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We report the case of a 46-year-old male patient presenting with a Claude Bernard-Horner Syndrome. Clinical evaluation showed a clonal B-cell population, lambda restricted. PET-scan captured femoral and axillary lymph nodes. Therefore the diagnosis of a marginal zone lymphoma was posted for which an attitude of watchful waiting was suggested. Eighteen months later, the patient developed an inguinal adenopathy. This lymph node led to the diagnosis of a nodular sclerosing Hodgkin lymphoma. Initial treatment with ABVD showed a good response, but the patient relapsed after eight months. A second biopsy confirmed the diagnosis of a marginal zone lymphoma but also identified giant Reed-Sternberg cells, (CD15+, CD30+ and CD20+). The initial biopsy was revised. This last diagnosis of a nodal marginal zone lymphoma with presence of Reed-Sternberg cells is rarely described in the literature. Several scientific theories can be found. Some cases described a transformation of non-Hodgkin lymphoma that presented Reed-Sternberg cells, other cases mentioned a collision or composite tumor. An accidental finding of Reed-Sternberg cells can be seen by after an infectious disease such as EBV. The presence of only Reed-Sternberg cells in a non-Hodgkin lymphoma is not sufficient to make a diagnosis of collision tumor.

Malignant paragangliomas pose a real challenge for the practitioners. They are rare complex tumors, very heterogeneous in their evolution and prognosis. Given the rarity of this tumor group, there is no consensus on therapeutic management. Through this illustrative case study, we report the case of a 29 year old female patient followed for malignant paraganglioma due to which she initially had surgery. After a six month interval, multifocal recurrence was detected on Octreoscan PET-CT (Positron Emission Tomography-Computer Tomography). The patient underwent monthly injection of Somatuline for one year and then discontinued therapy due to disease progression. Cytoreduction was then performed followed by radiotherapy. After a year, the patient had massive disease progression. Dacarbazine-based chemotherapy was initiated. The patient had an almost complete metabolic response after eight cycles. This study aims to highlight the different therapeutic options in the management of malignant paragangliomas., SCOPUS: ar.j, info:eu-repo/semantics/published

Despite the combined adjuvant treatment of radiotherapy plus chemotherapy with temozolomide (TMZ) followed by 6 cycles of temozolomide after surgery, the prognosis of patients with glioblastoma remains poor. We conducted a monocentric prospective study to explore the tolerance and potential efficacy of an early temozolomide cycle after surgery.Patients with newly diagnosed glioblastoma (unmutated IDH1) and of poor prognosis (age50 years, biopsy or partial resection or unmethylated MGMT promoter) were prospectively included from June 2014 to 2017. They all received a cycle of 5 days of temozolomide between surgery and the combined adjuvant treatment.Twelve patients of median age 64.5 years (45-73) were included in the study. The median doses of temozolomide administered were respectively 265mg (225-300) for the early cycle; 130mg (110-150) for the concomitant treatment and 310mg (225-400) for the adjuvant one. Side effects during treatment were grade III lymphopenia, grade III neutropenia, fatigue and nausea/vomiting respectively in 4, 1, 7 and 5 patients. Progression-free survival and overall survival were respectively 90% and 91.7% at 6 months; 58.3 and 71.3% at 12 months; 31.1 and 71.3% at 18 months.Early postsurgical temozolomide treatment prior to standard adjuvant therapy for poor prognosis glioblastoma patients in our small prospective series presents toxicity and survival similar to those published in the literature for the general population of glioblastoma. These encouraging results should be confirmed by a multicentric study comparing this regiment with the standard treatment.

L’utilisation de médicaments cytotoxiques comme agent anticancéreux ou immunosuppresseur est aujourd’hui une pratique courante dans le traitement de nombreuses pathologies. Beaucoup sont encore administrés par voie injectable. Des services très différents sont amenés à les utiliser quotidiennement, ce qui expose les personnels travaillant à la pharmacie de l’hôpital, dans les services de soins hospitaliers ou à domicile. Le projet "CYTOPRO" visait à évaluer l’exposition aux cytotoxiques dans divers services de soins et à la pharmacie du CHU de Lille.

Primary osseous Hodgkin's lymphoma is a very rare entity. Cases reported in the literature are limited with often insufficient initial exploration. We report a new case of a 24 years old patient with a diagnosis of primary osseous Hodgkin lymphoma of the lumbosacral region with extension to the soft tissues, without simultaneous lymph node involvement confirmed both by conventional and metabolic imaging. The patient received a combination chemotherapy (two courses BEACOPP

Les paragangliomes malins présentent un réel challenge pour les praticiens. Il s'agit de tumeurs rares, de caractérisation complexe, et très hétérogènes dans leur évolution et pronostic. Devant la rareté de ce groupe tumoral, il n'existe pas de consensus sur la prise en charge thérapeutique. A travers ce cas illustratif, nous rapportons l'observation d'une patiente de 29 ans suivie pour un paragangliome malin traitée initialement par chirurgie. Après six mois d'intervalle, récidive multifocale fixant à l'Octreo PET-CT (Positron Emission Tomography- Computer Tomography), la patiente a été mise sous injection mensuelle de Somatuline pendant un an puis arrêté suite à une progression. Une 2ème chirurgie de cytoréduction a été réalisée suivie d'une radiothérapie. Après un an, la patiente a présenté une progression massive. Une chimiothérapie à base de Dacarbazine a été initiée et dont l'évaluation a montré une réponse métabolique quasi complète après huit cures. Le but de ce travail est d'exposer les différentes options thérapeutiques possibles dans la prise en charge des paragangliomes malins.

