A Long-Term Extension Study of Bevacizumab in Patients With Solid Tumors.

BACKGROUND: Bevacizumab has been studied in numerous clinical trials in multiple types of cancer; however, patients may receive bevacizumab over an extended period of time. This study assessed the long-term safety and tolerability of bevacizumab among patients with solid tumors. MATERIALS AND METHODS: Patients enrolled in a Roche/Genentech-sponsored trial who had derived benefit from bevacizumab therapy as monotherapy or in combination with anticancer drugs were eligible for continuation of bevacizumab in this long-term extension (LTE) study. The primary endpoints were the incidence of adverse events (AEs) of Common Terminology Criteria for AEs (CTCAE) grade ≥3 related to bevacizumab treatment, serious AEs (SAEs), and deaths. RESULTS: Ninety-five patients with the following cancer types were enrolled in the LTE: ovarian cancer or peritoneal carcinoma (n = 41), non-small cell lung cancer (n = 16), glioblastoma multiforme (n = 14), breast cancer (n = 11), colorectal cancer (n = 7), or renal cell carcinoma (n = 6). The median (range) duration of bevacizumab treatment was 15.6 (0.0-81.0) months during the LTE and 57.5 (16.4-134.9) months overall (parent trial + LTE), with three patients receiving bevacizumab for >10 years. Overall, 17 patients (17.9%) experienced SAEs, and 21 (22.1%) had a bevacizumab-related AE of CTCAE grade ≥3 (proteinuria and hypertension were the most common). Four patients died: three from disease progression and one from an AE considered unrelated to bevacizumab. CONCLUSION: The safety outcomes observed support the tolerability of long-term bevacizumab in patients with various solid tumors, with a median extended treatment duration of almost 5 years overall and >10 years in some individual patients. ClinicalTrials.gov identifier: NCT01588184. IMPLICATIONS FOR PRACTICE: In this long-term extension study of patients with solid tumors, the median duration of bevacizumab treatment (including parent trials) was just under 5 years, with a long-term exposure in some patients of 7 to >10 years. Grade ≥3 adverse events related to bevacizumab were consistent with the established safety profile, with proteinuria and hypertension being the most common. Patients received bevacizumab over an extended period of time (beyond the length of most clinical trials), and the overall safety outcomes observed support the tolerability of long-term bevacizumab treatment in patients with solid tumors, with clinical benefit achieved over an extended period.

Adapting Logic to Physics: The Quantum-Like Eigenlogic Program.

Considering links between logic and physics is important because of the fast development of quantum information technologies in our everyday life. This paper discusses a new method in logic inspired from quantum theory using operators, named Eigenlogic. It expresses logical propositions using linear algebra. Logical functions are represented by operators and logical truth tables correspond to the eigenvalue structure. It extends the possibilities of classical logic by changing the semantics from the Boolean binary alphabet { 0 , 1 } using projection operators to the binary alphabet { + 1 , - 1 } employing reversible involution operators. Also, many-valued logical operators are synthesized, for whatever alphabet, using operator methods based on Lagrange interpolation and on the Cayley-Hamilton theorem. Considering a superposition of logical input states one gets a fuzzy logic representation where the fuzzy membership function is the quantum probability given by the Born rule. Historical parallels from Boole, Post, Poincaré and Combinatory Logic are presented in relation to probability theory, non-commutative quaternion algebra and Turing machines. An extension to first order logic is proposed inspired by Grover's algorithm. Eigenlogic is essentially a logic of operators and its truth-table logical semantics is provided by the eigenvalue structure which is shown to be related to the universality of logical quantum gates, a fundamental role being played by non-commutativity and entanglement.

Romiplostim for temozolomide-induced thrombocytopenia in glioblastoma: The PLATUM trial.

