Changing paradigms--an update on the multidisciplinary management of malignant glioma.

Treatment of malignant glioma requires a multidisciplinary team. Treatment includes surgery, radiotherapy, and chemotherapy. Recently developed agents have demonstrated activity against recurrent malignant glioma and efficacy if given concurrently with radiotherapy in the upfront setting. Oligodendroglioma with 1p/19q deletions has been recognized as a distinct pathologic entity with particular sensitivity to radiotherapy and chemotherapy. Randomized trials have shown that early neoadjuvant or adjuvant administration of procarbazine, lomustine, and vincristine chemotherapy prolongs disease-free survival; however, it has no impact on overall survival. Temozolomide, a novel alkylating agent, has shown modest activity against recurrent glioma. In combination with radiotherapy in newly diagnosed patients with glioblastoma, temozolomide significantly prolongs survival. Molecular studies have demonstrated that the benefit is mainly observed in patients whose tumors have a methylated methylguanine methyltransferase gene promoter and are thus unable to repair some of the chemotherapy-induced DNA damage. For lower-grade glioma, the use of chemotherapy remains limited to recurrent disease, and first-line administration is the subject of ongoing clinical trials. Irinotecan and agents like gefitinib, erlotinib, and imatinib targeting the epidermal growth factor receptor and platelet-derived growth factor receptor have shown some promise in recurrent malignant glioma. This review summarizes recent developments, focusing on the clinical management of patients in daily neuro-oncology practice.

Low transformation growth factor-β1 production and collagen synthesis correlate with the lack of hepatic periportal fibrosis development in undernourished mice infected with Schistosoma mansoni

Undernourished mice infected (UI) submitted to low and long-lasting infections by Schistosoma mansoni are unable to develop the hepatic periportal fibrosis that is equivalent to Symmers’ fibrosis in humans. In this report, the effects of the host’s nutritional status on parasite (worm load, egg viability and maturation) and host (growth curves, biology, collagen synthesis and characteristics of the immunological response) were studied and these are considered as interdependent factors influencing the amount and distribution of fibrous tissue in hepatic periovular granulomas and portal spaces. The nutritional status of the host influenced the low body weight and low parasite burden detected in UI mice as well as the number, viability and maturation of released eggs. The reduced oviposition and increased number of degenerated or dead eggs were associated with low protein synthesis detected in deficient hosts, which likely induced the observed decrease in transformation growth factor (TGF)-β1 and liver collagen. Despite the reduced number of mature eggs in UI mice, the activation of TGF-β1 and hepatic stellate cells occurred regardless of the unviability of most miracidia, due to stimulation by fibrogenic proteins and eggshell glycoproteins. However, changes in the repair mechanisms influenced by the nutritional status in deficient animals may account for the decreased liver collagen detected in the present study.

Prophylactic isolated limb perfusion for localized, high-risk limb melanoma: results of a multicenter randomized phase III trial. European Organization for Research and Treatment of Cancer Malignant Melanoma Cooperative Group Protocol 18832, the World Health Organization Melanoma Program Trial 15, and the North American Perfusion Group Southwest Oncology Group-8593.

PURPOSE: Patients with primary cutaneous melanoma > or = 1.5 mm in thickness are at high risk of having regional micrometastases at the time of initial surgical treatment. A phase III international study was designed to evaluate whether prophylactic isolated limb perfusion (ILP) could prevent regional recurrence and influence survival. PATIENTS AND METHODS: A total of 832 assessable patients from 16 centers entered the study; 412 were randomized to wide excision (WE) only and 420 to WE plus ILP with melphalan and mild hyperthermia. Median age was 50 years, 68% of patients were female, 79% of melanomas were located on a lower limb, and 47% had a thickness > or = 3 mm. RESULTS: Median follow-up duration is 6.4 years. There was a trend for a longer disease-free interval (DFI) after ILP. The difference was significant for patients who did not undergo elective lymph node dissection (ELND). The impact of ILP was clearly on the occurrence-as first site of progression - of in-transit metastases (ITM), which were reduced from 6.6% to 3.3%, and of regional lymph node (RLN) metastases, with a reduction from 16.7% to 12.6%. There was no benefit from ILP in terms of time to distant metastasis or survival. Side effects were higher after ILP, but transient in most patients. There were two amputations for limb toxicity after ILP. CONCLUSION: Prophylactic ILP with melphalan cannot be recommended as an adjunct to standard surgery in high-risk primary limb melanoma.