Les métastases extracrâniennes découlant de glioblastome sont rares et le mécanisme de leur diffusion n'est pas bien connu. Nous rapportons le cas d'un homme suivi pour un glioblastome traité par chirurgie suivie d'une radiothérapie encéphalique avec Temozolamide en concomitant, et qui a présenté une métastase des parties molles.

International audience; Melanomas have a high rate of brain metastases. Both the functional prognosis and the overall survival are poor in these patients. Until now, surgery and radiotherapy represented the two main modalities of treatment. Nevertheless, due to the improvement in the management of the extracerebral melanoma, the systemic treatment may be an option in patients with brain metastases. Immunotherapy with anti-CTLA4 (cytotoxic T-lymphocyte-associated protein 4) - ipilimumab - or BRAF (serine/threonine-protein kinase B-raf) inhibitors - vemurafenib, dabrafenib - has shown efficacy in the management of brain metastases in a- or pauci-symptomatic patients. Studies are ongoing with anti-PD1 (programmed cell death 1) and combinations of targeted therapies associating anti-RAF (raf proto-oncogene, serine/threonine kinase) and anti-MEK (mitogen-activated protein kinase kinase).

The incidence of glioblastoma increases with age, with a median age, at diagnosis, of 65 years. Indeed, the optimization of standard of care of elderly glioblastoma patients in an aging population in Western countries becomes crucial. The age remains the main prognostic factor of glioblastoma. Survival among elderly patients is significantly less than among younger patients. The median survival of elderly glioblastoma patients is generally inferior to 6 months. More aggressive tumor behavior, less aggressive treatments, increased toxicity of therapies and more unfavorable clinical factors and comorbidities could explain a higher severity of the disease in the elderly. The balance between treatment efficacy and quality of life is a major focus because of the shorter life expectancy of patients. The standard of care of glioblastoma in elderly patients remains controversial. Large optimal resection, when achievable, should be preferred to biopsy. Survival is longer after adjuvant radiotherapy, either normofractionated over 6-weeks course or hypofractionated over 3-weeks course, for patients with good clinical status. Hypofractionation is often preferred because of shorter procedure. Chemotherapy alone with temozolomide can be proposed to patients with methylated MGMT promoter. A phase III randomized study, testing short-course adjuvant radiotherapy with or without temozolomide in elderly patients with good clinical status, is ongoing.

Gliomas are the most frequent primary brain tumors. Their care is difficult because of the proximity of organs at risk. The treatment of glioblastoma includes surgery followed by chemoradiation with the protocol of Stupp et al. The addition of bevacizumab allows an increase in progression-free survival by 4 months but it does not improve overall survival. This treatment is reserved for clinical trials. Intensity modulation radiotherapy may be useful to reduce the neurocognitive late effects in different types of gliomas. In elderly patients an accelerated radiotherapy 40 Gy in 15 fractions allows a similar survival to standard radiotherapy. O(6)-methylguanine-DNA methyltransferase (MGMT) status may help to choose between chemotherapy and radiotherapy. There is no standard for the treatment of recurrent gliomas. Re-irradiation in stereotactic conditions allows a median survival of 8 to 12.4 months. Anaplastic gliomas with 1p19q mutation have a greater sensibility to chemotherapy by procarbazine, lomustine and vincristine. Chemoradiotherapy in these patients has become the standard treatment. Many studies are underway testing targeted therapies, their place in the therapeutic management and new radiotherapy techniques.

The incidence of brain metastases from breast cancer is increasing with diagnosis and therapeutics progress, especially with systemic therapies. The occurrence of multiple brain metastases remains a delicate situation when surgery and stereotactic radiosurgery are not indicated, nor available. Treatment strategy is based on the patient's general condition and extracranial disease status. Whole brain radiation therapy remains the gold standard local treatment but its efficacy is limited with a median overall survival of 6 months. New strategies are needed for increasing survival and patients' quality of life. Combining radiation therapy and chemotherapy has been a subject of interest. This article sums up the different radiotherapy plus concomitant systemic therapies combinations for the treatment of brain metastases from breast cancer.

