Volume 5
Archive

1: Acta Cytol. 2006 Nov-Dec;50(6):706-9.

Fine needle aspiration cytology diagnosis of an extracranial meningioma presenting as a mass in the medial canthus.

Munjal K, Pancholi V, Nandedkar S, Verma R.

Publication Types:

• Case Reports
• Letter

PMID: 17152289 [PubMed - indexed for MEDLINE]

 

2: Acta Cytol. 2006 Nov-Dec;50(6):691-6.

Chordoid glioma of the third ventricle: Report of a case with cytologic features and utility during intraoperative consultation.

Takei H, Bhattacharjee MB, Adesina AM.

Department of Pathology, Baylor College of Medicine, Houston, Texas 77030-3498, USA. htakei@bcm.tmc.edu

BACKGROUND: Chordoid glioma is a rare, low grade neoplasm with a unique chordoid appearance as well as distinct clinicopathologic and immunohistochemical features. Its cytologic features have not been described. CASE: A 42-year-old woman with recent-onset amnesia and confusion underwent magnetic resonance imaging, which revealed a 5-cm mass lesion arising in the third ventricle. Intraoperative squash smears showed cellular sheets as well as nests and strands of epithelioid tumor cells with bland nuclei and polygonal to elongated cytoplasm in a mucinous background. Binucleation was commonly seen. The tumor was intimately admixed with a benign lymphoplasmacytic infiltrate and scattered Russell bodies. Histologically, the tumor cells were arranged in a syncytium with prominent lymphoplasmacytic infiltrates and scattered small foci of necrosis in a mucinous matrix. The foremost differential diagnosis was chordoid meningioma. Immunohistochemically, the tumor cells were positive for glial fibrillary acid protein (GFAP), vimentin, epithelial membrane antigen, CD34, neuron-specific enolase and CK-7 and negative for synaptophysin, S-100 protein, neurofilament, and estrogen and progesterone receptors. CONCLUSION: Intraoperative smear cytology in this case of chordoid glioma revealed distinctive cytologic features, reflecting the unique histologic pattern. Cytologic features, such as binucleation, absence of intranuclear pseudoinclusions and GFAP immunoreactivity, are particularly helpful in differentiating chordoid glioma from chordoid meningioma.

Publication Types:

• Case Reports

PMID: 17152286 [PubMed - indexed for MEDLINE]

 

3: Acta Cytol. 2006 Nov-Dec;50(6):608-16.

Cytopathology of the central nervous system. Part I. Utility of crush smear cytology in intraoperative diagnosis of central nervous system lesions.

Iqbal M, Shah A, Wani MA, Kirmani A, Ramzan A.

Department of Pathology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar, India. mohdiqballone@yahoo.com

OBJECTIVE: To evaluate the utility of rapid intraoperative crush smear cytologic diagnosis of central and peripheral nervous system lesions and to determine the accuracy and relevance of the accuracy of the intraoperative cytologic diagnosis when compared to the final paraffin section diagnosis. STUDY DESIGN: The crush (squash) smear technique was introduced at Sher-i-Kashmir Institute of Medical Sciences in May 2003. The 8 months of 2003 were used for standardization of the procedure. In 2004, 151 patients with open neurosurgical specimens or stereotactic biopsies were diagnosed intraoperatively by crush smears, and the diagnosis was compared with final diagnosis on paraffin sections of the same tissue samples. No supplementation of frozen sections was used. RESULTS: Of 151 cases, 144 were diagnosed accurately intraoperatively by crush smear cytology when compared with the respective paraffin section diagnoses. The diagnostic accuracy attained was 95.36%. Each case was diagnosed within 10 minutes after receipt of sample. Neurosurgical procedure (open or stereotaxy) did not affect diagnostic accuracy. CONCLUSION: In the expert hands of a pathologist with good exposure neurosurgical specimens, crush smear cytology is an accura and reliable procedure for the intraoperative diagnosis central nervous system tumors.

Publication Types:

• Comparative Study

PMID: 17152270 [PubMed - indexed for MEDLINE]

 

4: Arch Pathol Lab Med. 2006 Nov;130(11):1718-21.

 
Follicular dendritic cell sarcoma arising in the dura mater of the spine.

Choi JW, Lee JH, Kim A, Kim CH, Chae YS, Kim I.

Department of Pathology, College of Medicine, Korea University, Seoul, Korea.

There have been some individual case reports and a few large series of reports describing the clinicopathologic features of follicular dendritic cell sarcoma. This tumor originates from the dendritic cells of lymphoid follicles and is extremely rare in the extranodal location. We report the case of a 68-year-old man who presented with low back pain. A mass was found in the lumbar dura mater and extended to the right epidural space. The tumor was composed of nodules, sheets, and interlacing fascicles of oval-to-spindle cells intermingled with the dense infiltrates of small lymphocytes. Immunohistochemical staining revealed that the tumor cells were positive for CD21, CD23, CD35, and clusterin, and focally positive for CD68, CD20, and CD79a. To our knowledge, this is the first case of follicular dendritic cell sarcoma occurring in the dura mater of the spine.

Publication Types:

• Case Reports

PMID: 17076538 [PubMed - indexed for MEDLINE]

 

5: Arch Pathol Lab Med. 2006 Nov;130(11):1669-72.

 
Extensively necrotic retinoblastoma is associated with high-risk prognostic factors.

Chong EM, Coffee RE, Chintagumpala M, Hurwitz RL, Hurwitz MY, Chevez-Barrios P.

Department of Ophthalmology, Baylor College of Medicine, Houston, Tex, USA.