Salvage radiosurgery for selected patients with recurrent malignant gliomas.

Purpose. To analyse the survival after salvage radiosurgery and to identify prognostic factors. Methods. We retrospectively reviewed 87 consecutive patients, with recurrent high-grade glioma, that underwent stereotactic radiosurgery between 1997 and 2010. We evaluated the survival after initial diagnosis and after reirradiation. The prognostic factors were analysed by bivariate and multivariate Cox regression model. Results. The median age was 48 years old. The primary histology included anaplastic astrocytoma (47%) and glioblastoma (53%). A margin dose of 18 Gy was administered in the majority of cases (74%). The median survival after initial diagnosis was 21 months (39 months for anaplastic astrocytoma and 18.5 months for glioblastoma) and after reirradiation it was 10 months (17 months for anaplastic astrocytoma and 7.5 months for glioblastoma). In the bivariate analyses, the prognostic factors significantly associated with survival after reirradiation were age, tumour and treatment volume at recurrence, recursive partitioning analyses classification, Karnofsky performance score, histology, and margin to the planning target volume. Only the last four showed significant association in the multivariate analyses. Conclusion. stereotactic radiosurgery is a safe and may be an effective treatment option for selected patients diagnosed with recurrent high-grade glioma. The identified prognostic factors could help individualise the treatment.

Value of F-18-FDG PET/CT for determining malignant pleural effusion in patients with cancer

Objectif : Les épanchements pleuraux sont fréquents chez les patients porteurs de cancer et déterminer s'ils sont de nature tumorale ou non relève d'une grande importance clinique, particulièrement pour le groupe des carcinomes pulmonaires NON à petites cellules (NSCLC). Le PET/CT s'est montré d'une grande utilité et est actuellement indiscutablement reconnu comme outils nécessaire dans la prise en charge et notamment la stadification et le suivi des cancers, et particulièrement des cancers pulmonaires. Sa capacité à pouvoir distinguer les épanchements pleuraux malins des épanchements pleuraux non tumoraux, « bénins » n'est pas précisément connue et n'a pas jusqu'à présent été investiguée de manière approfondie. Matériel et méthodes : Nous avons examiné la captation du FDG (indice SUVmax) des épanchements pleuraux de 50 PET/CT réalisés chez 47 patients (29 hommes, 18 femmes, 60±16 ans) avec épanchements pleuraux et cancer connu (24 NSCLC, 7 lymphomes, 5 cancer du sein, 4 GIST, 3 mésothéliomes, 2 cancer ORL, 2 tératomes malins, 1 carcinome colorectal, 1 carcinome oesophagien, 1 mélanome). Ces résultats ont été corrélés aux résultats des examens cytopathologiques réalisés après ponction de ces mêmes épanchements dans un intervalle médian de 21 jours (interquartile range -3 to 23). L'examen du liquide d'épanchement comportait la mesure du pH, la distribution relative des différents éléments cellulaires (macrophages, neutrophils, éosinophiles, basophiles, lymphocytes, plasmocytes), la numération cellulaire et bien entendu présence de cellules tumorales. Résultats : Parmis les épanchements, 17 étaient malins (34%) (6 NSCLC, 5 lymphomes, 2 cancers mammaires, 2 mésothéliomes, 2 tératomes malins). Les SUV étaient plus élevés dans les épanchements malins que dans les épanchements bénins [3.7 (95%IC 1.8-5.6) vs. 1.7 g/ml (1.5-1.9), p = 0.001], avec une corrélation entre les épanchements malins et le SUV (coefficient de Spearman ρ = 0.50, p = 0.001). Il n'a pas été observé de corrélation entre aucun des autres paramètres cyptopathologiques ou radiologiques analysé (aire sous la courbe ROC 0.83 ± 0.06). En utilisant un seuil du SUV de 2.2-mg/l, 12 examens PET/CT étaient interprétés comme positifs and 38 comme négatifs avec une sensibilité et une spécificité, valeur prédictive positive et négative de 53%, 91%, 75% and 79% respectivement. Concernant le groupe des NSCLC seulement (n = 24), aire sous la courbe ROC était de 0.95 ± 0.04. Sept examens étaient considérés comme positifs et 17 comme négatifs avec une sensibilité, une spécificité, valeur prédictive positive et négative de 83%, 89%, 71 et 94% respectivement. Conclusion : Le PET/CT peut aider à différencier la nature bénigne ou maligne des épanchements avec une haute spécificité chez les patients avec tumeur connue, en particulier dans un contexte de carcinome NON à petites cellules.