Recent years have seen the emergence of new molecules for the treatment of patients with metastatic cutaneous melanoma, with significant benefits in terms of survival and the opening of new therapeutic perspectives. In addition, many techniques are currently being developed for locoregional treatment of metastatic sites. Management of metastatic melanoma is thus fast-changing and is marked by innovative therapeutic approaches. However, the availability of these new treatments has prompted debate among healthcare professionals concerning their use and their place in therapeutic strategy.Since 2008, the French National Cancer Institute (INCa) has been leading a project to define and diffuse national clinical practice guidelines. It has performed a review of these treatment methods, which it aims to circulate, and it is seeking to develop recommendations in order to allow nationwide implementation of innovative approaches while promoting good use thereof.The clinical practice guidelines development process is based on systematic literature review and critical appraisal by experts within a multidisciplinary working group, with feedback from specialists in cancer care delivery. The recommendations are thus based on the best available evidence and expert agreement. Prior to publication, the guidelines are reviewed by independent practitioners in cancer care delivery.This article presents the national recommendations for first- and second-line systemic treatment and for locoregional treatment of metastatic sites in patients presenting metastatic cutaneous melanoma.

Brain metastases affect 37% of patients suffering from metastatic melanoma, and their prognosis remains poor, with an overall survival lower than six months. At the moment, there is no standard therapeutic strategy for management of melanoma brain metastases. In some cases, having recourse to a systemic treatment is justified, for example, when brain metastases are combined with a progressive peripheral disease, or with unresecable brain lesions. In France, the use of fotemustine, which received the AMM approval, for metastatic melanoma treatment, is one of the treatments recommended in the case of brain metastases as this chemotherapy, that is active on the melanoma passes the blood-brain barrier. Temozolomide also shows some activity in the brain metastases treatment of melanoma that remains modest in monotherapy but seems interesting when it is combined with radiotherapy. The place of new drugs, in particular ipilimumab and vemurafenib, in the strategy of melanoma brain metastases treatment, still has to be defined and may improve the prognosis of these patients and their quality of life. The new targeted therapies, the widespread use of stereotactic radiosurgery and the improvement in neurosurgical operations would need a prospective clinical assessment, all the more so, in most of clinical studies, the presence of metastases is an exclusion criterion.

The authors report a case of Dropped Head Syndrome with an unusually rapid onset after an accident in a patient with a history of Hodgkin's lymphoma cured by chemotherapy and mantle field radiotherapy and compare this case to the rare published cases of chronic Dropped Head Syndrome occurring after this type of treatment. A 56-year-old man was treated at the age 36 years for supra-diaphragmatic Hodgkin's lymphoma by chemotherapy and mantle field radiotherapy according to a standard technique and standard doses (40Gy, 20 fractions, 27 days). Seventeen years after the end of treatment, he experienced a violent whiplash injury, rapidly followed by a Dropped Head Syndrome, similar to the cases of chronic Dropped Head Syndrome already described in the context of Hodgkin's lymphoma (permanent flexion of the head, only reduced in the supine position). Physical and neurophysiological examination, electromyogram, and magnetic resonance imaging confirmed the diagnosis of Dropped Head Syndrome. Very few treatment options are available for the major disability related to Dropped Head Syndrome. This type of subacute onset of Dropped Head Syndrome has not been previously described. The good results of radiation therapy after chemotherapy allow a dose reduction to 30Gy in the involved regions. This, together with recent progress in treatment planning, should allow eradication of these complications.

During the last decades, advances in diagnostic and therapeutic technologies have modified the management of brain metastases, which is currently tailored to the type of primary site and to prognostic factors isolated in multivariate analyses. The aim of this article is to take stock of the current state of knowledge regarding prognostic factors in the setting of brain metastases from breast cancer as well as prognostic classifications proposed in this context. An appropriate multidisciplinary treatment for each prognostic class will be then discussed in light of the results of major randomized controlled trials enrolling patients with brain metastases from breast cancer.

Malignant melanoma is a relatively rare but potentially aggressive tumor in children and adolescents. We report the case of a metastatic malignant melanoma in a 17-year-old girl, first diagnosed on cytological features of a fine-needle lymph node aspiration and then histologically confirmed by both examination of the metastatic adenopathy and a clinically harmless skin lesion of the scalp, which harbored focal microscopic pattern of melanoma. A fluorescent in situ hybridization study revealed that both metastatic and primary cutaneous tumours contained the same and pejorative chromosomal aberration consisting in CCND1 amplification (11q13). This observation raises actual limits and challenges in the fields of diagnosis and treatment of fast-killing melanomas.

Despite progress in the initial management of glioblastoma (GB), the vast majority of patients will experience recurrence within 2-3 years. The medical treatment of these recurrences is being modified by the use of antiangiogenic therapies. Twenty-four patients, who relapsed from GB after chemoradiation followed by adjuvant temozolomide in Rennes, were treated by conventional chemotherapy (nitrosourea) or by the combination of irinotecan and bevacizumab. In this retrospective analysis, overall survival from diagnosis of recurrence was significantly longer in patients treated with the combination of bevacizumab and irinotecan than with nitrosourea (5 months versus 11.5 months). The combination of irinotecan and bevacizumab appeared to provide clinical benefit to patients with recurrent GB.