OBJECTIVE: To determine the efficacy of the thrombopoietin receptor agonist romiplostim for the prevention of temozolomide-induced thrombocytopenia in newly diagnosed glioblastoma. METHODS: In the PLATUM phase II open-label, multicenter, single-arm trial, patients diagnosed with Common Terminology Criteria for Adverse Events grade 3 or 4 thrombocytopenia during chemoradiotherapy received weekly subcutaneous romiplostim injections. PLATUM aimed at demonstrating that the percentage of thrombocytopenic patients treated with romiplostim able to complete 6 cycles of maintenance temozolomide chemotherapy exceeded 10% (p0 = 0.10; pA = 0.35). Using type I error equal to 0.05% and 95% power, 31 patients had to be recruited. According to a Fleming 2-step design with a preplanned interim analysis after recruitment of 20 patients (step 1), the trial was terminated early for success. RESULTS: Twenty patients were enrolled in step 1. Median age was 61 years (range 33-73). Twelve patients received 6 temozolomide cycles, corresponding to a success rate of 60% (95% confidence interval 36%-81%). Four patients discontinued temozolomide because they did not respond to romiplostim, 2 for progression, and 2 for adverse events unrelated to romiplostim. CONCLUSION: The thrombopoietin receptor agonist romiplostim improves exposure to chemotherapy in patients with glioblastoma experiencing temozolomide-induced thrombocytopenia. CLINICALTRIALSGOV IDENTIFIER: NCT02227576. CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that for patients with glioblastoma and thrombocytopenia, romiplostim is effective for the secondary prophylaxis of temozolomide-induced thrombocytopenia.

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma.

BACKGROUND: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. PATIENTS AND METHODS: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. RESULTS: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). CONCLUSION: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. IMPLICATIONS FOR PRACTICE: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

Lomustine and Bevacizumab in Progressive Glioblastoma.

BACKGROUND: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma. METHODS: We randomly assigned patients with progression after chemoradiation in a 2:1 ratio to receive lomustine plus bevacizumab (combination group, 288 patients) or lomustine alone (monotherapy group, 149 patients). The methylation status of the promoter of O6-methylguanine-DNA methyltransferase (MGMT) was assessed. Health-related quality of life and neurocognitive function were evaluated at baseline and every 12 weeks. The primary end point of the trial was overall survival. RESULTS: A total of 437 patients underwent randomization. The median number of 6-week treatment cycles was three in the combination group and one in the monotherapy group. With 329 overall survival events (75.3%), the combination therapy did not provide a survival advantage; the median overall survival was 9.1 months (95% confidence interval [CI], 8.1 to 10.1) in the combination group and 8.6 months (95% CI, 7.6 to 10.4) in the monotherapy group (hazard ratio for death, 0.95; 95% CI, 0.74 to 1.21; P=0.65). Locally assessed progression-free survival was 2.7 months longer in the combination group than in the monotherapy group: 4.2 months versus 1.5 months (hazard ratio for disease progression or death, 0.49; 95% CI, 0.39 to 0.61; P<0.001). Grade 3 to 5 adverse events occurred in 63.6% of the patients in the combination group and 38.1% of the patients in the monotherapy group. The addition of bevacizumab to lomustine affected neither health-related quality of life nor neurocognitive function. The MGMT status was prognostic. CONCLUSIONS: Despite somewhat prolonged progression-free survival, treatment with lomustine plus bevacizumab did not confer a survival advantage over treatment with lomustine alone in patients with progressive glioblastoma. (Funded by an unrestricted educational grant from F. Hoffmann-La Roche and by the EORTC Cancer Research Fund; EORTC 26101 ClinicalTrials.gov number, NCT01290939 ; Eudra-CT number, 2010-023218-30 .).

CSF CA 15-3 in breast cancer-related leptomeningeal metastases.

UNLABELLED: The sensitivity of CSF cytology, the standard method for diagnosis of leptomeningeal metastases (LM), is low. Serum cancer antigen 15-3 (CA 15-3) is frequently used for the monitoring of patients with breast cancer (BC) and is a laboratory test available in most centers. The aim of the current study was to determine the feasibility of measuring CSF CA 15-3 and CA 15-3 CSF/serum ratio in patients with BC-related LM. Serum and CSF CA 15-3 values were evaluated in 20 BC patients with LM (Group 1), 20 patients with LM from other primary cancers (Group 2), 20 BC patients with parenchymal brain metastases only (Group 3) and 20 controls (Group 4). CSF and serum were collected on the same day. Serum and CSF CA 15-3 were assessed by an automatized immuno-enzymatic technology (TRACE(®) technology, KRYPTOR Automate, Brahms Society, France). In univariate analysis, BC patients with LM (Group 1) compared to other groups, a significantly elevated serum CA 15-3 (median 51 U/ml, range 12-2819) and CSF CA 15-3 (median 8.7 U/ml, range 0.1-251) was observed. Additionally, the CSF/serum ratio of CA 15-3 was significantly higher in this group of patients (median 0.18, range 0.002-4.40). Multivariate analysis identified a cut-off for CSF CA15-3 with 80 % sensitivity and 70 % specificity. CONCLUSIONS: The current study confirms the feasibility of determining CSF CA 15-3 using a widely available technology. Evaluation of the CSF CA 15-3 may be useful in the diagnosis and management of BC-related LM but further studies are needed.

