism in patients with autonomously functioning thyroid nodules.

Carboplatin-paclitaxel compared to Carboplatin-Paclitaxel-Bevacizumab in advanced or recurrent endometrial cancer: MITO END-2 - A randomized phase II trial.

OBJECTIVE: Increased Vascular Endothelial Growth Factor Receptor (VEGF) expression in endometrial cancer (EC) is associated with a poor prognosis. Preliminary clinical data reported Bevacizumab effectiveness in EC both as single agent and in combination with chemotherapy. METHODS: In a phase II trial, patients with advanced (FIGO stage III-IV) or recurrent EC were randomized to receive Carboplatin-Paclitaxel standard dose for 6-8 cycles vs Carboplatin-Paclitaxel and Bevacizumab 15 mg/kg in combination with chemotherapy and maintenance until disease progression or unacceptable toxicity. The primary endpoint was progression free survival (PFS). RESULTS: 108 patients were randomized; PFS (10.5 vs 13.7 months, HR 0.84 p = 0.43), overall response rate (ORR 53.1% vs 74.4%) and overall survival (OS) (29.7 vs 40.0 months, HR 0.71 p = 0.24) resulted in a non-significant increase in Bevacizumab treated patients. The PFS increase became significant when an exploratory analysis with the Breslow test was used. Moreover, patients treated with Bevacizumab experienced a significant increase in 6-month disease control rate (70.4% vs 90.7%). Cardiovascular events were more frequent in the experimental arm ("de novo" grade ≥2 hypertension 21% vs 0% and grade ≥2 thromboembolic events 11% vs 2% in the Bevacizumab vs standard treatment arm, respectively). CONCLUSIONS: Bevacizumab combined with chemotherapy in the treatment of advanced/recurrent EC failed to demonstrate a significant increase in PFS in the MITO END-2 trial. Nevertheless, these preliminary data suggests some effectiveness of the antiangiogenic agent which merits further exploration in a larger population with a better molecular characterization.

Diagnostic role of (18)F-FDG-PET or PET/CT in salivary gland tumors: A systematic review.

Salivary gland tumors are rare neoplasms that have not been extensively studied with (18)F-FDG-PET- or PET/CT up to now. This review aims to evaluate the diagnostic performance of PET in this particular setting, analyzing the available literature. A comprehensive literature search in the PubMed/MEDLINE, Embase and Scopus databases was performed including articles up to November 2014, resulting in the selection of 22 articles. The studies selected suggest that: (1) PET is not useful in discriminating benign from malignant SGTs because of the overlap of uptake in both conditions; (2) PET not only is complementary to conventional imaging techniques for the staging and restaging but in some cases could also be superior to them; (3) PET may often have a highly positive impact on clinical decision making. Despite many limitations affecting the analysis, PET seems to be useful in SGTs. However, more extensive studies and cost-effectiveness analyses are desirable to determine its correct position in the diagnostic flow chart.

Feeding preferences and voluntary feed intake of dairy cows: Effect of conservation and harvest time of birdsfoot trefoil and chicory.