CONTEXT: Retinoblastoma is the most common malignant intraocular tumor in children. It has been shown that adjuvant therapy following enucleation in patients with high-risk histopathologic features significantly decreases the mortality. We describe the association of extensive necrosis of tumor and intraocular structures with 2 of the major risk factors: optic nerve invasion and choroidal invasion. This may alert the pathologist who makes the observation of extensive necrosis to carefully search for histologic features associated with adverse outcome. OBJECTIVE: To determine whether extensively necrotic retinoblastoma is associated with high-risk histologic prognostic factors for metastatic disease and patient survival. DESIGN: Retrospective case series. Forty-three eyes of 43 patients with retinoblastoma who underwent enucleation between 1990 and 2001 were evaluated. Medical records, histopathology specimens, pathology reports, and clinical photographs were reviewed. Tumors were designated as exhibiting extensive necrosis if more than 95% of tumor cells and intraocular tissues were necrotic. The main outcome measure was the association of extensive tumor necrosis with 3 high-risk histopathologic features: extraocular extension, optic nerve invasion, or choroidal invasion. Metastatic disease, patient survival, and associations with pathologic findings were also analyzed. RESULTS: Optic nerve head invasion (P < .001), post-lamina-cribrosal invasion (P < .001), and choroidal invasion by tumor (P = .004) were observed more frequently in eyes with extensive necrosis compared with eyes without extensive necrosis. Two of the 11 patients with extensively necrotic intraocular retinoblastoma died from metastatic disease (P = .06). None of the 32 patients without extensive necrosis developed metastatic disease or died. CONCLUSIONS: Extensive ocular tissue and tumor necrosis is associated with histologic high-risk prognostic factors for tumor metastasis and mortality.

Publication Types:

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't

PMID: 17076529 [PubMed - indexed for MEDLINE]

 

6: Arch Pathol Lab Med. 2006 Nov;130(11):1630-8.

 
Comment in:

• Arch Pathol Lab Med. 2006 Nov;130(11):1602.

An algorithmic approach to the brain biopsy--part I.

Kleinschmidt-DeMasters BK, Prayson RA.

Department of Pathology, University of Colorado Health Sciences Center, 4200 E Ninth Ave, B216, Denver, CO 80262, USA. bk.demasters@uchsc.edu

CONTEXT: The formulation of appropriate differential diagnoses for a slide is essential to the practice of surgical pathology but can be particularly challenging for residents and fellows. Algorithmic flow charts can help the less experienced pathologist to systematically consider all possible choices and eliminate incorrect diagnoses. They can assist pathologists-in-training in developing orderly, sequential, and logical thinking skills when confronting difficult cases. OBJECTIVE: To present an algorithmic flow chart as an approach to formulating differential diagnoses for lesions seen in surgical neuropathology. DESIGN: An algorithmic flow chart to be used in teaching residents. RESULTS: Algorithms are not intended to be final diagnostic answers on any given case. Algorithms do not substitute for training received from experienced mentors nor do they substitute for comprehensive reading by trainees of reference textbooks. Algorithmic flow diagrams can, however, direct the viewer to the correct spot in reference texts for further in-depth reading once they hone down their diagnostic choices to a smaller number of entities. The best feature of algorithms is that they remind the user to consider all possibilities on each case, even if they can be quickly eliminated from further consideration. CONCLUSIONS: In Part I, we assist the resident in learning how to handle brain biopsies in general and how to distinguish nonneoplastic lesions that mimic tumors from true neoplasms.

PMID: 17076524 [PubMed - indexed for MEDLINE]

 

7: Br J Cancer. 2006 Aug 7;95(3):416-22. Epub 2006 Jul 25.

 
Increasing incidence of childhood tumours of the central nervous system in Denmark, 1980-1996.

Raaschou-Nielsen O, Sorensen M, Carstensen H, Jensen T, Bernhardtsen T, Gjerris F, Schmiegelow K.

Institute of Cancer Epidemiology, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen O, Denmark. ole@cancer.dk

The registered incidence rate of childhood central nervous system (CNS) tumours has increased in several countries. It is uncertain whether these increases are biologically real or owing to improved diagnostic methods. We explored the medical records of 626 CNS tumours diagnosed in Danish children between 1980 and 1996. Population-based registers were used to extract data on mortality and background population. Temporal patterns were analysed by regression techniques. Most tumours were verified by computed tomography (78%) or magnetic resonance imaging (14%). Overall, the incidence rate increased by 2.9% per year (95% confidence interval (CI): 1.3;4.5) and the mortality rate increased by 1.4% per year (95% CI: -0.4;3.3). Among children aged 0-4 years, the survival rate after diagnosis remained almost unchanged, whereas among children aged 5-14 years, the 10-year survival rate improved from 59 to 74%. These data suggest that the incidence rate of CNS tumours among Danish children has truly increased, although alternative explanations cannot be excluded.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 16868540 [PubMed - indexed for MEDLINE]

 

8: Br J Cancer. 2006 Jul 3;95(1):130.

 
Comment on:

• Br J Cancer. 2006 May 8;94(9):1348-9; author reply 1352-3.

Concerning mobile phone use and risk of acoustic neuroma.

Boice JD, McLaughlin JK.

Publication Types:

• Comment
• Letter

PMID: 16804530 [PubMed - indexed for MEDLINE]

 

9: Br J Neurosurg. 2006 Jun;20(3):175-6.

 
Cervical cord presyrinx.

Nair N, Kalsi P, Papadopoulos MC.

Department of Neurosurgery, Atkinson Morley's Wing, St. George's Hospital, London, UK.

Publication Types:

• Case Reports

PMID: 16801055 [PubMed - indexed for MEDLINE]

 

10: Br J Neurosurg. 2006 Jun;20(3):169-72.

 
Intracranial metastasis from medullary carcinoma of the thyroid 25 years after primary surgery.

Kabir SM, Zafar MS, Brydon HL.

