Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Isolation of the first metallo - â - lactamase producing Klebsiella pneumoniae in Lebanon

Introduction. A 58 year-old man was admitted to theSaint Joseph Hospital-Raymond and Aida Najjar polyclinicin Beirut on July 17, 2007 to undergo surgery for a moderatelydifferentiated colonic adenocarcinoma (T3N0). Followingseveral discharges and re-admissions, an extendedspectrum beta-lactamase (ESBL) producing Escherichia colisusceptible to imipenem was isolated. The patient was puton imipenem and metronidazole. Three weeks later, imipenem(IMP) resistant Klebsiella pneumoniae was isolated.Methods and results. The antimicrobial susceptibilityprofile of the imipenem-resistant Klebsiella pneumoniaestrain and related minimum inhibitory concentrations ofantibiotics were determined. Hydrolysis of IMP was evaluatedand production of metallo-â-lactamase (MBL) was detectedby a double disk-synergy test, ethylene diamine tetraaceticacid (EDTA) inhibited the imipenemase activity,whereas clavulanate and tazobactam did not, this suggestingthe production of a metallo-â-lactamase. Isoelectricfocusing analysis was performed and indicated the presenceof a cefotaximase (blaCTX-M-15). Polymerase chain reaction(PCR) was used and detected the presence of blaIMP-1and blaCTX-M genes.Conclusions. During the last decade, many hospitaloutbreaks caused by ESBL-producing Enterobacteriaceaespp. have been reported in Lebanon. To our knowledge, thisis the first report of a clinical isolate of K. pneumoniae producingan MBL in Lebanon (AU)

Introducción. El 17 de julio de 2007 un varón de58 años de edad fue ingresado en Hospital de Saint Joseph-Raymond and Aida Najjar Polyclinic de Beirut parasometerse a una intervención quirúrgica por un adenocarcinomamoderadamente diferenciado de colon (T3N0).Después de varias altas y rehospitalizaciones se aisló unaEscherichia coli productora de betalactamasa de espectroextendido y sensible al imipenem (IMP). El paciente fuetratado con imipenem y metronidazol. Una semana mástarde se efectuó un cultivo en el que se determinó Klebsiellapneumoniae resistente al imipenem.Métodos y resultados. Se determinó el perfil de sensibilidadantimicrobiana de la cepa de Klebsiella pneumoniaeresistente al imipenem y las concentracionesmínimas inhibitorias de los antibióticos. Se evaluó la hidrólisisdel IMP y se detectó la producción de metalo-betalactamasa(MBL) mediante el ensayo de sinergia condoble disco. El ácido etilendiaminotetraacético (EDTA)inhibió la actividad de la imipenemasa, mientras queclavulanato y tazobactam no, lo que indica la producciónde metalo-betalactamasa. Se efectuó un análisis porenfoque isoeléctrico que indicó la presencia de cefotaximasa(blaCTX-M-15). Para detectar la presencia de losgenes blaIMP-1 y blaCTX-M se empleó la reacción encadena de polimerasa (polymerase chain reaction [PCR]).Conclusiones. Durante la última década se han documentadomuchos brotes hospitalarios causados por especiesde enterobacterias productoras de ESBL en Líbano.A nuestro entender éste es el primer informe de unacepa clínica de K. pneumoniae productora de MBL en Líbano. (AU)

Isolation of the first metallo-beta-lactamase producing Klebsiella pneumoniae in Lebanon.

INTRODUCTION: A 58 year-old man was admitted to the Saint Joseph Hospital-Raymond and Aida Najjar polyclinic in Beirut on July 17, 2007 to undergo surgery for a moderately differentiated colonic adenocarcinoma (T3N0). Following several discharges and re-admissions, an extended spectrum beta-lactamase (ESBL) producing Escherichia coli susceptible to imipenem was isolated. The patient was put on imipenem and metronidazole. Three weeks later, imipenem (IMP) resistant Klebsiella pneumoniae was isolated. METHODS AND RESULTS: The antimicrobial susceptibility profile of the imipenem-resistant Klebsiella pneumoniae strain and related minimum inhibitory concentrations of antibiotics were determined. Hydrolysis of IMP was evaluated and production of metallo-beta-lactamase (MBL) was detected by a double disk-synergy test, ethylene diamine tetraacetic acid (EDTA) inhibited the imipenemase activity, whereas clavulanate and tazobactam did not, this suggesting the production of a metallo-beta-lactamase. Isoelectric focusing analysis was performed and indicated the presence of a cefotaximase (blaCTX-M-15). Polymerase chain reaction (PCR) was used and detected the presence of blaIMP-1 and blaCTX-M genes. CONCLUSIONS: During the last decade, many hospital outbreaks caused by ESBL-producing Enterobacteriaceae spp. have been reported in Lebanon. To our knowledge, this is the first report of a clinical isolate of K. pneumoniae producing an MBL in Lebanon.