The anti-CTLA-4 Mab ipilimumab is an efficient treatment of metastatic melanoma as a single agent and combined with dacarbazine chemotherapy. The benefit is observed in 10 to 20 % of the patients but it is the only drug to demonstrate an increase in overall survival of patients with metastatic melanoma. The pattern of response is new with delayed and prolonged responses over time. New evaluation criteria have been proposed to evaluate the efficacy of this new therapy. The safety profile is new also with frequent and potentially severe side effects related to the activation of the immune system. The challenges are now to identify biomarkers able to predict ipilimumab benefit and to know how to use ipilimumab in combination with new targeted therapies of melanoma in order to optimize the treatment efficacy.

The incidence of malignant gliomas in the aging population of industrialized countries is increasing. This observation justifies an important ongoing clinical research effort specifically dedicated to this population. The first results of prospective studies have showed the interest of radiotherapy and chemotherapy with temozolomide. The effect of combined concomitant and adjuvant chemotherapy with radiotherapy is currently being evaluated in a phase III study. The likely beneficial effect of surgical resection needs to be formally demonstrated in this fragile population. Initial functional status, quality of life and concomitant systemic pathologies are important factors to tailor the treatment according to patients status.

MGMT status is now regarded as a strong predictive factor of response to standard treatment of newly diagnosed glioblastomas involving temozolomide (TMZ) and radiotherapy. MGMT promoter methylation is also a prognostic factor - independent of treatment - in anaplastic gliomas. The predictive function can be explained by the role of the DNA repair enzyme MGMT, which antagonizes the effects of alkylating agents such as TMZ. MGMT promoter methylation could also reflect a particular molecular phenotype with its own specific prognostic significance. Since MGMT status determination is becoming a crucial biological marker in new clinical glioma trials, and is beginning to be used in day-to-day clinical practice, there is currently a strong need to determine the best technique for MGMT analysis. A French multicenter study has been set up for this purpose.

International audience; Pulmonary Langerhans histiocytosis (PLH) is a rare disease due to the accumulation of Langerhans cells at the level of the bronchioles. These dendritic immunocytes form granulomata and destroy the wall of the airway. We report a case of PLH developing at the same time as Hodgkin's lymphoma in a young woman who smoked tobacco and cannabis. We observed a complete remission of the PLH lesions parallel to the remission of the Hodgkin's lymphoma after chemotherapy, in the absence of any change in the consumption of tobacco and cannabis. This observation leads us to discuss the potential relationships between PLH on one hand, and smoking, the lymphoma and its treatment on the other.

To evaluate the effect of Temozolomide on female fertility and the relevance of our coverage in preservation of fertility.From 2005 to 2009, 24 patients treated with Temozolomide for a low-grade glioma were included in the study (12 women who underwent a fertility preservation consultation and 12 women who did not). A retrospective study of their medical records and sending a questionnaire were undertaken to assess their fertility after treatment.Of the 24 patients, 15 patients had no fertility preservation and the remaining nine had a cryopreservation of embryos with or without an oocyte cryopreservation. Four patients are or have been pregnant (delivery, spontaneous miscarriage, pregnancy being in the group of preserving fertility and a current pregnancy in the group where no fertility preservation has been achieved).First study on the effect of Temozolomide on female fertility.Temozolomide is not totally gonadotoxic.

Pulmonary Langerhans histiocytosis (PLH) is a rare disease due to the accumulation of Langerhans cells at the level of the bronchioles. These dendritic immunocytes form granulomata and destroy the wall of the airway. We report a case of PLH developing at the same time as Hodgkin's lymphoma in a young woman who smoked tobacco and cannabis. We observed a complete remission of the PLH lesions parallel to the remission of the Hodgkin's lymphoma after chemotherapy, in the absence of any change in the consumption of tobacco and cannabis. This observation leads us to discuss the potential relationships between PLH on one hand, and smoking, the lymphoma and its treatment on the other.

Temozolomide has significantly improved the outcome of patients with glioblastoma. However, the optimal duration of continuation treatment after chemoradiation remains uncertain. This retrospective analysis aims at assessing the feasibility, the tolerance, and the potential benefit of prolonging adjuvant temozolomide more than six months, which is the reference protocol.Forty-six patients were included in the analysis. Median age at diagnosis was 61 years old (range 40 to 77). Forty-five patients received a conformal external beam radiation with concurrent temozolomide-based chemotherapy. Then, 37 patients received adjuvant chemotherapy with temozolomide. The treatment was continued until progression or toxicity.During the adjuvant phase, no treatment discontinuation for toxicity was necessary. Eight patients required dose adaptation because of toxicity. Thirty-two patients presented tumor progression during the adjuvant phase. Overall median survival was 12.3 months (range 11-13.2 months) and progression-free survival (PFS) was 7.6 months (range 5.6-9.6 months).These results suggest feasibility of delivering temozolomide beyond the six months of the standard protocol, with mild toxicity and survival data at least comparable to those from literature. Prospective assessments are ongoing.