Bioactive forages contain compounds, such as tannins, that are active against pathogens. They have been successfully used in ruminants to control parasite infections. Because cattle may find bioactive forages unpalatable, it is of interest to know if an afternoon harvest time, which has been shown to increase the percentage of nonstructural carbohydrates (NSC), hence palatability, may mitigate this. The objectives of this study were to quantify voluntary intake and preference of dairy cows for 2 bioactive forages, harvested in the morning and evening, in addition to determining their time spent grazing on each forage species. The forage species evaluated were fresh chicory harvested at 0700 h (FCAM) and 1800 h (FCPM), fresh birdsfoot trefoil harvested at 0700 h (FBAM) and 1800 h (FBPM), birdsfoot trefoil baleage harvested the previous summer at 0700 h (BBAM) and at 1800 h (BBPM), and third-cut alfalfa baleage harvested the previous summer and used as control (CON). Single forages were offered ad libitum in 30-min tests to 14 dairy cows to determine intake in a 7 × 7 Latin square (experiment 1). Every possible pair of forages (21 pairs) was then presented for a 30-min test to 8 different dairy cows, and feed intake was measured (experiment 2). Finally, time spent grazing on chicory and birdsfoot trefoil was measured on 12 dairy cows (experiment 3). The tests consisted of 2 d of restriction on 1 of the 2 fields for 1h, and 2 d of free-choice sessions (1h) between the 2 fields adjacent to each other. Grazing time and location of the animals on the field was assessed through 2-min scan sampling. In experiment 1, the highest voluntary intakes were for CON, BBPM, and BBAM. In experiment 2, BBPM was preferentially consumed over all other forages followed by CON and BBAM. Multidimensional scaling showed that preference for BBPM, CON, and BBAM in dimension 1 was positively associated with dry matter and nitrogen content, and negatively associated with hemicellulose and soluble N/total N. No relationships between dimension coordinates and any of the measured chemical composition variables could be found for the other 2 dimensions. In experiment 3, cows spent 71% of their time grazing in the birdsfoot trefoil field and 23% in the chicory field during the free-choice sessions. In conclusion, cows in the present experiments showed an overall preference toward baled forages compared with fresh forages, most notably toward birdsfoot trefoil baleage. Cow preference did not appear to be linked to harvest time (a.m. vs. p.m.).

Improved Natural Killer cell activity and retained anti-tumor CD8(+) T cell responses contribute to the induction of a pathological complete response in HER2-positive breast cancer patients undergoing neoadjuvant chemotherapy.

BACKGROUND: Locally advanced HER2-overexpressing breast cancer (BC) patients achieve a high rate of pathological complete responses (pCR) after neoadjuvant chemotherapy (NC). The apparently unaltered immune proficiency of these patients together with the immune-modulating activities of NC drugs suggest a potential contribution of host immunity in mediating clinical responses. We thus performed an extensive immunomonitoring in locally advanced BC patients undergoing NC to identify immunological correlates of pCR induction. METHODS: The immune profile of 40 HER2-positive and 38 HER2-negative BC patients was characterized at diagnosis and throughout NC (Paclitaxel and Trastuzumab, or Docetaxel and Epirubicin, respectively). The percentages of circulating immune cell subsets including T and B lymphocytes, Natural Killer (NK) cells, regulatory T cells, T helper 17 lymphocytes, were quantified by multiparametric flow cytometry. NK cells functional activity was evaluated through the analysis of NF-kB nuclear translocation by Multispectral flow cytometry, and with the in vitro monitoring of Trastuzumab-mediated antibody-dependent cell cytotoxicity (ADCC). CD8(+) T cell responses against six different tumor-associated antigens (TAA) were characterized by IFN-γ ELISPOT and IFN-γ/IL-2 DualSpot assays. RESULTS: After NC, HER2-positive patients showed a significant increase in the number of NK cells and regulatory T cells irrespective of the pathological response, whereas patients undergoing a pCR disclosed higher percentages of T helper 17 cells. Notably, a significant increase in the number of activated NK cells was observed only in HER2-positive patients achieving a pCR. Characterization of anti-tumor T cell responses highlighted sustained levels of CD8(+) T cells specific for survivin and mammaglobin-A throughout NC in patients undergoing a pCR in both arms. Moreover, HER2-positive patients achieving a pCR were characterized by a multi-epitopic and polyfunctional anti-tumor T cell response, markedly reduced in case of partial response. CONCLUSIONS: These results indicate that maintenance of functional T cell responses against selected antigens and improvement of NK cell proficiency during NC are probably critical requirements for pCR induction, especially in HER2-positive BC patients. Trail registration: TRIAL REGISTRATION NUMBER: NCT02307227, registered on ClinicalTrials.gov ( http://www.clinicaltrials.gov , November 26, 2014).

Spontaneous muscle haematomas: management of 10 cases.

This is a retrospective study about the treatment of spontaneous muscle haematomas (SMH) that are an uncommon disease that occurs especially in elderly patients with acquired coagulopathy. We report the management of 10 cases admitted to our Emergency Surgical Unit (ESU) between March 2011 and October 2012. For this analysis we have considered some parameters such as age, drug history, current symptoms, location of the haematoma, cause, and imaging examination. Our attention focused on: clinical presentation, differential diagnosis, diagnostic imaging techniques and treatments.