Salvage intracerebrospinal fluid thiotepa in breast cancer-related leptomeningeal metastases: a retrospective case series.

There is currently a paucity of data on salvage intracerebrospinal fluid (intra-CSF) chemotherapy in leptomeningeal metastases (LM). This report is a single-institution experience with salvage treatment in patients with breast cancer (BC) and LM. This retrospective cohort describes 24 consecutive patients with BC selected for a second-line of treatment for LM. The first line of LM treatment consisted of intra-CSF liposomal cytarabine in all patients combined with systemic therapy in 18 cases and radiotherapy in four cases. Second-line (salvage) treatment utilized intra-CSF thiotepa in all and systemic chemotherapy in nine patients. No patient received CNS-directed radiotherapy. The median Eastern Cooperative Oncology Group performance status at initiation of intra-CSF thiotepa treatment was 3 (range 1-4). The median progression-free survival and median survival following intra-CSF thiotepa was 3.1 months (range 3 days-2 years) and 4.0 months (range 6 days-2.5 years), respectively. The median overall survival from LM diagnosis was 9.5 months (range 1.3 months-2.7 years). No grade 3 or higher toxicity was observed. Recognizing the limits of a retrospective study, intra-CSF thiotepa has an acceptable toxicity profile and appears to be a reasonable option for selected BC patients.

Prolonged survival of patients with breast cancer-related leptomeningeal metastases.

BACKGROUND/AIM: Prolonged overall survival (OS) has been reported for selected patients with leptomeningeal metastases (LM). The management and treatment of such patients is poorly-described. We report our experience on breast cancer (BC)-associated LM and patients with prolonged survival. PATIENTS AND METHODS: Eleven patients with BC and LM had an OS >12 months in which treatment is described. RESULTS: Combined intra-cerebro spinal fluid (CSF) and systemic treatment were administered until disease progression or toxicity in all but two patients. Involved-field radiotherapy was administered to two patients. Median OS in this selected cohort following LM diagnosis, was 21.0 (range=13-33.3) months. CONCLUSION: Prolonged OS but also prolonged responses can be observed in BC with LM. An individualized and multi-disciplinary approach is advised for the management of these patients.

[Symptomatic management of brain metastasis]. / Prise en charge symptomatique des métastases cérébrales.

Indications and choice of antiepileptic drugs (AED), treatments for cerebral edema and prophylactic and curative treatments of thromboembolic complications of brain metastasis are discussed.

Leptomeningeal metastasis in melanoma: a prospective clinical study of nine patients.

BACKGROUND: Melanoma has the highest rate of spread to the leptomeninges and the incidence of melanoma has been steadily rising. This article describes recent experience at the Lille University Hospital, between 2007 and 2011 and discusses the possibilities for treatment of leptomeningeal metastasis. PATIENTS AND METHODS: Nine patients were diagnosed with leptomeningeal metastasis of melanoma. The standard criteria were used for the diagnosis. The treatment consisted of a combination of intrathecal chemotherapy, systemic chemotherapy and best supportive care. RESULTS: The overall median survival from the time of leptomeningeal metastasis diagnosis was eight weeks (range=1-168 weeks). In two cases, the median overall survival was 104 weeks. For these patients, there was a clear benefit in intrathecal chemotherapy combined with systemic treatment. No complication was observed. CONCLUSION: Despite a poor prognosis, treatment of melanoma leptomeningeal metastasis is needed in order to improve the quality of life, neurological progression-free survival and overall survival of patients.

Diffuse brainstem glioma: prognostic factors.