Clinical implications of molecular neuropathology and biomarkers for malignant glioma.

Malignant gliomas are currently diagnosed based on morphological criteria and graded according to the World Health Organization classification of primary brain tumors. This algorithm of diagnosis and classification provides clinicians with an estimated prognosis of the natural course of the disease. It does not reflect the expected response to specific treatments beyond surgery (eg, radiotherapy or alkylating chemotherapy). Clinical experience has revealed that gliomas sharing similar histomorphological criteria might indeed have different clinical courses and exhibit highly heterogenous responses to treatments. This was very impressively demonstrated first for oligodendrogliomas. The presence or lack of combined deletions of the chromosomal segments 1p/19q was associated with different benefit from radiotherapy and chemotherapy. We review current molecular markers for malignant gliomas and discuss their current and future impact on clinical neuro-oncology.

Angiogenesehemmung in der Neuroonkologie. Eine vielversprechende Therapiestrategie gegen maligne Gliome [Angiogenesis inhibition in neurooncology. A very promising therapy strategy for malignant glioma]

The application of angiogenesis inhibitors in neurooncology is increasing. Initially, these drugs seemed to be very promising because of the surprisingly high neuroradiological response rates that were observed in first clinical trials. Meanwhile, this enthusiasm is waning, as the high response rates did not translate into substantial improvements in progression-free and overall survival. Tumor progression during or after antiangiogenic therapy is often associated with rapid clinical neurological deterioration and sometimes even with diffuse infiltrative gliomatosis-like neuroradiological phenotypes. Thus, the characterization and understanding of escape mechanisms are needed. The identification of criteria for defining the personalized use of angiogenesis inhibitors remains a challenge.

Malignant glioma after ependymoma: an unusual secondary malignancy

Purpose : Secondary malignancies (SM) are a known long-­‐term problem in children surviving brain tumors. We report on two unusual cases of SM observed after treatment of ependymoma. Case reports : 1. The first case is a female survivor of a low-­‐grade ependymoma (Grade II). She had been treated at the age of 3 months with surgery and chemotherapy. A relapse of the primary tumor happened two years later, which was completely removed and treated with local radiotherapy to the posterior fossa. Fifteen years after the first cancer, she developed a pontine glioma near the location of the previous radiotherapy. 2. The second case is a femal survivor of an ependymoma (Grade III) which was removed and irradiated when she was 4 years old. The child developed a pontine glioma near the location of the previous radiotherapy ten years after the diagnosis of the first cancer. Further extension of the disease showed after biopsy PNET-­‐ like features. Both patients passed away. Discussion and Conclusion : Second malignant neoplasia is a rare phenomenon and this risk should not overshadow the great success in treating cancer of childhood. Among the studied risk factors, young age and radiotherapy are well established. The reported patients were followed annually to ensure their remission and both developed symptoms and an unusual unreported secondary cancer a few months after the annual monitoring that was considered as normal. This issue highlights the complexity of monitoring cancer survivors and raises the question of the best way for their long-­‐term follow-­‐up.