Department of Neurosurgery, North Staffordshire Royal Infirmary, Stoke-on-Trent, UK. rezaulkabir@hotmail.com

Medullary carcinoma of the thyroid is an uncommon tumour. In most patients, it is confined to the neck with or without involvement of the local cervical nodes. It rarely metastasizes to the mediastinum, lungs or liver. Intracranial metastasis is extremely rare with very few reported cases in the literature. We report an unusual case of an intracranial metastasis from a medullary carcinoma of the thyroid that occurred 25 years after primary surgery. We discuss the unusual features of our case together with a review of the literature.

Publication Types:

• Case Reports

PMID: 16801053 [PubMed - indexed for MEDLINE]

 

11: Br J Neurosurg. 2006 Jun;20(3):156-9.

 
Psychosis-like syndrome associated with intermittent intracranial hypertension caused by a large arachnoid cyst of the left temporal lobe.

Vakis AF, Koutentakis DI, Karabetsos DA, Kalostos GN.

Department of Neurosurgery, University of Crete, Medical School, Heraklion University Hospital, Heraklion, Crete, Greece.

Lesions on certain brain areas can cause psychiatric signs. Symptomatic arachnoid cysts can produce a variety of symptoms like headache, seizures, increased ICP, and rarely psychiatric disorders. We report a case of a young woman with a left temporal lobe arachnoid cyst, presented with headache and an atypical psychosis. A 72-h epidural ICP recording revealed incidental elevation of ICP. After a permanent shunt was placed, patient's symptoms improved substantially, and antipsychotic medication was significantly reduced.

Publication Types:

• Case Reports

PMID: 16801049 [PubMed - indexed for MEDLINE]

 

12: Br J Neurosurg. 2006 Jun;20(3):150-2.

 
In-vivo measurement of brain relaxation after lobectomies.

Mukerji N, Soh C, Mitchell P.

Department of Neurosurgery, Regional Neurosciences Centre, Newcastle General Hospital, Newcastle-upon-Tyne, UK.

Very little data exists on the visco-elastic properties of the living human brain tissue and collection of such data is vital for mechanical modelling. The purpose of this study was to measure the rate of relaxation of brain that has been compressed by tumour after surgical decompression. Seven patients who underwent a lobectomy for an intracranial space occupying lesion were included in the study. All underwent two CT scans within the first 24 h after the surgery. Volumes of the residual void on the serial CT scan were calculated using tools in the image acquisition software. There was a rapid expansion of the brain to fill up the void space in the first 24 h after surgery. The average rate of relaxation of the compressed brain is 2.25(0.76 - 6.64) ml/h. The graphs plotted for the volume of the void space against the time after surgery when the CT scans were done can be used to further explore the dynamics of brain relaxation. The rate of brain relaxation in the first 24 h after removal of a mass lesion averages 2.25(0.76 - 6.64) ml/h in this study. Further studies using more frequent data collection would allow for more accurate definition of the rate of relaxation.

PMID: 16801047 [PubMed - indexed for MEDLINE]

 

13: Br J Neurosurg. 2006 Jun;20(3):139-45.

 
Anterior tentorium-based epidermoid tumours: results of radical surgical treatment in 96 cases.

Goel A, Muzumdar D, Desai K.

Department of Neurosurgery, King Edward VII Memorial Hospital and Seth G.S. Medical College, Parel, Mumbai, India. atulgoel62@hotmail.com

A retrospective analysis of 96 surgically treated tentorium and anterior tentorial hiatus-based epidermoid tumours from 1997 - 2004 is presented. The most prominent symptoms were headache (53.1%) and ataxia (44.8%). The average tumour size was 4.4 cm. Surgical approaches included posterior cranial fossa route (85 cases), basal subtemporal middle fossa route (9 cases) and combined posterior fossa and subtemporal routes in two cases. Total tumour resection was performed in 46 patients. Eight and four patients developed transient and sustained postoperative neurological deficits respectively. There was mortality in two patients. There was non-symptomatic recurrence of the tumour in two cases. Ninety-four patients are leading active functional lives. Radical and safe resection of anterior tentorium-based epidermoid tumours is associated with symptomatic relief and lasting cure. Extensive drilling of the petrous bone can be avoided. Gentle dissection of the tumour and capsule from the critical neurovascular structures can limit post-operative morbidity.

PMID: 16801045 [PubMed - indexed for MEDLINE]

 

14: Br J Neurosurg. 2006 Feb;20(1):57-62.

 
Central neurocytoma in third and fourth ventricles with aqueductal involvement.

Wong J, Teo C, Kwok B.

Department of Neurosurgery, Prince of Wales Hospital, Sydney, New South Wales, Australia. johnny.wong@dr.nswama.com

Central neurocytomas are characterized by their intraventricular locations, usually arising from the lateral ventricles and their benign clinical course. Variations in location, histology and clinical behaviour have been reported in recent years. The authors present two cases of central neurocytomas arising in the third and fourth ventricles with aqueductal involvement. The atypical features in their location and behaviour are discussed. The cases represent the extended spectrum of central neurocytomas.

Publication Types:

• Case Reports

PMID: 16698614 [PubMed - indexed for MEDLINE]

 

15: Br J Neurosurg. 2006 Feb;20(1):55-7.

 
Emergency placement of a self-expandable covered stent for carotid artery injury during trans-sphenoidal surgery.

Leung GK, Auyeung KM, Lui WM, Fan YW.

Division of Neurosurgery, Department of Surgery, Queen Mary Hospital, Hong Kong, SAR, China. gilbertleung2002@yahoo.com

A patient sustained internal carotid artery (ICA) injury during trans-sphenoidal surgery. Bleeding from the resultant pseudo-aneurysm was not fully controlled by surgical packing. Emergency endovascular deployment over the injured ICA segment of a self-expandable covered-stent ('Symbiot' stent), initially designed for use in coronary saphenous vein-graft, was successful in securing haemostasis.