OBJECT: Brainstem gliomas were regarded as a single entity prior to the advent of MRI; however, several studies investigating MRI have recognized that these lesions are a heterogeneous group, and certain subgroups have a better prognosis for long-term survival. The aim of this study was to conduct a retrospective analysis of prognostic factors of patients with brainstem gliomas confirmed by histopathological diagnosis, particularly regarding assessment of whether histological grade, age, and MRI findings are prognostic factors for patient survival. METHODS: The study evaluated 100 patients diagnosed with brainstem glioma. There were 63 adults (40 men and 23 women; age range 18-75 years, mean 41 years) and 37 children (19 boys and 18 girls; age range 2-12 years, mean 6.9 years). RESULTS: The mean overall survival of this population, measured from the date of biopsy, was 57 months for diffuse low-grade glioma and 13.8 months for diffuse high-grade glioma (p < 0.001). The mean survival among patients with nonenhancing contrast lesions on MRI was 54.2 months, whereas for patients with enhancing lesions, it was 21.7 months (p < 0.001). Comparisons between the Kaplan-Meier survival curves of adults and children revealed similar median survival periods of 25 and 16 months, respectively (p > 0.05). The multivariate analysis (Cox proportional hazards regression) revealed that only histological grade was a significant prognostic factor (p < 0.001). CONCLUSIONS: The study revealed that histological grade and MRI features were significant prognostic factors for survival in these patients, but in multivariate analysis, only histological grade remained a significant factor.

Correlation between magnetic resonance imaging findings and histological diagnosis of intrinsic brainstem lesions in adults.

Management of brainstem mass lesions remains a controversial issue, especially when the lesion cannot be excised and when infiltration occurs; moreover, the benefits of a stereotactic procedure are still under debate. In most studies, treatment decisions are based solely on MRI features and do not include a histopathological diagnosis. In the current study, we compared MRI characteristics with histopathological findings of intrinsic brainstem lesions and identified the characteristics associated with the diagnosis of pathologies other than diffuse glioma. From February 1988 through August 2007, 96 brainstem biopsies were performed at the Roger Salengro Hospital in Lille, France, on adult patients with intrinsic brainstem lesions not amenable to excision. Of the 96 patients, 42 were women and 54 were men, with a mean age of 41 years (range, 18-75 years). Data analysis of the MRI findings revealed focal (P < .05) and contrast enhancing lesions (P < .05), and these lesions were significant factors associated with the diagnosis of pathologies other than diffuse glioma. Focal lesions were a significant factor associated with a diagnosis of nontumor lesions (P < .05). In conclusion, the diagnostic effect of stereotactic biopsy on intrinsic brainstem lesions was greater in patients with focal or enhancing lesions shown by MRI, in whom the diagnosis of diffuse glioma was less frequent.

Stereotactic biopsy for brainstem tumors: comparison of transcerebellar with transfrontal approach.

BACKGROUND: An important aspect of evaluating patients submitted to stereotactic biopsy of the brainstem is the trajectory used. The literature describes two principal approaches: the suboccipital transcerebellar and the transfrontal; however, no studies exist comparing these two techniques. OBJECTIVE: The purpose of this study was to compare diagnosis success rates and complications between the suboccipital transcerebellar and transfrontal trajectories. METHODS: The study evaluated 142 patients submitted to stereotactic biopsy. The patients presented brainstem tumors in the following areas: pons (n = 31), midbrain (n = 36), medulla (n = 2), pons-medulla (n = 30), pons-midbrain (n = 33), and midbrain-pons-medulla (n = 10). On 123 patients, the transfrontal approach was used, and on 19 the suboccipital transcerebellar approach. RESULTS: Comparing success rates between the two approaches, it was observed that in the group of patients submitted to the transfrontal approach, 95.1% (117 cases) were successful, while in those submitted to the suboccipital transcerebellar approach, 84.2% (16 cases) were successful. Despite a higher success rate among patients in the first group, the difference was not statistically significant. Regarding complications, in patients who were biopsied via the transfrontal trajectory, the morbidity rate was 9.8% (12 cases), while in patients submitted to the suboccipital transcerebellar approach, the morbidity rate was 5.3% (1 case) and the mortality rate 5.3% (1 case). CONCLUSIONS: This study verified a higher diagnosis rate in patients submitted to the transfrontal approach than in those submitted to the suboccipital transcerebellar approach (95.1 vs. 84.2%); however, the difference was not statistically significant. Regarding complications, the rate was similar in both groups of patients.