Malignant pleural mesothelioma: leukocyte recruitment is not required for drug delivery induced by photodynamic therapy in a human xenograft model

Objective: The pre-treatment of tumor neo-vessels by photodynamic therapy (PDT) was shown to improve the distribution of chemotherapy administered subsequently. However, the precise mechanism by which PDT modifies the tumor vasculature is unknown. We have recently shown that leukocyteendothelial cell interaction was essential for PDT induced drug delivery to normal tissue. Our purpose was to determine if PDT could enhance drug distribution in malignant mesothelioma and if a comparable role for leucocytes existed.Methods: We grew human mesothelioma xenografts (H-meso-1) in the dorsal skinfold chambers of nude mice (n = 28). The rolling, sticking and recruitment of leucocytes was assessed in tumor and normal vessels following PDT (Visudyne 0?4 mg/kg, fluence rate 200 mW/cm2, fluence 60 J/cm2) using intravital microscopy. In parallel, the distribution of a macromolecule (FITC dextran, 2000 kDa) administered after PDT was determined. We compared these variables in control (no PDT), PDT + IgG (non specific antibody) and PDT + pan-selectin antibody (monoclonal P-E-L selectin antibody).Results: PDT significantly enhanced the distribution of FITC dextran in mesothelioma xenografts compared to controls. Interestingly, PDT enhanced the leukocyte-endothelial interaction significantly (rolling and recruitment)in tumor and surrounding normal vessels compared to controls. Leukocyte recruitment was significantly down-regulated by pan-selectin antibodies in tumor tissues. However, the suppression of leucocyte recruitement did not affect the extravasation of FITC-dextran in tumor tissue.Conclusion:PDTpre-treatment of the mesothelioma vasculature can enhance the distribution of macromolecular drugs administered subsequently. However, unlike normal vessels, leukocyte-endothelial cell interaction is not required for PDT induced leakage.

Role of Age and Sex in the Diagnosis of Early-stage Malignant Melanoma: A Cross-Sectional study.

Age and sex have been identified as predictors of outcome in malignant melanoma (MM). This aim of this multicentre, cross-sectional study was to analyse the role of age and sex as explanatory variables for the diagnosis of thin MM. A total of 2430 patients with MM were recruited. Cases of in situ-T1 MM were more frequent than T2-T4 MM (56.26% vs. 43.74%). Breslow thickness increased throughout decades of life (analysis of variance (ANOVA) p < 0.001), with a weak correlation between Breslow thickness and patient's age (r   = 0.202, p < 0.001). Breslow thickness was significantly less in women (1.79 vs. 2.38 mm, p = 0.0001). Binary logistic regression showed a significant (p < 0.001) odds ratio for age 0-29 years (1.18), and 30-59 years (1.16), and for women (1.09). Age and sex explained 3.64% of the variation observed in Tis-T1 frequency (R2 = 0.0364). Age and sex appear to explain a low percentage of the variation in the early detection of MM.

Role of double-balloon enteroscopy in malignant small bowel tumors.