Preferential accumulation of Abeta(1-42) on gel phase domains of lipid bilayers: an AFM and fluorescence study.

Peptide-membrane interactions have been implicated in both the toxicity and aggregation of beta-amyloid (Abeta) peptides. Recent studies have provided evidence for the involvement of liquid-ordered membrane domains known as lipid rafts in the formation and aggregation of Abeta. As a model, we have examined the interaction of Abeta(1-42) with phase separated DOPC/DPPC lipid bilayers using a combination of atomic force microscopy (AFM) and total internal reflection fluorescence microscopy (TIRF). AFM images show that addition of Abeta to preformed supported bilayers leads to accumulation of small peptide aggregates exclusively on the gel phase DPPC domains. Initial aggregates are observed approximately 90 min after peptide addition and increase in diameter to 45-150 nm within 24 h. TIRF studies with a mixture of Abeta and Abeta-Fl demonstrate that accumulation of the peptide on the gel phase domains occurs as early as 15 min after Abeta addition and is maintained for over 24 h. By contrast, Abeta is randomly distributed throughout both fluid and gel phases when the peptide is reconstituted into DOPC/DPPC vesicles prior to formation of a supported bilayer. The preferential accumulation of Abeta on DPPC domains suggests that rigid domains may act as platforms to concentrate peptide and enhance its aggregation and may be relevant to the postulated involvement of lipid rafts in modulating Abeta activity in vivo.

Control of amphiphilic block copolymer morphologies using solution conditions.

It is well known that the morphology of block copolymer aggregates depends on polymer properties such as the molecular weight, the relative block length, and the chemical nature of the repeat unit. Recently, we have shown that if aggregates are allowed to self-assemble in solution, then in addition to the above factors, a high degree of control over the aggregate architecture can be achieved by adjusting the solution conditions. Factors such as the water content in the solvent mixture, the solvent nature and composition, the presence of additives (ions, surfactants, and homopolymer) and the polymer concentration were successfully employed to control the aggregate shape and size. In this paper, we review a series of studies performed in our group to show how solution properties can control the architecture of aggregates prepared from a given copolymer. The control mechanism is explained in terms of the effect of each property on the forces that govern the formation of any given morphology, namely the core-chain stretching, corona-chain repulsion and interfacial tension.

Phase III randomized study of postradiotherapy chemotherapy with alpha-difluoromethylornithine-procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, vincristine (DFMO-PCV) versus PCV for glioblastoma multiforme.