[Pre-hospital management of adults with life-threatening emergencies]. / Prise en charge pré-hospitalière des urgences vitales de l'adulte en pratique civile.

In France, acute life-threatening situations are handled by the French Secours a Personne (assistance to persons) and emergency medical facilities. An unequivocal success, this early management of life-threatening emergency situations relies upon centralized call reception, medical dispatching, and immediate on-site emergency medical care. We describe the different emergency care providers and steps involved in the response to emergency situations. Each call centre (Samu, phone number 15; Sapeurs-Pompiers, 18) provides a response tailored to the nature of incoming calls for assistance. A check-list of grounds for an "automatic response" by the SDIS (Service Départemental d'Incendie et de Secours--the French fire brigade) is in use, ensuring that firefighters are often the first on the spot, while the knowledge and skills of the dispatching physician are essential to ascertain the patient's needs, to preserve life and vital functions, and to ensure the patient is sent to the appropriate emergency healthcare facility. In life-threatening emergency situations, patients must be brought straight to the appropriate reference emergency healthcare facility, as quickly as possible, without prior admittance to an emergency department. This is the procedure for extremely acute emergency situations in the following areas: trauma (multiple trauma and/or uncontrolled bleeding, spinal cord trauma), delivery bleeding, other life-threatening situations such as ischemic heart disease, cardiac arrest (sudden death), cerebrovascular stroke and ensuing brain damage, some acute respiratory situations such as anaphylactic shock, foreign-body inhalation, electrocution, drowning, drug overdose, certain forms of poisoning, and conditions requiring initial hyperbaric oxygen (diving accidents, acute carbon monoxide and smoke poisoning). The reasons for suboptimal emergency care in life-threatening situations are currently a major issue, with medical facilities being reduced in some areas, fewer voluntary firemen, hospital reorganization, tight funding, difficulties of medical dispatching, and the varying skills of "first-on-the-scene "emergency workers. Grievances include late emergency responses, inappropriate medical care, and dispatching to the wrong facility. This raises the question of equal opportunity for all in a country with widely varying geographic features and population density. Improvement in the system's efficiency will require a series of objectives to be met in varied and complementary--Enhanced functional coordination, by speeding up the deployment of the ANTARES digital radio-frequency transmission network (Adaptation Nationale des Transmissions Aux Risques Et aux Secours).--Implementation of a network of emergency services with varying degrees of emergency healthcare management related to the technical nature of the facilities. Three levels of emergency healthcare must be made available: level 1 is provided by local hospitals, level 2 includes support facilities available in general hospitals (not necessarily the nearest hospital), and level 3 provides specialized healthcare in large and/or training hospitals with specialized departments. Life-threatening emergency situations are to be handled by level 2 or 3 facilities. Specific facilities must be selected as reference centers. In France, the ARS (Agences Régionales de Santé) is in charge of this procedure, as it provide funding for healthcare continuity--Reducing inequalities in access to emergency care. This will involve improving the network of SDIS brigades, making local medical facilities more responsive, delegating more medical procedures, on-site telemedicine, providing more helicopters equipped with healthcare facilities, more automated external defibrillators, and more dedicated neuro-vascular units.--First aid training must be made widely available. The French National Academy of Medicine has approved ten recommendations regarding organization and facilities.

Correlation among magnetic resonance imaging findings, prognostic factors for survival, and histological diagnosis of intrinsic brainstem lesions in children.

OBJECT: The aim of this study was to compare MR imaging characteristics with histopathological findings of intrinsic brainstem lesions and also to show the prognostic factors in patients with diffuse brainstem glioma. METHODS: Between February 1988 and August 2007, 44 brainstem biopsies were performed at the Roger Salengro Hospital in Lille, France, in children with intrinsic brainstem lesions not amenable to excision. Twenty-six were female and 18 male, and the mean age was 6 years. RESULTS: Histological evaluation revealed diffuse brainstem glioma in all patients with diffuse nonenhancing brainstem lesions. Diffuse brainstem glioma was found in 18 patients (90%) with diffuse enhancing brainstem lesions. Pathological entities different from diffuse glioma were verified in 2 patients (10%)-1 with ependymoma and 1 with ganglioglioma. In 4 of 5 patients with a focal nonenhancing brainstem lesion, the histopathological diagnosis was diffuse low-grade glioma. In 6 of 10 patients with focal enhancing brainstem lesion, the diagnosis was diffuse brainstem glioma, and pathological entities different from diffuse brainstem glioma were verified in 2 (20%), both with pilocytic astrocytoma. The mean 1-year actuarial survival rates for patients classified with low-grade and high-grade glioma were 80.4% ± 0.08% and 48.6% ± 0.14%, respectively. CONCLUSIONS: The impact of stereotactic biopsy on intrinsic brainstem lesions was greater in patients with MR imaging-documented enhancing lesions in whom the diagnosis of diffuse glioma was less frequent. Patients with low-grade glioma seem to have longer survival than those with high-grade glioma.