Comparison between liquid and tablet levothyroxine formulations in patients treated through enteral feeding tube.

BACKGROUND: The majority of clinicians suggest that enteral feedings should be held 1-2 h prior to and after L-T4 administration despite lack of data for continuous enteral nutrition. AIM: The aim of this study was to: (1) compare the thyroid hormonal profile in patients submitted to L-T4 treatment in tablets or liquid formulation with an enteral feeding tube; (2) evaluate the nursing compliance with the two different formulations. SUBJECTS AND METHODS: 20 euthyroid patients submitted to total laryngectomy and thyroidectomy consecutively started L-T4 treatment in tablets (Group T) or in liquid formulation (Group L) with enteral feeding tube the day after surgery. Tablets were crushed before administration and enteral feeding was stopped for 30 min before and after L-T4 treatment, whereas liquid formulation was placed into the nasoenteric tube immediately. A questionnaire about the preparation and administration of thyroxine replacement therapy was given to the nurses. RESULTS: No difference of TSH, fT4 and fT3 before and after L-T4 treatment was observed among patients of Group L. A slightly serum TSH increase was observed in Group T, but not reaching statistical significance (2.50 ± 1.18 vs 2.94 ± 1.22 mUI/L), whereas no difference in fT4 and fT3 levels was found. Preparation and administration of liquid L-T4 was considered excellent by 12/13 nurses, whereas tablet formulation was considered poor by 10/13. CONCLUSIONS: Our data showed that liquid L-T4 formulation can be administered directly through feeding tube with no need for an empty stomach, with a significant improvement in therapy preparation and administration by nurses.

Inverse problems in 1D hemodynamics on systemic networks: a sequential approach.

In this work, a sequential approach based on the unscented Kalman filter is applied to solve inverse problems in 1D hemodynamics, on a systemic network. For instance, the arterial stiffness is estimated by exploiting cross-sectional area and mean speed observations in several locations of the arteries. The results are compared with those ones obtained by estimating the pulse wave velocity and the Moens-Korteweg formula. In the last section, a perspective concerning the identification of the terminal models parameters and peripheral circulation (modeled by a Windkessel circuit) is presented.

Imiquimod 5% cream versus cold knife excision for treatment of VIN 2/3: a five-year follow-up.

BACKGROUND: Vulvar intraepithelial neoplasia (VIN) is a premalingnant condition. For long time, surgery was considered the first-line therapy in the treatment of high grade VIN. Imiquimod was recently introduced as an alternative to surgery. AIM: To compare the overall complete response, the recurrence rate and the risk factors for relapse among patients with VIN 2/3 treated with Imiquimod or surgical excision. PATIENTS AND METHODS: Eighty women who had histological diagnosis of VIN 2 and VIN 3 were enrolled in this prospective study. Patients immunocompromised, with recurrent VIN, with well differentiated type VIN or VIN 1 and women treated more than once were excluded from the study. Patients were divided into two groups: group A was treated with Imiquimod, group B underwent surgical excision. Patients' characteristics analyzed were: age, smoking, degree of the primary lesion, state of margins, multifocal disease. We have evaluated the recurrence rate, the relapse rate, and the overall complete response, considering as recurrence the onset of a lesion after an initial complete response to Imiquimod and/or after the surgical treatment and as relapse all patients who had a recurrence plus those with medical treatment failure. RESULTS: Multifocal lesions (p = 0.03) and VIN 3 (p = 0.002) were associated with a higher risk of relapse. The recurrence rate was higher in the group B (p = 0.009), but the relapse rate was higher in the group A (p = 0.04). The overall complete response was better in the group B (p = 0.04). CONCLUSIONS: Although the advent of new medical options can decrease the morbidity associated with invasive surgical procedures, surgical treatments remain the best treatment modality for VIN with regard to relapse and overall complete response.

In vivo mathematical modeling of tumor growth from imaging data: soon to come in the future?