Although the efficacy of the nitrosourea-based combination chemotherapy procarbazine, N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosurea, and vincristine (PCV) has been previously demonstrated in the setting of anaplastic/intermediate-grade gliomas, the benefit for glioblastoma patients remains unproven. In the current study, we sought to determine whether the addition of alpha-difluoromethylornithine (eflornithine), an inhibitor of ornithine decarboxylase, which has shown encouraging results in the setting of recurrent glioma patients, to a nitrosourea-based therapy (PCV) would constitute a more effective adjuvant therapy in the treatment of glioblastoma multiforme patients in the postradiation therapy setting. Following conventional radiation therapy, 272 glioblastoma (GBM) patients were randomized to receive either alpha-difluoromethylornithine-PCV (DFMO-PCV; 134 patients) or PCV alone (138 patients), with survival and time to tumor progression being the primary endpoints. The starting dosage of DFMO was 3.0 g/m2 p.o. q8h for 14 days before and after treatment with N-(2-chloroethyl)-N-cyclohexyl-N-nitrosurea; PCV was administered as previously described1. Clinical and radiological (Gadolinium-enhanced MRI) follow-ups were nominally at the end of each 6 or 8 week cycle (PCV at 6 weeks; DFMO-PCV at 8 weeks). Laboratory evaluations for hematologic and other adverse effects were at 2 week intervals. There was no difference in median survival or median time-to-tumor progression between the two treatment groups, as measured from day of commencement of postradiotherapy chemotherapy [MS (months): DFMO-PCV, 10.5; Overall survival, as measured from time of tumor diagnosis at first surgery, was 13.3 and 14.2 months at the median and 6.2 and 8.7% at 5 years, respectively, for the DFMO-PCV and PCV arms. The treatment effect was unchanged after adjustment for age, performance status (KPS), extent of surgery, and other factors using the multivariate Cox proportional hazard model. Adverse effects associated with DFMO consisted of gastrointestinal (diarrhea nausea/vomiting), cytopenias, and minimal ototoxicity (limited to tinnitus) at the dose range tested. The addition of DFMO to the nitrosourea-based PCV regimen in this phase III study demonstrated no additional benefit in glioblastoma patients, underscoring the resistance of glioblastoma multiforme tumors to alkylating agents. For patients with anaplastic (intermediate grade) gliomas, in which the previously demonstrated benefit of post-radiation chemotherapy is more substantial, the evaluation of DFMO-PCV vs. PCV is still ongoing and hopefully will yield more encouraging results.

Quality of life and neuropsychological evaluation for patients with malignant astrocytomas: RTOG 91-14. Radiation Therapy Oncology Group.

UNLABELLED: With increasingly aggressive neurosurgical and radiation therapy modalities (gamma knife, external beam stereotactic radiation and interstitial brachytherapy with or without hyperthermia) offered to patients with malignant astrocytomas (MA), increasing national demand for medical outcome studies and rising health care costs amidst public, business, and governmental debate to cut spending, we as physicians are obligated to continue our research to find effective treatments for malignant astrocytoma (MA) and a cost-effective means to study their impact upon the patient's quality of life (QOL). PURPOSE: We report data that was collected within the Radiation Therapy Oncology Group (RTOG) on 126 patients with MA who were enrolled in RTOG 91-14. This study was undertaken to prospectively test the feasibility of performing quality of life (QOL) and neuropsychological evaluation (NPE) and collecting this data within the RTOG. RESULTS: The NPE and QOL parameters that were used in this study are cost effective. They are not only much cheaper than formal cognitive and memory testing, but also provide additional information regarding the patients' day to day functional abilities that are not provided by the current routinely used means, such as KPS. The Mini-Mental Status Exam (MMSE) provides greater sensitivity to patients' differences in neurological status and may be preferable to NFS as an eligibility criteria.

Myelopathies in the cancer patient: incidence, presentation, diagnosis and management.

Last month, the author discussed epidural spinal cord compression. This month he describes the incidence, clinical presentation, and management of CNS complications from intradural, extramedullary metastases; leptomeningeal carcinomatosis; intramedullary spinal cord metastasis; paraneoplastic myelopathies; radiation myelopathy, and chemo-induced myelopathy.

Myelopathies in the cancer patient: incidence, presentation, diagnosis and management. Part 1.

Neurological involvement with systemic cancer is frequently a cause of major disability. Second to brain metastases, metastasis to the spinal cord and its nerve roots constitutes the most common neurological complication of cancer with an estimated 5 to 10% of patients developing spinal cord involvement that leads to serious impairment of function. With advances in cancer therapy and consequent extension of survival, the overall incidence of neurological complications of cancer is on the rise. Spinal cord dysfunction, while usually nonfatal, leaves the patient with a major neurological disability. The author discusses epidural metastases, highlighting the importance of early recognition and management.

Trochlear nerve palsy following minor head trauma. A sign of structural disorder.

Trauma-induced superior oblique palsy usually results from contusion or avulsion of the trochlear nerve or from decompensation of a congenital trochlear nerve palsy. Severe craniocerebral trauma is often associated with the former mechanism, whereas more minor closed-head injuries can decompensate a congenital phoria. We report a patient who developed an isolated trochlear nerve palsy following minor head trauma. Investigation revealed an unsuspected tentorial vascular malformation that was compressing the trochlear nerve in its subarachnoid course. In the absence of other features (e.g., documentation of old head tilt, large vertical fusion amplitudes) that support decompensation of a congenital phoria, compressive lesions should be sought in cases of fourth cranial nerve palsies that follow minor head trauma.