Publication Types:

• Case Reports

PMID: 16698613 [PubMed - indexed for MEDLINE]

 

16: Br J Neurosurg. 2006 Feb;20(1):51-4.

 
Granular cell tumour of the neurohypophysis: a rare sellar tumour with specific radiological and operative features.

Aquilina K, Kamel M, Kalimuthu SG, Marks JC, Keohane C.

Department of Neurosurgery, Cork University Hospital, Wilton, Cork, Republic of Ireland. kristianaquilina@hotmail.com

Symptomatic granular cell tumours of the neurohypophysis are rare sellar lesions. Preoperative prediction of the diagnosis on the basis of radiological appearance is useful as these tumours carry specific surgical difficulties. This is possible when the tumour arises from the pituitary stalk, rostral to a normal pituitary gland. This has not been emphasized previously.

Publication Types:

• Case Reports

PMID: 16698612 [PubMed - indexed for MEDLINE]

 

17: Br J Neurosurg. 2006 Feb;20(1):48-50.

 
Symptomatic syringomyelia secondary to clinically obscure infratentorial tumour.

Bouras TI, Kouyialis AT, Boviatsis EJ, Sakas DE.

Department of Neurosurgery, University of Athens Medical School, Evangelismos General Hospital, Athens, Greece.

The formation of a cervical spinal cord syrinx as a result of an infratentorial mass, even though uncommon, has been reported in international literature. In such cases, syringomyelia is usually asymptomatic, while the tumour-related symptoms and signs predominate. We report a patient with a posterior fossa tumour and secondary syringomyelia. In this patient, syringomyelia symptoms and signs were present, and a cervical spine Magnetic Resonance Imaging (MRI) showed a large cervical syrinx. A more careful clinical examination though, revealed a sub-clinical posterior fossa syndrome and brain MRI revealed a large infratentorial meningioma. A posterior fossa craniotomy was performed, followed by complete tumour resection and almost complete remission of the syrinx and its related symptoms. The authors discuss the role of posterior fossa tumour induced tonsillar herniation in the development of secondary syringomyelia, the mechanisms leading to syrinx formation and the conditions that must be fulfilled for that to happen.

Publication Types:

• Case Reports
• Review

PMID: 16698611 [PubMed - indexed for MEDLINE]

 

18: Br J Neurosurg. 2006 Feb;20(1):40-2.

 
Craniotomy with prosthetic heart valves: a clinical dilemma.

Caird J, Chukwunyerenwa C, Ali Z, Rawluk D.

Department of Neurosurgery, Beaumont Hospital, Dublin, Ireland.

The authors report two cases of spontaneous intracranial haemorrhage after elective craniotomy for resection of cerebral tumour. Both patients had mechanical aortic valve prostheses and were on regular warfarin therapy. In both cases, warfarin therapy was discontinued 5 days prior to surgery and unfractionated heparin administered intravenously until 12 h before surgery. Both patients were re-anticoagulated with subcutaneous low molecular weight heparin within the first week postcraniotomy-both developed life-threatening intracranial haemorrhage requiring urgent evacuation. The authors emphasize the risk of re-anticoagulation without postoperative imaging and the disadvantages of therapeutic dose, low molecular weight heparin in the postoperative period.

Publication Types:

• Case Reports

PMID: 16698608 [PubMed - indexed for MEDLINE]

 

19: Brain. 2006 Dec;129(Pt 12):3290-306. Epub 2006 Sep 2.

 
Carbamazepine-resistance in the epileptic dentate gyrus of human hippocampal slices.

Jandova K, Pasler D, Antonio LL, Raue C, Ji S, Njunting M, Kann O, Kovacs R, Meencke HJ, Cavalheiro EA, Heinemann U, Gabriel S, Lehmann TN.

Institute of Neurophysiology Berlin, Germany.

Overexpression of drug efflux pumps at the blood brain barrier (BBB) has been suggested to be one important factor contributing to drug resistance in epilepsy. This would imply that resected brain tissue of drug-resistant patients is drug-sensitive in absence of the BBB. Here we studied the effects of carbamazepine (CBZ) at therapeutically relevant concentration on epileptiform activity electrophysiologically recorded in acute hippocampal slices of patients with mesial temporal lobe epilepsy (MTLE; 28 patients, 49 slices) or extra-hippocampal tumours (tumour; 6 patients, 11 slices). Epileptiform activity was induced by hilar stimulation (0.067 Hz) during elevation of extracellular potassium concentration ([K(+)](o)) and remained self-sustained in presence of 10-12 mM [K(+)](o). Quantitative analysis of data revealed that epileptiform activity in tissue of tumour-patients was predominantly suppressed by CBZ, indicating that the 'epilepsy model' used is CBZ-sensitive. In contrast, epileptiform activity in tissue of drug-resistant MTLE patients was resistant to CBZ in 82% of patients, partially suppressed in 11% and completely suppressed in 7%. The effects of CBZ in tissue of MTLE patients did not depend on the type of activity, hippocampal pathology, excitability of the tissue, or equilibration time of the drug. Considering that CBZ has direct access to all compartments of the slice, our results suggest that CBZ-resistance mechanisms are located within the parenchyma of the dentate gyrus and contribute to drug resistance in the majority of MTLE patients. BBB-located drug-resistance mechanisms per se may play a minor role in this region, because CBZ-sensitivity was only observed in 7% of CBZ-resistant patients.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 16951410 [PubMed - indexed for MEDLINE]

 

20: Cancer. 2006 Dec 18; [Epub ahead of print]

 
Celecoxib inhibits meningioma tumor growth in a mouse xenograft model.

Ragel BT, Jensen RL, Gillespie DL, Prescott SM, Couldwell WT.