Doxorubicin monotherapy is the standard first-line treatment in patients with advanced soft-tissue sarcomas. Ifosfamide still remains the standard 2nd line treatment after doxorubicin-failure. However, recent data have demonstrated that histological subtypes differ in their sensitivity to cytotoxic drugs. Therefore, gemcitabine should be considered as the best option after doxorubicin failure in leiomyosarcoma patients. Trabectedine should be used preferentially in myxoid liposarcomas and leiomyosarcomas patients whereas paclitaxel should be considered as a first or second-line treatment of choice in angiosarcoma patients. Further studies are needed in order to identify predictive factors of clinical benefit in advanced soft-tissue sarcoma patients treated with cytotoxic agents in combination or not with targeted therapies.

A risk-adapted strategy for adult patients with Hodgkin's lymphoma is based on risk factors at diagnosis. First line chemotherapy with the gold standard ABVD regimen, with 3 or 4 courses for patients without or with risk factors, respectively, followed by radiation therapy targeting the initially affected areas (involved-field RT), at a dose of 30 Gy, is the treatment of choice for all early-stage supradiaphragmatic disease. Treatment for disseminated disease is based on chemotherapy alone. According to prognostic index, 8 cycles of ABVD or more intensive regimen like BEACOP are indicated. At the present time, clinical trials including PET scans to evaluate early response to chemotherapy, aim to treat early stages with chemotherapy alone and modern radiation techniques are being developed to restrict the target volume to initially involved nodes only. For advanced stages, PET scan may help to define optimal treatment and primary failures from first line chemotherapy.

Malignant gliomas are the most frequent primary brain tumors in adults. Temozolomide is an oral alkylating cytotoxic agent of second generation, used in the treatment of high-grade gliomas. It is indicated in newly diagnosed glioblastoma multiform as well as in recurrent or progressive malignant gliomas, such as glioblastoma multiform or anaplastic astrocytoma. However, temozolomide is also used, off label, in other clinical situations and the main objective of this study was to establish recommendations and guidelines for relevant prescriptions of temozolomide in primary brain tumors and brain metastasis in adults. The literature review was analysed by experts who determined the evidence level (A to E) according to the scale of recommendations adopted by the "Haute Autorité de santé--HAS--(French National Authority for Health)". For high-grade and low-grade gliomas, based on the level of evidence from the literature, the use of temozolomide can be justified, with a B2 score attributed to these indications. In contrast, for the others indications, the use of temozolomide appeared to be more controversial or even not recommended (score C to E). Regarding the dosing schedule and administration scheme, as well as the co-administration with other anticancer drugs, a C score was attributed for the off label situations.

Malignant glucagonoma is an exceptional pancreatic endocrine tumour, with frequent dermatologic symptoms, diabetes and degradation of the general health status. Prognosis is unfavourable when liver metastases are present due to the usual inefficiency of chemotherapy. We report here an observation of a patient who was treated for a glucagonoma with multiple liver metastases, migratory necrolytic erythema, dilated cardiomypathy and diabetes that dramatically improved after a dacarbazin-based chemotherapy, allowing subsequent surgical resection of the primary. The patient was still alive and asymptomatic without progressive disease nearly two years after surgery.

Despite recent and significant progress, the prognosis of glioblastoma remains extremely poor. Concomitant chemoradiotherapy with temozolomide is now the standard of care for newly diagnosed glioblastoma. This treatment is well-tolerated and results in improvement of overall survival and dramatic increase of long term survivor rate, especially in good performance status patients. Besides, this benefit is particularly marked in patients with MGMT (methylguanine methyltransferase) methylated tumor, suggesting a growing place of molecular markers in pattern of care of such patients. At recurrence, the combination of bevacizumab (anti-VEGF) with irinotecan has shown surprising high response rates in a phase II trial for recurrent malignant gliomas. Many other targeted therapies are currently under investigation, alone or in association, at recurrence or up-front and during radiotherapy. For this reason, in the future a more precise understanding of gliomagenesis is needed for a better molecular stratification of patients.

For many tumour types, chemoradiotherapy is now the standard of care. Concomitant administration seems to improve the results over sequential schedules in many clinical situations. A lot of mechanisms of interaction between drugs and radiation have been described, according to the mechanism of cytotoxicity of the compound. Modifications of radio-induced DNA damages or of their repair have been involved for cisplatin or 5-fluoro-uracil. Synchronisation or cytokinetic cooperation is also usually described, particularly for taxanes. At the tissular level, reoxygenation of the tumour or inhibition of the proliferation could be obtained with different drugs, and today with targeted therapies. The study of these interactions in vitro or in vivo could help the physician in selecting the best drugs to use in conjunction with irradiation and in designing his clinical protocols.