AIMTo assess the double-balloon enteroscopy (DBE) role in malignant small bowel tumors (MSBT). METHODS This is a retrospective descriptive study performed in a single center. All consecutive patients who underwent a DBE with final diagnosis of a malignant neoplasm from 2004 to 2014 in our referral center were included. Patient demographic and clinical pathological characteristics were recorded and reviewed. MSBT diagnosis was achieved either by DBE directed biopsy with multiple tissue sampling, endoscopic findings or histological analysis of surgical specimen. We have analyzed double-balloon enteroscopy impact in outcome and clinical course of these patients. RESULTS Of 627 patients, 28 (4.5%) (mean age = 60 ± 17.3 years) underwent 30 procedures (25 anterograde, 5 retrograde) and were diagnosed of a malignant tumor. Patients presented with obscure gastrointestinal bleeding (n = 19, 67.9%), occlusion syndrome (n = 7, 25%) and diarrhea (n = 1, 3.6%). They were diagnosed by DBE biopsy (n = 18, 64.3%), histological analysis of surgical specimen (n = 7, 25%) and unequivocal endoscopic findings (n = 2, 7.1%). Gastrointestinal stromal tumor (n = 8, 28.6%), adenocarcinoma (n = 7, 25%), lymphoma (n = 4, 14.3%), neuroendocrine tumor (n = 4, 14.3%), metastatic (n = 3, 10.7%) and Kaposi sarcoma (n = 1, 3.6%) were identified. DBE modified outcome in 7 cases (25%), delaying or avoiding emergency surgery (n = 3), modifying surgery approach (n = 2) and indicating emergency SB partial resection instead of elective approach (n = 2). CONCLUSION DBE may be critical in the management of MSBT providing additional information that may be decisive in the clinical course of these patients.

Plasma and cerebrospinal fluid population pharmacokinetics of temozolomide in malignant glioma patients

RESUME : Objectif: Le glioblastome multiforme (GBM) est la tumeur cérébrale maligne la plus agressive qui conduit au décès de la majorité des patients moins d'une année après le diagnostic. La plupart des agents chimiothérapeutiques actuellement disponibles ne traversent pas la barrière hémato¬encéphalique et ne peuvent par conséquent pas être utilisés pour ce type de tumeur. Le Temozolomide (TMZ) est un nouvel agent alkylant récemment développé pour le traitement des gliomes malins. A ce jour, très peu d'informations sont disponibles sur la pénétration intra-cérébrale de cet agent. Au cours d'une étude pilote de phase II menée auprès de 64 patients atteints de GBM, l'administration précoce de TMZ combinée à une radiothérapie standard (RT) afin d'intervenir au plus tôt dans l'évolution de la maladie, a permis de prolonger la survie de ces patients, résultat qui pu être confirmé par la suite lors de l'étude randomisée de phase III. L'objectif de cette étude a été de déterminer les paramètres pharmacocinétique du TMZ dans le plasma et le liquide céphalo-rachidien (LCR), d'évaluer l'influence de certains facteurs individuels (âge, sexe, surface corporelle, fonction rénale/hépatique, co-médications, RT concomitante) sur ces différents paramètres, et enfin d'explorer la relation existant entre l'exposition au TMZ et certains marqueurs cliniques d'efficacité et de toxicité. Matériel et Méthode: Les concentrations de TMZ ont été mesurées par chromatographie liquide à haute performance (HPLC) dans le plasma et le LCR de 35 patients atteints de GBM nouvellement diagnostiqués (étude pilote) ou de gliomes malins en récidive (étude récidive). L'analyse pharmacocinétique de population a été réalisée à l'aide du programme NONMEM. L'exposition systémique et cérébrale, définie par les AUC (Area Under the time-concentration Curve) dans le plasma et le LCR, a été estimée pour chaque patient et corrélée à la toxicité, la survie ainsi que la survie sans progression tumorale. Résultats: Un modèle à 1 compartiment avec une cinétique d'absorption et de transfert Kplasma -> LCR de ordre a été retenu afin de décrire le profil pharmacocinétique du TMZ. Les valeurs moyennes de population ont été de 10 L/h pour la clairance, de 30.3 L pour le volume de distribution, de 2.1 h pour la 1/2 vie d'élimination, de 5.78 hE-1 pour la constante d'absorption, de 7.2 10E4 hE-1 pour Kplasma->LCR et de 0.76 hE-1 pour KLCR plasma. La surface corporelle a montré une influence significative sur la clairance et le volume de distribution, alors que le sexe influence la clairance uniquement. L'AUC mesurée dans le LCR représente ~20% de celle du plasma et une augmentation de 15% de Kplasma->LCR a été observée lors du traitement concomitant de radiochimiothérapie. Conclusions: Cette étude est la première analyse pharmacocinétique effectuée chez l'homme permettant de quantifier la pénétration intra-cérébrale du TMZ. Le rapport AUC LCR/AUC Plasma a été de 20%. Le degré d'exposition systémique et cérébral au TMZ ne semble pas être un meilleur facteur prédictif de la survie ou de la tolérance au produit que ne l'est la dose cumulée seule. ABSTRACT Purpose: Scarce information is available on the brain penetration of temozolomide (TMZ), although this novel methylating agent is mainly used for the treatment of ma¬lignant brain tumors. The purpose was to assess TNIZ phar¬macokinetics in plasma and cerebrospinal fluid (CSF) along with its inter-individual variability, to characterize covari¬ates and to explore relationships between systemic or cere¬bral drug exposure and clinical outcomes. Experimental Design: TMZ levels were measured by high-performance liquid chromatography in plasma and CSF samples from 35 patients with newly diagnosed or recurrent malignant gliomas. The population pharmacoki¬netic analysis was performed with nonlinear mixed-effect modeling software. Drug exposure, defined by the area un¬der the concentration-time curve (AUC) in plasma and CSF, was estimated for each patient and correlated with toxicity, survival, and progression-free survival. Results: A three-compartment model with first-order absorption and transfer rates between plasma and CSF described the data appropriately. Oral clearance was 10 liter/h; volume of distribution (VD), 30.3 liters; absorption constant rate, 5.8 hE-1; elimination half-time, 2.1 h; transfer rate from plasma to CSF (Kplasma->CSF), 7.2 x 10E-4hE-1 and the backwards rate, 0.76hE-1. Body surface area signifi¬cantly influenced both clearance and VD, and clearance was sex dependent. The AU CSF corresponded to 20% of the AUCplasma. A trend toward an increased K plasma->CSF of 15% was observed in case of concomitant radiochemo-therapy. No significant correlations between AUC in plasma or CSF and toxicity, survival, or progression-free survival were apparent after deduction of dose-effect. Conclusions: This is the first human pharmacokinetic study on TMZ to quantify CSF penetration. The AUC CSF/ AUC plasma ratio was 20%. Systemic or cerebral exposures are not better predictors than the cumulative dose alone for both efficacy and safety.