Department of Neurosurgery, University of Utah, Salt Lake City, Utah.

BACKGROUND.: Treatments for recurrent meningiomas are limited. We previously demonstrated universal expression of COX-2 in meningiomas and dose-dependent growth inhibition in vitro with celecoxib, a COX-2 inhibitor. We therefore tested the effects of celecoxib on meningioma growth in a mouse xenograft model. METHODS.: Meningioma cell lines (IOMM-Lee, CH157-MN, WHO grade I primary cultured tumor) were transplanted into flanks of nude mice fed mouse chow with celecoxib at varying concentrations (0, 500, 1000, 1500 ppm) ad libitum. Tumors were measured biweekly and processed for MIB-1, Factor VIII, COX-2, and VEGF, and assayed with transferase-mediated dUTP-biotin nick-end labeling (TUNEL). RESULTS.: Celecoxib reduced growth of mean tumor volume by 66% (P < .05), 25% (P > .05), and 65% (P < .05) compared with untreated controls in IOMM-Lee, CH157-MN, and benign tumors, respectively. IOMM-Lee tumors removed from celecoxib treatment regained a growth rate similar to the control. Blood vessel density decreased and apoptotic cells increased in treated flank tumors. Diminished COX-2 expression and VEGF were observed in treated IOMM-Lee tumors. Mean plasma celecoxib levels were 845, 1540, and 2869 ng/mL, for low-, medium-, and high-dose celecoxib, respectively. CONCLUSIONS.: Celecoxib inhibits meningioma growth in vivo at plasma levels achievable in humans. Celecoxib-treated tumors were less vascular with increased apoptosis. IOMM-Lee tumors treated with celecoxib showed decreased COX-2 and VEGF expression. COX-2 inhibitors may have a role in the treatment of recurrent meningiomas. Cancer 2007. (c) 2006 American Cancer Society.

PMID: 17177201 [PubMed - as supplied by publisher]

 

21: Cancer. 2006 Dec 7; [Epub ahead of print]

 
Venous thromboembolism occurs infrequently in meningioma patients receiving combined modality prophylaxis.

Gerber DE, Segal JB, Salhotra A, Olivi A, Grossman SA, Streiff MB.

Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

BACKGROUND.: Individuals with brain tumors have an increased risk of venous thromboembolism (VTE). Within this population, patients with meningiomas have been reported to have the highest incidence, exceeding rates associated with gliomas and brain metastases. However, earlier studies did not employ VTE prophylaxis, and VTE were detected with radionuclide scans, the reliability of which has since been questioned. Therefore, we conducted a retrospective review of postoperative meningioma patients receiving contemporary VTE prophylaxis and diagnostic methods to define the current incidence of and risk factors for symptomatic VTE in this population. METHODS.: Medical records were reviewed from all patients undergoing craniotomy for meningioma at Johns Hopkins Hospital in 2004 and 2005. The association between clinical characteristics and VTE was assessed using parametric and nonparametric statistical tests and survival analysis. RESULTS.: A total of 224 individuals met criteria for the review. The mean age was 52 years (standard deviation [SD] 14 years), and 167 patients (75%) were women. Median follow-up time was 230 days (interquartile range [IQR], 89-428 days). VTE was diagnosed in 11 patients (4.9%; 95% confidence interval, 2.5%-8.6%) at a median of 16 days (IQR, 7-33 days) postoperatively. The development of VTE was associated with older age (mean, 68 years vs 52 years; P = .0001), male gender (P = .007), and nonambulatory status postoperatively (P < .0001). CONCLUSIONS.: VTE occurs infrequently in postoperative meningioma patients who receive combined modality VTE prophylaxis. VTE risk factors in these patients include advanced age, male gender, and nonambulatory status postoperatively. Cancer 2007. (c) 2006 American Cancer Society.

PMID: 17154163 [PubMed - as supplied by publisher]

 

22: Cancer. 2006 Dec 7; [Epub ahead of print]

 
Up-front chemotherapy and radiation treatment in newly diagnosed nonsmall cell lung cancer with brain metastases: survey by Outcome Research Network for Evaluation of Treatment Results in Oncology.

Moscetti L, Nelli F, Felici A, Rinaldi M, De Santis S, D'Auria G, Mansueto G, Tonini G, Sperduti I, Pollera FC.

Department of Medical Oncology, Central Hospital of Belcolle, Viterbo, Italy.

BACKGROUND.: For patients with stage IV nonsmall cell lung cancer (NSCLC) who present with brain metastasis (BMs), standard platinum-based chemotherapy regimens have challenged the role of up-front whole-brain radiotherapy (WBRT). METHODS.: In this survey, the authors analyzed the decision tree by which 6 oncologic centers guided the pattern of care in an unselected population of patients with NSCLC who presented with BMs at first diagnosis. The impact of front-line, platinum-based chemotherapy also was evaluated. Individual data were reviewed from 156 eligible patients who were referred to participating centers. RESULTS.: Up-front treatment included chemotherapy in 110 patients and WBRT followed by chemotherapy in 46 patients. The selection of first treatment was guided based mainly on the presence of by BM symptoms, with chemotherapy selected for 24% of patients in the chemotherapy cohort and for 76% of patients in the chemotherapy and WBRT cohort. Regardless of treatment, the brain response was 29% (27% and 35% for the chemotherapy and WBRT cohorts, respectively; P value not significant). For the entire population, the overall response rate was 37%, progression-free survival was 6 months, and the median survival was 11 months. At multivariate analysis, significant predictors for survival were: brain response (hazard ratio [HR], 2.59; P = .0001), modified Radiation Therapy Oncology Group class (HR, 0.87; P = .003), and Eastern Cooperative Oncology Group performance status (HR, 1.49; P = .04). CONCLUSIONS.: For patients with NSCLC who present with BMs at first diagnosis, the results of the current survey confirmed that the expected benefit of platinum-based chemotherapy may be translated into clinical practice and that selected subsets of patients who receive frontline chemotherapy (ie, patients in whom BM symptoms are absent or are controlled by supportive therapy) may be spared from WBRT. Further prospective studies evaluating different approaches and interventions are warranted. Cancer 2007. (c) 2006 American Cancer Society.

