Microwave-assisted, solid-phase synthesis of a chiral 1,2,3,4-tetrahydro-quinoline library.

The synergy of a solution-phase preparation of scaffolds with a solid-phase combinatorial synthesis let to develop an efficient route to a small library of chiral, highly functionalized tetrahydroisoquinolines. Both loading on the Merrifield resin and the key acid-catalyzed Pictet-Spengler condensation were efficiently promoted by microwave irradiation. The library was designed such that up to five points of diversity would be potentially introduced, making the strategy in principle suitable for generation of a large number of compounds.

Molecular markers of gliomas: a clinical approach.

Over the last decade, the knowledge on the molecular genetic background of gliomas has dramatically increased. This information provides the basis for the molecular target therapies and molecular tests serve to complement the subjective nature of histopathologic criteria and add useful data regarding response to treatments and prognosis. In particular, the use of loss of heterozygosity (LOH) and methylation specific polymerase chain reaction (PCR) (MSP) based testing of gliomas is already in place and used clinically in several centers.

New approach in delivering chemotherapy: locoregional treatment for recurrent glioblastoma (rGBM).

The treatment of GBM tumor recurrence is generally a hopeless challenge, since recurred tumor is resistant to the most common therapeutic efforts. Some partial results can be achieved by targeting local disease control, in view of the fact that 95% of recurrences occur locally. We present results concerning three pilot studies, all performed in recurrent GBM patients who underwent second surgery and have been treated systemically with temozolomide and locally through an Ommaya reservoire according to the following schedules: a) in 20 rGBM, 4 mg novantrone was delivered day 1,5 every 30 days; in 26 rGBM, 4 mg novantrone was delivered every 20 days in association with locoregional radioimmunotherapy (RIT); in 12 rGBM pegylated liposomal doxorubicin 4 mg was delivered day 1,5,10,15,20 with 20 days interval.

Prognostic value of CXCL12 expression in 40 low-grade oligodendrogliomas and oligoastrocytomas.

Both clinical and biological features have been reported as prognostic factors in low-grade gliomas. Among these, histotype, tumor size, enhancement, age and genetic pattern. Microvessel density (MVD) has been correlated to clinical outcome in astrocytomas, but its impact in oligodendrogliomas and mixed tumors is not sure.

Nature-inspired indolyl-2-azabicyclo[2.2.2]oct-7-ene derivatives as promising agents for the attenuation of withdrawal symptoms: synthesis of 20-desethyl-20-hydroxymethyl-11-demethoxyibogaine.

Microwave assisted Diels-Alder cycloaddition of 5-Br-N-benzylpyridinone (2) with methyl acrylate is described to gain an easy access to 7-bromo-2-benzyl-3-oxo-2-aza-5 or 6-carbomethoxy bicyclo[2.2.2]oct-7-enes (3)-(6).

Sleep-dependent changes in cerebral oxygen consumption in newborn lambs.

During rapid-eye-movement (REM) sleep in adult subjects, the cerebral metabolic rate of oxygen consumption (CMRO(2)) is as high as that during wakefulness. We investigated whether CMRO(2) during active sleep is already at the waking level in newborn life, to support the role of active sleep as a state of endogenous brain activation during early postnatal development. Newborn lambs, 2-5 days old (n = 6), were instrumented with electrodes for sleep-state scoring, catheters for blood sample withdrawal and pressure monitoring, and a transit-time ultrasonic blood-flow probe around the superior sagittal sinus.

An efficient enantioselective approach to cyclic beta-amino acid derivatives via olefin metathesis reactions.

The asymmetric synthesis of polyfunctionalized piperidine- and pyrrolidine-based scaffolds, specifically designed for the preparation of cyclic, conformationally constrained beta-amino acids, is realized combining a biocatalytic access to a versatile chiral building block with a wide range of transformations based on olefin metathesis.

Thiocolchicine-podophyllotoxin conjugates: dynamic libraries based on disulfide exchange reaction.

A dynamic combinatorial library of thiocolchicine-podophyllotoxin derivatives based on the disulfide bond exchange reaction is described. The influence of a biological target on the composition of the reaction mixture has been demonstrated. Use of high-resolution ESI mass spectrometry to evaluate the composition of the mixture shows promise for the design of new large libraries.

Reclassification of oligoastrocytomas by loss of heterozygosity studies.