Clinicopathological features of breast cancers predict the development of leptomeningeal metastases: a case-control study.

The incidence of leptomeningeal metastases (LM) in patients with breast cancer (BC) is increasing as a result of increased screening and improved patient survival. However, the median survival time after diagnosis of LM is between 5 weeks (without any treatment) and 5 months (for aggressively treated patients). In an attempt to identify clinicopathological risk factors for LM, we carried out a case-control study of 100 women with BC. Fifty patients with BC and LM were enrolled and an additional 50 patients with BC and no CNS metastases including leptomeningeal spread were selected as controls. Patients who had developed LM were selected between December 2006 and August 2008. The control group was matched for: age at diagnosis, year of diagnosis, and initiation of chemotherapy at BC diagnosis. The ILC type (P = 0.03), ER-negative (P = 0.01) and PR-negative status (P = 0.03), and initial M+ status at BC diagnosis (P = 0.008) tended to be more frequent in LM patients. These characteristics should lead to early appropriate assessments being performed in this targeted population when a neurological complaint appears, in order to detect LM as soon as possible.

[Virtual endoscopic navigation and body transparency based on computed tomography. A step towards in vivo imaging]. / Navigation endoscopique et transparences corporelles par scanner à RX, une étape en imagerie in vivo.

Progress in HR-CTdata processing has led to lower X-ray exposure and to better diagnostic performance. We describe 19 adult patients (among 5000) examined by HR CT with 64 detectors, acquisition and exposure protocols in mSv, spiral, 0.6-mm slices, 5To PACS. After the two usual processing steps (60 gray values, 5122 and 10242 matrices, dedicated workstations for coronaroscopy and virtual coloscopy, 2D multiplanar reformation, surfacic, 3D volumes with dissection and navigation), a third original data processing step on additional workstations was added. Variable matrix extrapolated images, flexible colored curves (different from anatomical conventions), lighting (sources) and transparencies (unavailable with traditional endoscopy) were used. The digital film is a 16-minute "journey "consisting of 19 endo-body navigations in 5 regions, from the head to the bronchi, from the heart to the coronary arteries, and from the digestive tract to the abdomen and pelvis. One possible application is post-operative verification of an aortic graft. The movie is illustrated here with ten plates. This new approach is cost-effective and beneficial for the patient, in terms of early diagnosis and therapeutic follow-up. Ethical issues are also examined.

Anatomical location of effective deep brain stimulation electrodes in chronic cluster headache.

Deep brain stimulation of the posterior hypothalamus is a therapeutic approach to the treatment of refractory chronic cluster headache, but the precise anatomical location of the electrode contacts has not been clearly assessed. Our aim was to study the location of the contacts used for chronic stimulation, projecting each contact centre on anatomic atlases. Electrodes were implanted in a series of 10 patients (prospective controlled trial) in the so-called 'posteroinferior hypothalamus' according to previously described coordinates, i.e. 2 mm lateral, 3 mm posterior and 5 mm below the mid-commissural point. The coordinates of the centre of each stimulating contact were measured on postoperative computed tomography or magnetic resonance imaging scans, taking into account the artefact of the electrode. Each contact centre (n=10; left and right hemispheres pooled) was displayed on the Schaltenbrand atlas and a stereotactic three dimensional magnetic resonance imaging atlas (4.7 tesla) of the diencephalon-mesencephalic junction for accurate anatomical location. Of the 10 patients with 1-year follow-up, 5 responded to deep brain stimulation (weekly frequency of attacks decrease >50%). In responders, the mean (standard deviation) coordinates of the contacts were 2.98 (1.16) mm lateral, 3.53 (1.97) mm posterior and 3.31 (1.97) mm below the mid-commissural point. All the effective contacts were located posterior to the hypothalamus. In responders, structures located <2 mm from the centres of effective contacts were: the mesencephalic grey substance (5/5), the red nucleus (4/5), the fascicle retroflexus (4/5), the fascicle longitudinal dorsal (3/5), the nucleus of ansa lenticularis (3/5), the fascicle longitudinal medial (1/5) and the thalamus superficialis medial (1/5). The contact coordinates (Wilcoxon test) and the structures (Fisher's exact test) were not significantly different between responders and non-responders. These findings suggest that failure of deep brain stimulation treatment in cluster headache may be due to factors unrelated to electrode misplacement. They also suggest that the therapeutic effect is probably not related to direct hypothalamic stimulation. Deep brain stimulation might modulate either a local cluster headache generator, located in the hypothalamus or in the mesencephalic grey substance, or non-specific anti-nocioceptive systems.