PMID: 17154161 [PubMed - as supplied by publisher]

 

23: Cancer. 2006 Nov 1;107(9):2228-36.

 
Focal and craniospinal irradiation for patients with intracranial germinoma and patterns of failure.

Nguyen QN, Chang EL, Allen PK, Maor MH, Ater JL, Mahajan A, Wolff JE, Weinberg JS, Woo SY.

Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

BACKGROUND: The authors compared the patterns of failure in patients with intracranial germinoma who were managed with either chemotherapy and focal irradiation or with craniospinal irradiation (CSI). METHODS: A retrospective review was conducted on 21 patients with intracranial germinoma and treated with radiotherapy (RT) to the central nervous system at The University of Texas M. D. Anderson Cancer Center from 1981 to 2002. The study group was comprised of 13 males and 8 females with a median age at diagnosis of 19 years. Nine patients received chemotherapy prior to focal RT. Twelve patients received CSI. RESULTS: The actuarial 10-year survival rate for all patients was 86%. The overall survival rate at 10 years was 89% for patients who received focal RT and 83% for patients who received CSI (P = .73). The 10-year local control rate in the brain for patients who received focal irradiation was 59% compared with 100% for patients who received CSI (P = .08). The rate of distant control in the spine at 5 years was 62% for patients who received focal irradiation and 100% for patients who received CSI (P = .04). CONCLUSIONS: Although focal techniques of irradiation with chemotherapy are attractive methods that limited the volume irradiated, the strategy appeared to be associated with increased rates of failures in the brain and spine. (c) 2006 American Cancer Society.

Publication Types:

• Comparative Study

PMID: 17019739 [PubMed - indexed for MEDLINE]

 

24: Cancer Genet Cytogenet. 2007 Jan 1;172(1):33-7.

 
The 61 A/G EGF polymorphism is functional but is neither a prognostic marker nor a risk factor for glioblastoma.

Vauleon E, Auger N, Benouaich-Amiel A, Laigle-Donadey F, Kaloshi G, Lejeune J, Delattre JY, Thillet J, Sanson M.

INSERM, U711, Biologie des Interactions Neurones & Glie, 75651 Paris cedex 13, France; Universite Pierre et Marie Curie, Faculte de Medecine, Paris, France.

The A/G61 polymorphism located in the 5'UTR of the EGF gene has been found to be both a risk factor and a prognostic factor in glioblastoma (GBM), but the functional consequences have not been investigated. Here we show, in vitro, that this polymorphism is functional, in that the G allele promoter is 40% more active than the A variant (P < 0.001). However, analysis of a large series of 209 GBM patients and 214 control subjects did not confirm that A/G61 polymorphism is a significant risk factor for GBM, despite a trend for higher GG frequency in these patients. Furthermore, A/G61 polymorphism was not a prognostic factor for survival in GBM patients, although it does appear to affect progression-free survival.

PMID: 17175377 [PubMed - in process]

 

25: Cancer Genet Cytogenet. 2006 Oct 15;170(2):175-9.

 
Cytogenetics of pineoblastoma: four new cases and a literature review.

Brown AE, Leibundgut K, Niggli FK, Betts DR.

Department of Oncology, University Children's Hospital, Zurich, Switzerland.

Pineoblastoma represents a class of primitive neuroectodermal tumors (PNET) with poorly differentiated neuroepithelial cells that are histologically indistinguishable from medulloblastomas. It is a rare tumor, typically arising in childhood, and to date only a few cytogenetic cases have been published. We report four new cases in which conventional cytogenetics demonstrated the presence of an abnormal clone. The tumors showed a variety of ploidy levels, from hypodiploid to hypertetraploid. Both structural and numerical aberrations were frequent, and in three out of the four cases a large degree of cell-to-cell variation was observed. The most frequently involved chromosome in structural rearrangements was chromosome 1, observed in three of the four cases. The short arm was involved in two of the three cases; in the third case, the anomaly was in the long arm. Two cases showed unbalanced gain of chromosome 17q, one of them showing i(17)(q10). Together, the four cases illustrate the complex karyotypic nature of this tumor type and represent a step toward determining whether a nonrandom cytogenetic picture exists and how this may be related to other associated tumor types.

Publication Types:

• Case Reports
• Review

PMID: 17011992 [PubMed - indexed for MEDLINE]

 

26: Cancer Res. 2006 Dec 15;66(24):11991-7.

 
Antitumor effect of 2-methoxyestradiol in a rat orthotopic brain tumor model.

Kang SH, Cho HT, Devi S, Zhang Z, Escuin D, Liang Z, Mao H, Brat DJ, Olson JJ, Simons JW, Lavallee TM, Giannakakou P, Van Meir EG, Shim H.

Department of Hematology/Oncology,Emory University, School of Medicine, Atlanta, Georgia 30322, USA.