Temozolomide is an alkylating agent approved for treatment of glioblastoma in association with radiotherapy.We report the case of a 56 year old woman presenting with alveolo-interstitial pneumonia after treatment with Temozolomide. Initially she received induction treatment with Temozolomide and concomitant radiotherapy for bifocal high grade glioblastoma. A month later she received, as scheduled, the first course of Temozolomide maintenance chemotherapy. Grade II dyspnoea developed a few days later. High resolution computed tomography showed alveolo-interstitial opacities with basal predominance, associated with alveolar nodules. Broncho-alveolar lavage showed a lymphocytosis. No bacteria were isolated from microbiological samples. A final diagnosis of drug-induced pneumonia was based on the time sequence and absence of other causes.There is little literature concerning the pulmonary toxicity of Temozolomide. However, our case report of drug-induced pneumonia and similar observations in the databases of regional pharmacovigilance centres suggest that this side effect should be included in the summary of product characteristics.

To assess waiting time effect in patient with multiform glioblastoma (GBM) treated with 3D conformal planned postoperative radiotherapy and to investigate the impact of chemotherapy as first adjuvant treatment.We retrospectively analyzed 94 consecutive patients with histologically proven GBM. Surgery was considered as macroscopically complete in 33 cases (35%). Median irradiation dose was 60 Gy (8-63, mean 56 Gy). Dose per fractions was 1.8 Gy (five patients), 2 Gy (76 patients) and 2.7 Gy (13 patients). Forty patients received adjuvant pre-radiotherapy chemotherapy as intra-operative carmustine (nine patients) and adjuvant five-day protocol temozolomide alone (31 patients) or with cisplatinum (two patients). All patients received only one chemotherapy cycle.There were 56 males and 38 females. Median age was 62.1 years old (7-82, mean: 59.2 year). Median follow-up was nine months (1-49). For overall patients, median waiting time between fist clinical sign and start of the non surgical treatment was 68 days ((3-274, mean: 81.9 days). For those who received chemotherapy as first treatment, this waiting time was 54 days (3-221, mean 68.3 days). For overall patients, median waiting time between surgery and beginning of radiotherapy was 46 days (8-401, mean 59.3 days). For patients who did not receive chemotherapy as first adjuvant treatment this waiting time was 46 days (-278, mean 55.4 days). Median local control was 14.5 months. Six, 12-, 18-, and 24-month local control rates were 75.6+/-4.6%, 57.6+/-6.2%, and 36.7+/-8% and 27.6+/-8.2%, respectively. According to multivariate analysis, we retrieved two independent prognostic factors of local control, macroscopically total removal of the tumor [RR=2.85, IC 95% (1.3-6.5), p=0.012] and irradiation dose above 60 Gy, [RR=3.14, IC 95% (1.5-6.6), p=0.002]. Median overall survival was 14.3 months. Six-, 12-, 18, and 24-month overall survival rates were 84+/-3.9%, 55.1+/-5.9%, 34.2+/-6.3% and 30.4+/-6.7%, respectively. There was no independent prognostic factor.In our series neither waiting times nor adjuvant immediate chemotherapy were prognosticator of local control and overall survival outcome of patients with glioblastoma.

Malignant gliomas of which glioblastomas represent the ultimate grade of malignancy are characterized by dismal prognoses because malignant glioma cells present both important proliferation and neoangiogenesis processes and can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) but seem less resistant to autophagic cell death (type II programmed cell death). Autophagic cell death represents an alternative mechanism to overcome, at least partly, the dramatic resistance of glioblastomas to pro-apoptotic-related therapies. Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which then should restore a level of sensitivity to pro-apoptotic drugs. We conclude this work with an algorithm showing the optimal current treatment for glioblastoma with the potent future innovations.

Malignant gliomas of which glioblastomas represent the ultimate grade of malignancy are characterized by dismal prognoses because malignant glioma cells present both important proliferation and neoangiogenesis processes and can actively migrate through the narrow extra-cellular spaces in the brain, often travelling relatively long distances, making them elusive targets for effective surgical management. Invasive malignant glioma cells show a decrease in their proliferation rates and a relative resistance to apoptosis (type I programmed cell death) as compared to the highly cellular centre of the tumour, and this may contribute to their resistance to conventional proapoptotic chemotherapy and radiotherapy. The multidisciplinary up to date treatment for glioblastoma patients combined maximal surgical removal of the tumor with postoperative radiotherapy and concomitant chemotherapy with temozolomide. Temozolomide is a proautophagic (type II programmed cell death) drug and can thus circumvent part of the glioblastoma resistance to apoptosis. Another way to potentially overcome apoptosis resistance is to decrease the migration of malignant glioma cells in the brain, which then should restore a level of sensitivity to proapoptotic drugs. The Na(+)/K(+)-ATPase or sodium pump is an ion transporter which in addition to exchanging cations, is also the ligand for cardenolides and is directly involved in the migration of cancer cells in general and of glioma cells in particular. We have shown that the alpha1 subunit of the sodium pump is highly expressed in glioma cells compared to normal brain tissues and we are the first to propose the alpha1 subunit of the sodium pump as a new target in the context of malignant glioma treatment. Using a novel cardenolide with unique structural features, which markedly inhibits sodium pump activity and binds to the alpha1 subunit, we have shown marked anti-proliferative and anti-migratory effects on human glioblastoma cells (and other cancer cell types). We have characterized at least partially the anti-cancer mechanism of action of the novel cardenolide. It is a ligand of the alpha1 subunit of the pump which impairs the proliferation and migration of glioblastoma cells by disorganizing the actin cytoskeleton and inducing severe autophagic process in glioblastoma cells. Collectively, these data suggests that the novel cardenolide is an attractive candidate for preclinical and clinical development, at least in the area of glioblastoma. This compound should reach phase I clinical trials in the summer of 2008.