Loss of 1p, 19q, and 10q heterozygosity prospectively predicts prognosis of oligodendroglial tumors--towards individualized tumor treatment?

The purpose of this study was to determine whether chromosome 10q loss is a predictor of tumor aggressiveness and poor clinical outcome in patients with oligodendroglial tumors alone or together with loss of heterozygosity (LOH) on chromosomes 1p and 19q. A microsatellite analysis was performed on sections from 130 patients with grade II and grade III oligodendroglial tumors to assess the allelic status of chromosomes 1p, 19q, and 10q, plus detailed clinical and radiological information was taken prospectively. Median age at diagnosis was 45.5 years. Seventy-eight patients had disease progression after initial therapy; median progression-free survival (PFS) was 27.5 months. Age <47 years, postoperative Karnofsky performance score >65, no contrast enhancement on MRI, grade II, and complete removal on surgery were significantly correlated with a better PFS. Median overall survival (OS) was 40.5 months. Pure oligodendroglioma and temozolomide chemotherapy were correlated with better OS. 10q LOH was correlated with anaplastic grade and 1p19q LOH correlated with pure oligodendroglioma. There was a significant association between LOH status and the tumors' response to chemotherapy: 92.3% with 1p19q LOH, 83.3% without allelic losses, 50% with 1p19q10q LOH, and 14.5% with 10q LOH. Patients with 10q LOH alone had PFS of 6 months and a 3-year survival rate of 1%, when compared with 36 months and 85%, respectively, in patients with 1p19q LOH but without 10q LOH. 1p loss was correlated with better PFS (P < .005) and OS (P = .0007), whereas 10q loss was correlated with decreased PFS (P < .0001) and OS (P < .0001). 10q LOH predicted a survival disadvantage in patients with oligodendroglial tumors irrespective of 1p/19q LOH status.

Safety and efficacy of deep brain stimulation in refractory cluster headache: a randomized placebo-controlled double-blind trial followed by a 1-year open extension.

Chronic cluster headache (CCH) is a disabling primary headache, considering the severity and frequency of pain attacks. Deep brain stimulation (DBS) has been used to treat severe refractory CCH, but assessment of its efficacy has been limited to open studies. We performed a prospective crossover, double-blind, multicenter study assessing the efficacy and safety of unilateral hypothalamic DBS in 11 patients with severe refractory CCH. The randomized phase compared active and sham stimulation during 1-month periods, and was followed by a 1-year open phase. The severity of CCH was assessed by the weekly attacks frequency (primary outcome), pain intensity,sumatriptan injections, emotional impact (HAD) and quality of life (SF12). Tolerance was assessed by active surveillance of behavior, homeostatic and hormonal functions.During the randomized phase, no significant change in primary and secondary outcome measures was observed between active and sham stimulation. At the end of the open phase, 6/11 responded to the chronic stimulation(weekly frequency of attacks decrease [50%), including three pain-free patients. There were three serious adverse events, including subcutaneous infection, transient loss of consciousness and micturition syncopes. No significant change in hormonal functions or electrolytic balance was observed. Randomized phase findings of this study did not support the efficacy of DBS in refractory CCH, but open phase findings suggested long-term efficacy in more than 50% patients, confirming previous data, without high morbidity. Discrepancy between these findings justifies additional controlled studies (clinicaltrials.gov number NCT00662935).