Grade 4 malignant glioma (GBM) is a fatal disease despite aggressive surgical and adjuvant therapies. The hallmark of GBM tumors is the presence of pseudopalisading necrosis and microvascular proliferation. These tumor cells are hypoxic and express hypoxia-inducible factor-1 (HIF-1), a prosurvival transcription factor that promotes formation of neovasculature through activation of target genes, such as vascular endothelial growth factor. Here, we evaluated whether 2-methoxyestradiol, a microtubule and HIF-1 inhibitor, would have therapeutic potential for this disease in a 9L rat orthotopic gliosarcoma model using a combination of noninvasive imaging methods: magnetic resonance imaging to measure the tumor volume and bioluminescence imaging for HIF-1 activity. After imaging, histologic data were subsequently evaluated to elucidate the drug action mechanism in vivo. Treatment with 2-methoxyestradiol (60-600 mg/kg/d) resulted in a dose-dependent inhibition of tumor growth. This effect was also associated with improved tumor oxygenation as assessed by pimonidazole staining, decreased HIF-1alpha protein levels, and microtubule destabilization as assessed by deacetylation. Our results indicate that 2-methoxyestradiol may be a promising chemotherapeutic agent for the treatment of malignant gliomas, with significant growth inhibition. Further studies are needed to assess the effect of low or intermediate doses of 2-methoxyestradiol in combination with chemotherapeutic agents in clinical studies focused on malignant gliomas. In addition to showing tumor growth inhibition, we identified three potential surrogate biomarkers to determine the efficacy of 2-methoxyestradiol therapy: decreased HIF-1alpha levels, alpha-tubulin acetylation, and degree of hypoxia as determined by pimonidazole staining.

Publication Types:

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't

PMID: 17178898 [PubMed - in process]

 

27: Cancer Res. 2006 Dec 15;66(24):11878-87.

 
Cationic albumin-conjugated pegylated nanoparticles allow gene delivery into brain tumors via intravenous administration.

Lu W, Sun Q, Wan J, She Z, Jiang XG.

Department of Pharmaceutics, School of Pharmacy, Fudan University (Fenglin Campus), P.O. Box 130, 138 Yi Xue Yuan Road, Shanghai 200032, P.R. China.

Patients with malignant gliomas have a poor prognosis because these tumors do not respond well to conventional treatments. Studies of glioma xenografts suggest that they may be amenable to gene therapy with cytotoxic genes, such as the proapoptotic Apo2 ligand/tumor necrosis factor-related apoptosis-inducing ligand (Apo2L/TRAIL). Gene therapy of gliomas ideally employs i.v. given vectors, thus excluding viral vectors as they cannot cross the brain microvascular endothelium or blood-brain barrier. Recently, we reported the synthesis of cationic albumin-conjugated pegylated nanoparticles (CBSA-NP) and showed their accumulation in mouse brain cells upon i.v. administration. In this study, plasmid pORF-hTRAIL (pDNA) was incorporated into CBSA-NP, and the resulting CBSA-NP-hTRAIL was evaluated as a nonviral vector for gene therapy of gliomas. Thirty minutes after transfection of C6 glioma cells, CBSA-NP-hTRAIL was internalized and mostly located in the cytoplasm, whereas NP-hTRAIL was entrapped in the endolysosomal compartment. At 6 and 48 hours after transfection, respectively, released pDNA was present in the nuclei and induced apoptosis. At 30 minutes after i.v. administration of CBSA-NP-hTRAIL to BALB/c mice bearing i.c. C6 gliomas, CBSA-NP-hTRAIL colocalized with glycoproteins in brain and tumor microvasculature and, via absorptive-mediated transcytosis, accumulated in tumor cells. At 24 and 48 hours after i.v. administration of CBSA-NP-hTRAIL, respectively, hTRAIL mRNA and protein were detected in normal brain and tumors. Furthermore, repeated i.v. injections of CBSA-NP-hTRAIL induced apoptosis in vivo and significantly delayed tumor growth. In summary, this study indicates that CBSA-NP-hTRAIL is a promising candidate for noninvasive gene therapy of malignant glioma.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17178885 [PubMed - in process]

 

28: Cancer Res. 2006 Dec 15;66(24):11840-50.

 
Retargeted oncolytic measles strains entering via the EGFRvIII receptor maintain significant antitumor activity against gliomas with increased tumor specificity.

Allen C, Vongpunsawad S, Nakamura T, James CD, Schroeder M, Cattaneo R, Giannini C, Krempski J, Peng KW, Goble JM, Uhm JH, Russell SJ, Galanis E.

Molecular Medicine Program, Mayo Clinic, Rochester, Minnesota 55905, USA.

Among the best-characterized genetic alterations in gliomas is the amplification of the epidermal growth factor receptor (EGFR) gene, present in approximately 40% of glioblastoma multiforme, and frequently associated with the EGFRvIII gene rearrangement. We have previously shown that attenuated vaccine strains of measles virus have potent antitumor activity against gliomas, and identified H protein mutations, which ablate recognition of the natural measles virus receptors CD46 and SLAM. Retargeted recombinant viruses were generated from the measles Edmonston-NSe vaccine strain displaying a single-chain antibody against EGFRvIII at the COOH terminus of H and containing the marker green fluorescent protein (GFP) gene in position 1. Two different H mutants were employed: H(SNS) (V451S, Y481N, and A527S)-CD46 blind, and H(AA) (Y481A and R533A)-CD46 and SLAM blind. MV-GFP virus was used as a positive control. Both EGFRvIII-retargeted viruses had significant antitumor activity against EGFRvIII-expressing glioblastoma multiforme but no cytopathic effect against normal cells. In an orthotopic model of EGFRvIII-expressing GBM39 xenografts, there was comparable therapeutic efficacy between retargeted strains and unmodified MV-GFP and statistically significant prolongation of survival in treated animals compared with the control group (P = 0.001). Formation of syncytia was observed in tumors treated with retargeted viruses, with a surrounding infiltrate consisting of macrophages and natural killer cells. In summary, EGFRvIII-retargeted oncolytic measles virus strains have comparable therapeutic efficacy with the unmodified MV-GFP strain against EGFRvIII-expressing glioma lines and xenografts with improved therapeutic index, a finding with potential translational implications in glioma virotherapy.

Publication Types:

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't

PMID: 17178881 [PubMed - in process]

 

29: Cancer Res. 2006 Dec 15;66(24):11771-80.