The future challenges in oncology imaging are to assess the response to treatment even earlier. As an addition to functional imaging, mathematical modeling based on the imaging is an alternative, cross-disciplinary area of development. Modeling was developed in oncology not only in order to understand and predict tumor growth, but also to anticipate the effects of targeted and untargeted therapies. A very wide range of these models exist, involving many stages in the progression of tumors. Few models, however, have been proposed to reproduce in vivo tumor growth because of the complexity of the mechanisms involved. Morphological imaging combined with "spatial" models appears to perform well although functioning imaging could still provide further information on metabolism and the micro-architecture. The combination of imaging and modeling can resolve complex problems and describe many facets of tumor growth or response to treatment. It is now possible to consider its clinical use in the medium term. This review describes the basic principles of mathematical modeling and describes the advantages, limitations and future prospects for this in vivo approach based on imaging data.

Evaluation of E6 and E7 mRNA expression in HPV DNA positive breast cancer.

Several studies have suggested a possible role for HPV in the pathogenesis of the breast cancer. We investigated the presence of the HPV DNA in breast cancers and non malignant disease breast tissues by the use of a standard HPV detection method (INNO-Lipa HPV), in order to detect HPV DNA in metastatic nodes, to investigate a possible cervical HPV co-infection, and to evaluate the E6/E7 mRNA expression in HPV DNA positive breast cancer tissues. The rate of HPV infection was significantly higher in the cancer group than in controls (9/31 vs. 0/12, p = 0.04). One out of eight metastatic axillary nodes was positive for HPV infection; 2/3 of the positive HPV breast cancer patients were co-infected at the cervical site. The role of the virus in breast oncogenesis is still unclear, since our analysis failed in demonstrating the expression of viral E6 and E7 in positive HPV positive breast tumor tissues.

Isolated sphenoid inflammatory diseases associated with visual impairment: 15-year experience at a single institution.

We present a retrospective series of 11 patients treated for isolated sphenoid inflammatory disease (ISID) with visual impairment in the period between 1994 and 2008. The series included 7 females and 4 males. All patients, preoperatively assessed by CT or MR, underwent endoscopic sinus surgery and broad-spectrum antibiotic therapy. The procedure was always performed in an emergency setting, with an interval from the onset of visual impairment ranging between 1 and 40 days (mean 9 days). The possibility of recovery was related to both the modality of onset and severity of the deficit. All patients with reduction of the visual field reported significant improvement after surgery. Patients with decreased visual acuity obtained partial or complete resolution, while in patients with preoperative blindness no improvement was observed. Moreover, no postoperative improvement was noticed in the case of severe deficits with sudden onset, whereas the treatment of mild deficits was successful even some weeks after their occurrence. In conclusion, although some factors may predict the likelihood of recovery, any patient with ISID associated with visual impairment should receive immediate medical and surgical treatment. Endoscopic surgery should be considered the technique of choice.

Biological effects of low frequency high intensity ultrasound application on ex vivo human adipose tissue.

In the present work the effects of a new low frequency, high intensity ultrasound technology on human adipose tissue ex vivo were studied. In particular, we investigated the effects of both external and surgical ultrasound-irradiation (10 min) by evaluating, other than sample weight loss and fat release, also histological architecture alteration as well apoptosis induction. The influence of saline buffer tissue-infiltration on the effects of ultrasound irradiation was also examined. The results suggest that, in our experimental conditions, both transcutaneous and surgical ultrasound exposure caused a significant weight loss and fat release. This effect was more relevant when the ultrasound intensity was set at 100 % (~2.5 W/cm², for external device; ~19-21 W/cm2, for surgical device) compared to 70 % (~1.8 W/cm² for external device; ~13-14 W/cm2 for surgical device). Of note, the effectiveness of ultrasound was much higher when the tissue samples were previously infiltrated with saline buffer, in accordance with the knowledge that ultrasonic waves in aqueous solution better propagate with a consequently more efficient cavitation process. Moreover, the overall effects of ultrasound irradiation did not appear immediately after treatment but persisted over time, being significantly more relevant at 18 h from the end of ultrasound irradiation. Evaluation of histological characteristics of ultrasound-irradiated samples showed a clear alteration of adipose tissue architecture as well a prominent destruction of collagen fibers which were dependent on ultrasound intensity and most relevant in saline buffer-infiltrated samples. The structural changes of collagen bundles present between the lobules of fat cells were confirmed through scanning electron microscopy (SEM) which clearly demonstrated how ultrasound exposure induced a drastic reduction in the compactness of the adipose connective tissue and an irregular arrangement of the fibers with a consequent alteration in the spatial architecture. The analysis of the composition of lipids in the fat released from adipose tissue after ultrasound treatment with surgical device showed, in agreement with the level of adipocyte damage, a significant increase mainly of triglycerides and cholesterol. Finally, ultrasound exposure had been shown to induce apoptosis as shown by the appearance DNA fragmentation. Accordingly, ultrasound treatment led to down-modulation of procaspase-9 expression and an increased level of caspase-3 active form.