The management of gliomas remains challenging and requires a multidisciplinary approach that involves neurosurgeons, radiation therapists and oncologists. For patients with glioblastomas, progress has been made in recent years with the introduction of a combined modality treatment associating radiation therapy and concomitant chemotherapy with the novel alkylating agent temozolomide. This combination resulted in a significant prolongation of survival and increase in the number of patients with survival well beyond two years. Since then, interest in developing new agents in this disease has dramatically increased. In parallel, molecular markers, such as methylation status of MGMT or identification of the translocation of 1p and 19q in oligodendrogliomas have allowed to identify distinct subtypes with exquisite response to treatment or different prognosis. These developments have implications for the development of clinical trials of new potential drug treatments. In this article, we provide a review of the current management of low- and high-grade gliomas, including astrocytomas, oligodendrogliomas and glioblastomas and provide an outlook into future potential therapies.

Inaugural tracheobronchitis is a rare but known manifestation of Hodgkin's disease. Clinical signs are often misleading, retarding diagnosis and treatment. We report a case of Hodgkin's disease revealed by wheezing with minimal hemoptysis. Histology of the endoscopic biopsies demonstrated Hodgkin type infiltration of the trachea with mixed cellularity. The patient was given chemotherapy and mediastinal radiotherapy and achieved complete remission.

The authors report a peculiar form of Hodgkin's disease that is associated with Epstein-Barr virus infection. A 16-year-old patient was admitted for an autoimmune haemolytic anaemia associated with IgG auto-immune antibodies, linked to general clinical complications, cervical adenopathies and splenomegalia. The patient underwent hemicavectomy that was not histologically investigated. The ganglionar exeresis helped to establish the histological diagnosis of Hodgkin's disease, classic form with nodular sclerosis. Tumour cells were CD30 CD15 positive and neighbouring lymphoid cells were CD3 and CD20 positive. In situ hybridation allowed the detection of Epstein-Barr virus in tumour cells. Under ABVD chemotherapy supplemented with acyclovir and initial corticotherapy, mid-treatment evolution appears to be favourable. This observation is consistent with the hypothesis that tumour cells are of B cell origin during Hodgkin's disease, together with the involvement of Epstein-Barr virus in lymphomagenesis.

Carmustine wafers (Gliadel) and temozolomide (Temodal) were recently approved for initial management of glioblastoma. Gliadel) is a polymer wafer containing carmustine. These wafers are designed to be placed in the surgical cavity after glioblastoma resection to deliver local chemotherapy. This treatment is intended for tumors for which gross total resection is possible. Temozolomide is administered concomitantly with radiotherapy for six weeks followed by six cycles of adjuvant temozolomide (EORTC 26981, also known as "Stupp's protocol"). Temozolomide administered according to this protocol produced a median survival benefit of 2 months in glioblastomas, and carmustine a similar benefit in high-grade gliomas. The two-year survival rate was 26.5% with radiotherapy plus temozolomide compared with 10.4% with radiotherapy alone. In patients with complete resection, two-year survival reached 38%. These two new treatments are essentially intended for patients younger than 70 years and with a Karnofsky index70. Ongoing studies are evaluating the possible value of combining these two treatments.

High grade gliomas are the most frequent and malignant primary brain tumours in adults. Prognosis depends on age, performance status and histological grade. Associated with symptomatic treatments, surgery, radiotherapy and chemotherapy represent the main weapons of the specific multidisciplinary therapy of malignant gliomas. Surgery is necessary for histological diagnosis. In malignant gliomas, surgery may improve survival in case of complete removal, and debulking provides an improvement of the quality of life and a symptomatic relief. Radiation therapy has been shown to improve survival in malignant glioma. The place of chemotherapy is growing not only for anaplastic oligodendrogliomas, more chemosensitive (particularly when they harbor 1p19q codeletions), but also for glioblastomas patients, which have been shown to benefit from radiotherapy plus concomitant and adjuvant temozolomide. This effect was particularly clear for patients with MGMT inactivation in the tumour, confirming here also the impact of molecular biology for future management of gliomas.