Oligoastrocytomas (OAs) are WHO grade II or III tumors composed of a mixture of 2 neoplastic cell types morphologically resembling the cells in oligodendrogliomas and diffuse astrocytomas. Investigations on the genetic profile of OAs may yield important information for their classification and help for their clinical management. We have studied, in 94 OAs (46 WHO grade II and 48 WHO grade III), the patterns of loss of heterozygosity (LOH) of 4 genomic regions: 1p, 19q, 17p and 10q.

Production and post-surgical modification of VEGF, tPA and PAI-1 in patients with glioma.

Malignant gliomas are associated with risk of thromboembolism, but the molecular link between tumor and peripheral pro-coagulant status has not been elucidated. Vascular Endothelial Growth Factor (VEGF), tissue-type Plasminogen Activator (tPA), Plasminogen Activator Inhibitor-1 (PAI-1) and lipoprotein (lp) (a) influence the pro-coagulant status. To assess whether the presence of the tumor influenced the peripheral levels of VEGF, tPA, PAI-1 and lp(a), we studied the expression and secretion of VEGF, tPA, PAI-1 and lp(a) in glioma specimens, in peripheral blood and in primary glioma-derived cultures.

Systemic temozolomide combined with loco-regional mitoxantrone in treating recurrent glioblastoma.

Twenty-two recurrent GBM patients were enrolled for second tumor debulking with local positioning of a Rickam reservoir, in order to locally deliver chemotherapy with the aim of controlling local tumor recurrence. We designed a protocol using systemic temozolomide (150 mg/sqm days 1-5 every 28) in association with mitoxantrone, delivered through the reservoir (4 mg/day 1-5 every 28) positioned into the area of tumor exeresis. After re-operation a residual tumor mass no larger than 2 cm was identified in 18/22 patients.

Anaplasia is rare and does not influence prognosis in adult medulloblastoma.

Histopathologic grading based on increasing anaplasia predicts clinical behavior of pediatric medulloblastomas. The present study was aimed at grading 86 medulloblastomas of adult patients (aged 18 and older) by anaplasia and analyzing the predictive power. Nodularity, desmoplasia, nuclear size, nuclear pleomorphism, necrosis, and endothelial proliferations have been evaluated.

Expression of drug resistance proteins Pgp, MRP1, MRP3, MRP5 and GST-pi in human glioma.

Chemotherapy in glioma is poorly effective: the blood-brain barrier and intrinsic and/or acquired drug resistance of tumor cells could partly explain this lack of major effect. We investigated expression of P-glycoprotein (Pgp), multidrug resistance protein (MRP) 1, MRP3, MRP5 and glutathione-S-transferase pi (GST-pi) in malignant glioma patients. Cytofluorimetric analysis of 48 glioma specimens and 21 primary cultures showed high levels of MRP1, moderate levels of MRP5 and low levels of Pgp, GST-pi and MRP3.

A multicentre prospective collection of newly diagnosed glioblastoma patients in Lombardia, Italy.

The objective was to set the basis for a prospective, multicentre data collection on newly diagnosed adult glioblastoma patients diagnosed in Lombardia by means of a common database used by neurological and neurosurgical units of various hospitals, providing epidemiological, therapy and follow-up data. All adult patients with a newly diagnosed glioblastoma in 9 Lombardia hospitals from 31 March 2003 to 31 March 2004 were followed prospectively by a form elaborated by the Lombardia Neuro-oncology Group. Demographic data were recorded, as well as symptoms at onset, entity of tumour resection, post-surgical Karnofsky Performance Score, radio- and chemotherapy, presence/absence of venous thrombosis, type of antiepileptic treatment, time to tumour progression and survival time (ST).

CXCL12 expression is predictive of a shorter time to tumor progression in low-grade glioma: a single-institution study in 50 patients.

The clinical course of 50 patients with low-grade glioma (31 male, 19 female) undergoing surgery at a single Institution from 1992 to 1996 was analyzed in relationship with known prognostic factors as far as time to tumor progression (TTP) and survival time (ST) are concerned. Moreover, microvessel density (MVD) and expression of the angiogenesis-related chemokine CXCL12 were investigated in surgical specimens. Age at diagnosis ranged from 1 to 68 years (median 30).

Intratumoral delivery of mitoxantrone in association with 90-Y radioimmunotherapy (RIT) in recurrent glioblastoma.

Twenty-six recurrent Glioblastoma (rGBM) patients sequentially treated at the National Neurological Institute 'C Besta' were enrolled for a second surgery in order to remove recurrent tumor and to place an Ommaya reservoire to allow local delivery of chemotherapy and local pre-targeted radio-immunotherapy (RIT). All patients had partial tumor resection and 75% of them had a residual tumor mass after exeresis larger than 2 cm. After surgery all patients were managed with a second line systemic chemotherapy (PCV).