FOLFOX2 in the treatment of advanced colorectal cancer: a comparison between elderly and middle aged patients.

The effectiveness of chemotherapy in elderly patients is still a matter of debate. We analyzed the toxicity and efficacy of the original FOLFOX2 regimen in middle aged and elderly patients affected by metastatic colorectal cancer. Consecutive patients with metastatic CRC and measurable disease were eligible. Seventy-eight partially pretreated patients were enrolled: 58 patients were defined as middle aged (<70 years) and 20 were elderly patients (>70 years). Elderly patients in comparison to middle-aged patients in a higher percentage were males. No significant differences were found in hematological and non-hematological toxicity between the two groups. No significant differences were found in the response rates, time to progression (5.9 vs. 6.0 months respectively), or median overall survival (20.9 and 21.8 months, respectively) between middle aged and elderly patients. The FOLFOX2 regimen provides equivalent feasibility, efficacy, and survival gain in middle-aged and in elderly patients with metastatic CRC.

Mesenchymal differentiation of glioblastoma stem cells.

Glioblastoma multiforme is a severe form of cancer most likely arising from the transformation of stem or progenitor cells resident in the brain. Although the tumorigenic population in glioblastoma is defined as composed by cancer stem cells (CSCs), the cellular target of the transformation hit remains to be identified. Glioma stem cells (SCs) are thought to have a differentiation potential restricted to the neural lineage. However, using orthotopic versus heterotopic xenograft models and in vitro differentiation assays, we found that a subset of glioblastomas contained CSCs with both neural and mesenchymal potential. Subcutaneous injection of CSCs or single CSC clones from two of seven patients produced tumor xenografts containing osteo-chondrogenic areas in the context of glioblastoma-like tumor lesions. Moreover, CSC clones from four of seven cases generated both neural and chondrogenic cells in vitro. Interestingly, mesenchymal differentiation of the tumor xenografts was associated with reduction of both growth rate and mitotic index. These findings suggest that in a subclass of glioblastomas the tumorigenic hit occurs on a multipotent stem cell, which may reveal its plasticity under specific environmental stimuli. The discovery of such biological properties might provide considerable information to the development of new therapeutic strategies aimed at forcing glioblastoma stem cell differentiation.

Biomolecular characterization of human glioblastoma cells in primary cultures: differentiating and antiangiogenic effects of natural and synthetic PPARgamma agonists.

Gliomas are the most commonly diagnosed malignant brain primary tumors. Prognosis of patients with high-grade gliomas is poor and scarcely affected by radiotherapy and chemotherapy. Several studies have reported antiproliferative and/or differentiating activities of some lipophylic molecules on glioblastoma cells. Some of these activities in cell signaling are mediated by a class of transcriptional factors referred to as peroxisome proliferator-activated receptors (PPARs). PPARgamma has been identified in transformed neural cells of human origin and it has been demonstrated that PPARgamma agonists decrease cell proliferation, stimulate apoptosis and induce morphological changes and expression of markers typical of a more differentiated phenotype in glioblastoma and astrocytoma cell lines. These findings arise from studies mainly performed on long-term cultured transformed cell lines. Such experimental models do not exactly reproduce the in vivo environment since long-term culture often results in the accumulation of further molecular alterations in the cells. To be as close as possible to the in vivo condition, in the present work we investigated the effects of PPARgamma natural and synthetic ligands on the biomolecular features of primary cultures of human glioblastoma cells derived from surgical specimens. We provide evidence that PPARgamma agonists may interfere with glioblastoma growth and malignancy and might be taken in account as novel antitumoral drugs.