Recurrent malignant gliomas: survival following interstitial brachytherapy with high-activity iodine-125 sources.

The authors report survival data for the first 41 patients treated for recurrent malignant gliomas with interstitial brachytherapy at the University of California, San Francisco (1980-1984). Iodine-125 (125I) sources were temporarily implanted using stereotaxic techniques. The median survival period for 18 patients with recurrent glioblastomas was 52 weeks after brachytherapy; two patients are alive more than 5 years after brachytherapy. The median survival period for 23 patients with recurrent anaplastic astrocytomas is 153 weeks after brachytherapy, with 10 patients alive more than 3 years and four patients alive more than 4 years after brachytherapy. Both groups did significantly better (p less than 0.01) than groups of patients with the same diagnoses and similar general characteristics who were treated at recurrence with chemotherapy alone. Because of deterioration of their clinical condition and evidence of recurrence from computerized tomographic scans, 17 (41%) of 41 patients required reoperation 20 to 72 weeks after brachytherapy. Despite the invariable presence of apparently viable tumor cells mixed with necrotic tissue in the resected specimen, nine patients have survived more than 2 years after reoperation and two of the nine are still alive 4 years after reoperation. The authors conclude that brachytherapy with temporarily implanted 125I sources for well-circumscribed, hemispheric, recurrent malignant gliomas is effective and offers a chance for long-term survival even though focal radiation necrosis can seriously degrade the quality of survival in a minority of patients.

Phase I-II study of eflornithine and mitoguazone combined in the treatment of recurrent primary brain tumors.

Eflornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, and mitoguazone (MGBG), a competitive inhibitor of S-adenosylmethionine decarboxylase, were evaluated in a phase I-II study for patients with primary recurrent malignant brain tumors. All patients had failed prior radiation therapy and most had also failed prior chemotherapy. Two dose schedules were used, with the second schedule (Group II) a modification of the first schedule (Group I). The Group II schedule, with different dose levels, was better tolerated than the Group I schedule. Gastrointestinal and myelotoxicity were dose-limiting in most patients, and tinnitus was dose-limiting in two patients. Nineteen of 33 evaluable patients had anaplastic gliomas, in whom response was observed in 21%, stable disease in 53%, and immediate progression after one course of therapy in 26%. Of six patients with glioblastoma multiforme, two had brief stabilization of disease. An additional patient with brainstem glioma and ependymoma also had disease stabilization. Four patients with medulloblastoma, a spinal cord mixed glioma, and one with oligodendroglioma failed DFMO-MGBG. Based on this study, we believe that a combination of DFMO and MGBG is well-tolerated and deserves further evaluation for patients with anaplastic gliomas, particularly those that appear to be biologically slow growing.

Risk of intracranial hemorrhage in glioma patients receiving anticoagulant therapy for venous thromboembolism.

To determine the risk of intracranial hemorrhage in patients with malignant gliomas who are treated with anticoagulant drugs for late postoperative venous thromboembolism, the authors retrospectively reviewed the computerized data base of all patients with primary brain tumors seen at the University of California, San Francisco, over a 9-year period. Of 915 patients 18 years of age or older who had a pathological diagnosis of malignant glioma and an initial Karnofsky performance scale score of 60% or higher, 36 (4%) developed venous thromboembolism 6 to 246 weeks postoperatively and 22 were treated with anticoagulant drugs. Anticoagulant therapy usually consisted of intravenous heparin for 7 to 10 days, followed for at least 3 to 6 months by either subcutaneous heparin (5000 to 8000 U twice daily) or oral warfarin. All patients were closely monitored to ensure control of hypertension, compliance with therapy, maintenance of prothrombin time within the therapeutic range, and early recognition of adverse side effects. No patient had an intracranial hemorrhage. Thus, anticoagulant agents can be safely administered after intracranial operations for malignant gliomas without increased risk of morbidity or mortality if the patients are carefully monitored according to established guidelines.