Dacarbazine (DTIC) is the first-line chemotherapy for metastatic malignant melanoma without cerebral metastasis. Its clinical and hematological safety is usually good. Hypersensitivity in hepatic failure patients is the most serious side effect described.This was a retrospective study of the prevalence of hypersensitivity in patients treated with DTIC for metastatic melanoma between 11/01/2002 and 10/31/2003. Hypersensitivity was diagnosed in the event of fever, hypereosinophilia (500/mm3) with or without liver dysfunction (twice pre-therapeutic values). Clinical data, DTIC administration modalities, number of courses and clinical and laboratory safety data were recorded.Twenty patients were included, 11 women and 9 men of median age 58.6 years (22-82 years) with multiple metastases in all cases. DTIC was the first-line treatment for 19 patients, being administered for 4 days to 10 patients and for 1 day to the other 10 patients, depending on their overall health status. Five hypersensitivity-like manifestations were observed, all in the 4-day treatment group. In 3 patients, fever and hypereosinophilia were seen without liver dysfunction at D3 of the second course of treatment. In 2 patients, treatment was stopped after the second course because of disease progression. In the third patient, 4 courses were given with recurrence of symptoms, although the latter were controlled during the fifth course with corticosteroids and antihistamines given 15 minutes before the start of treatment. Two patients experienced severe forms of hypersensitivity with fever, hypereosinophilia, liver dysfunction (cytolysis and cholestasis) and delayed medullar aplasia, after the first and second course respectively. In one patient, bone marrow examination showed a block at the promyelocytic stage consistent with a toxic etiology. Treatment with DTIC was stopped, and all signs regressed with symptomatic treatment.Hypersensitivity with DTIC seems to be frequent, being observed in 20% of our patients, with early onset (after the first or second course) and absence of dose-dependence. We describe for the first time two cases of medullar aplasia occurring in association with DTIC hypersensitivity. During phase I studies, the hematologic toxicity of DTIC was moderate, rarely affecting red cells, and was observed with higher doses than those used in metastatic malignant melanoma. We suggest that this aplasia forms part of the signs of hypersensitivity because of the bone marrow morphology, the existence of anemia and concomitant resolution with all the others signs of hypersensitivity.Laboratory monitoring (NFS, liver enzymes) is thus justified, particularly after the first and second courses of DTIC. In case of fever and hypereosinophilia without liver dysfunction, DTIC may be continued together with symptomatic treatment. In the event of hepatic dysfunction, and of course severe hematological disorders, potentially fatal complications can occur and treatment must be stopped.

Glioblastomas are the most frequent and the most aggressive primary brain tumors in adults. Therapeutic strategy is challenging because of radioresistance and chemoresistance explaining the poor prognosis (median survival of 12 months). Standard therapy consisted until recently of surgery and postoperative radiotherapy while the impact of chemotherapy (investigated as adjuvant, neo adjuvant therapy or concomitant with irradiation) was a matter of debate. However a recent phase III study has concluded to the benefit of adjuvant temozolomide administered during and after radiotherapy. This strategy is yet to become a standard.

This review aims to discuss the main advances in gliomas, primary cerebral lymphomas and cerebral metastasis. The recent development of molecular biology and cerebral imaging allows a better understanding and management of gliomas and phase III studies have concluded to the benefit of adjuvant temozolomide administered during and after radiotherapy for glioblastomas: this strategy is yet to become a standard. Optimal treatment for primary central nervous system lymphoma remains to be defined, and several studies aims to precise the value of radiotherapy as consolidation treatment. Several trials reviewing the current treatment options for brain metastasis (whole brain radiation therapy, surgical resection stereotactic radiosurgery and chemotherapy) are highlighted.

During these last 25 years, despite numerous phases III studies, standard of treatment in glioblastoma multiforme (GBM) consisted of surgery and post-operative radiotherapy, while benefit of chemotherapy was a matter of debate. A phase III study, conducted by EORTC and NCI Canada and involving 573 patients, concluded clearly to the benefit of adding temozolomide during and after radiotherapy as adjuvant treatment. Using this schedule, median survival increase from 12,1 to 14,6 months, and 2 year survival rate from 8 to 26%. In the same time, for anaplastic oligodendroglioma (AO) the phase III study conducted by Cairncross, that compared radiotherapy to a schedule that deliver a chemotherapy with PCV followed by radiotherapy, failed to determine a significant benefit on overall survival, despite the particular chemosensitivity of theses tumors. Moreover, these two studies did underlined impact of biological markers (methylation of the promoter of O6 methylguanine DNA transferase (MGMT) gene for GBM and chromosomes 1p and 19q deletion for AO), that may become decisional markers in the future. We review here the new place of chemotherapy in the adjuvant treatment of GBM and anaplastic gliomas, as well as the impact of these pivotal studies on second lines therapies, and future clinical research.