Legal europeanization as legal transformation : some insights from Swiss 'outer Europe'

The "Europeanization" of non-EU countries' laws is predominantly seen as an "export" of the EU acquis, especially in the case of so-called "quasi-member" states such as Switzerland. Based on an examination of the Swiss experience, this paper highlights the flaws of this conceptualization: the Europeanization of Swiss Law is a highly differentiated phenomenon, encompassing several forms of approximation to EU Law. All of these forms fall short of an "export" of norms, and result in the creation of something new: a "Europeanized law" that is similar to, but qualitatively different from, EU Law. Another drawback of the "export" metaphor is the emphasis it places on the isomorphism of positive legislation. Europeanization goes deeper than that. As shown in this paper, it is a process of transformation involving not only positive law, but also legal thinking. The Swiss case demonstrates how significant such deeper transformations can be: the Europeanization of positive law has induced an alteration of the traditional canon of legal interpretation. It also demonstrates how problematic such transformations can be: the above-mentioned alteration has not given rise to a new and universally accepted canon of interpretation. This reflects the tension between the need for clear "rules of reference" for EU legal materials - which are required in order to restore coherence and predictability to an extensively Europeanized legal system - and the reluctance to give a legal value to foreign legal materials - which is rooted in a traditional understanding of the concept of "law". Such tension, in turn, shows what deep and difficult transformations are required in order to establish a viable model of legal integration outside supranational structures.