The role of the neurologist.

The contribution of the neurologist should focus on timely diagnosis with accurate differential diagnosis, indications for surgery and post-surgical treatment (in the setting of a multidisciplinary team), and follow-up of disease course/treatment-related complications.

Local drug delivery in recurrent malignant gliomas.

In recurrent malignant gliomas, we scheduled a protocol by adding to systemic temozolomide a local treatment delivered through a reservoire positioned in the surgically created cavity, consisting of either mitoxantrone, liposome-loaded doxorubicine or nimustine (ACNU). The progression-free survival (PFS) and survival time (ST) of the whole group of 112 patients were 8.3 and 11 months, respectively, in GBM patients, and 14 and 18 months in AA patients.

Combinatorial solid-phase synthesis of 6-hydroxy-1,2,3,4-tetrahydro-beta-carbolines from l-5-hydroxytryptophan.

A library of biologically relevant 6-hydroxy-tetrahydro-beta-carbolines (6-OH-THBCs) based on the L-5-OH-tryptophan scaffold was prepared. A solid-phase synthesis was developed, utilizing aminomethyl polystyrene resin and solid-phase-optimized reactions, such as Pictet-Spengler condensation. The library was designed such that three points of diversity would be readily introduced, making the strategy potentially suitable for generation of a large number of compounds.

Facets and determinants of quality of life in patients with recurrent high grade glioma.

Objectives: To assess patients with recurrent high grade brain glioma with the aim of evaluating facets of quality of life (QOL) and their association with mood, cognition, and physical performance.

Methods: Ninety four glioma patients (four groups with different duration of glioma recurrence) were compared with 24 patients with other chronic neurological diseases and 48 healthy subjects. The Functional Living Index-Cancer (FLIC) provided QOL self evaluations, and standardised scales and neuropsychological tests assessed physical performance, mood, and cognition.

Sleep-related brain activation does not increase the permeability of the blood-brain barrier to glucose.

We compared blood-brain barrier (BBB) permeability to glucose between quiet wakefulness and rapid-eye-movement (REM) sleep to assess whether changes in BBB permeability play a role in coupling glucose supply to the physiologic metabolic needs of the brain. Male Sprague-Dawley rats were prepared with electrodes for wake-sleep state scoring and with arterial and venous catheters. Using the single-pass, dual-label indicator method, unidirectional glucose extraction by the brain and cerebral blood flow (CBF) were simultaneously measured during states of quiet wakefulness (n=12) or REM sleep (n=7).

Combined chemotherapy and radiotherapy for intracranial germinomas in adult patients: a single-institution study.

We report on our experience in the treatment of intracranial germinomas (18 pure germinomas and two germinomas with syncytiotrophoblastic giant cells) according to a strategy of radiotherapy doses and fields reduction after a neoadjuvant chemotherapy (Cisplatin-vinblastine and bleomycin combination). Radiation therapy was delivered after the completion of the third and last course of chemotherapy. For the solitary germinoma the target volume was the gross tumour volume.

Headache in brain tumours: a symptom to reappraise critically.

Headache can be either a late or early symptom of a brain tumour, depending on the location of the tumour. A constant, progressively increasing pain, or a change in the character of headache pain, may alert the physician to this occurrence. Fortunately most people with headache, even persistent or severe headaches, do not have a tumour.

Sleep-dependent changes in the coupling between heart period and arterial pressure in newborn lambs.

This study assessed whether sleep-dependent changes in the relationship between heart period (HP) and mean arterial pressure (MAP) occur in newborn life. Electrodes for electrocorticographic, electromyographic, and electrooculographic monitoring and an arterial catheter for blood pressure recordings were implanted in 11 newborn lambs. HP and MAP beat-to-beat values were computed from 120-s blood pressure recordings during quiet wakefulness, active sleep, and quiet sleep.

CXCL12 in malignant glial tumors: a possible role in angiogenesis and cross-talk between endothelial and tumoral cells.

CXCL12 (stromal cell-derived factor-1/CXCL12) regulates leukocyte, endothelial and hematopoietic precursor migration, bone-marrow myelopoiesis and angiogenesis. CXCL12 and its receptor CXCR4 are over-expressed in malignant gliomas, which are highly vascularized tumors with a poor prognosis. We studied the expression of CXCL12 and CXCR4 in glioma cell lines, endothelial cells, tissue sections and endocavitary fluids from patients with gliomas.