 
Tenascin-C stimulates glioma cell invasion through matrix metalloproteinase-12.

Sarkar S, Nuttall RK, Liu S, Edwards DR, Yong VW.

Department of Oncology, University of Calgary, Calgary, Alberta, Canada.

The capacity of glioma cells to invade extensively within the central nervous system is a major cause of the high morbidity rate of primary malignant brain tumors. Glioma cell invasion involves the attachment of tumor cells to extracellular matrix (ECM), degradation of ECM components, and subsequent penetration into adjacent brain structures. These processes are accomplished in part by matrix metalloproteinases (MMP) within a three-dimensional milieu of the brain parenchyma. As the majority of studies have used a two-dimensional monolayer culture system, we have used a three-dimensional matrix of collagen type I gel to address glioma-secreted proteases, ECM, and invasiveness of glioma cells. We show that in a three-dimensional collagen type I matrix, the presence of tenascin-C, commonly elevated in high-grade gliomas, increased the invasiveness of glioma cells. The tenascin-C-mediated invasiveness was blocked by metalloproteinase inhibitors, but this did not involve the gelatinases (MMP-2 and MMP-9) commonly implicated in two-dimensional glioma growth. A thorough analysis of 21 MMPs and six members of a disintegrin and metalloproteinase domain showed that MMP-12 was increased in gliomas by tenascin-C in three-dimensional matrix. Furthermore, examinations of resected specimens revealed high MMP-12 levels in the high-grade glioblastoma multiforme tumors. Finally, a function-blocking antibody as well as small interfering RNA to MMP-12 attenuated the tenascin-C-stimulated glioma invasion. These results identify a new factor, MMP-12, in regulating glioma invasiveness through interaction with tenascin-C.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17178873 [PubMed - in process]

 

30: Cancer Res. 2006 Dec 15;66(24):11726-35.

 
Ectopic doublecortin gene expression suppresses the malignant phenotype in glioblastoma cells.

Santra M, Zhang X, Santra S, Jiang F, Chopp M.

Department of Neurology, Henry Ford Health Sciences Center, Detroit, Michigan 48202, USA.

Doublecortin (DCX) is one of the three genes found from Affymetrix gene chip analysis related to glioma patient survival. Two other genes (e.g., osteonectin and semaphorin 3B) are well characterized as antioncogenic and tumor suppressor genes. However, there is no report about the involvement of DCX in cancer. Here, we show that gene transfer technology into DCX-deficient glioblastoma cell lines, such as A172, U87, U251N, RG2, and 9L, with DCX cDNA significantly suppressed growth of these glioma cells. U87 cells with ectopic expression of DCX exhibit a marked suppression of the transformed phenotype as growth arrested in the G(2) phase of the cell cycle progression, small colony formation in soft agar, and no tumor formation in nude rats. This transformed phenotype can be restored by knocking down DCX expression with DCX small interfering RNA. DCX was highly phosphorylated in glioma cells. Phosphorylation in the glioma cells was greater than in noncancer cells such as mouse NIH 3T3 and human embryonic kidney 293T cells. Coimmunoprecipitation of the phosphorylated DCX and spinophilin/neurabin II from DCX-synthesizing glioma cells indicated their interaction. This interaction would lead to a block of anchorage-independent growth as neurabin II is a synergistic inhibitor of anchorage-independent growth with p14ARF (ARF). Interaction between phosphorylated DCX and neurabin II may induce the association of the protein phosphatase 1 catalytic subunit (PP1) with neurabin II and inactivate PP1 and block mitosis during G(2) and M phases of the cell cycle progression. Thus, DCX seems to be a tumor suppressor of glioma.

Publication Types:

• Research Support, N.I.H., Extramural

PMID: 17178868 [PubMed - in process]

 

31: Cancer Res. 2006 Dec 15;66(24):11709-17.

 
A Ras inhibitor tilts the balance between Rac and Rho and blocks phosphatidylinositol 3-kinase-dependent glioblastoma cell migration.

Goldberg L, Kloog Y.

Department of Neurobiochemistry, The George S. Wise Faculty of Life Sciences, Tel Aviv University, Tel Aviv, Israel.

Glioblastoma multiforme are highly aggressive tumors for which no adequate treatment has yet been developed. Glioblastoma multiforme show large amounts of active Ras, considered an appropriate target for directed therapy. Here, we show that the Ras inhibitor S-trans, trans-farnesyl thiosalicylic acid (FTS) can avert the transformation of human glioblastoma multiforme cells by inhibiting both their migration and their anchorage-independent proliferation. FTS, by down-regulating Ras activity in glioblastoma multiforme cells, inhibited phosphatidylinositol 3-kinase signaling, resulting in decreased activity of Rac-1. At the same time, activation of RhoA was increased. These two small GTPases are known to control the arrangement of the actin cytoskeleton. By tilting the balance between Rac-1 and RhoA activities, FTS caused the glioblastoma multiforme cells to undergo profound changes in morphology, including rearrangement of actin into stress fibers and assembly of focal adhesions, both of which are governed by RhoA signaling. These morphologic changes allowed strong attachment of the cells to the matrix, rendering them immobile. The results show that FTS should be considered as a candidate drug for glioblastoma multiforme therapy because it targets not only cell proliferation but also cell migration and invasion, which together constitute the most problematic aspect of these malignancies.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17178866 [PubMed - in process]

 

32: Cancer Res. 2006 Sep 15;66(18):9054-64.

 
Tumor stromal-derived factor-1 recruits vascular progenitors to mitotic neovasculature, where microenvironment influences their differentiated phenotypes.

Aghi M, Cohen KS, Klein RJ, Scadden DT, Chiocca EA.

Program in Neurosurgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.

Mechanisms underlying tumor vasculogenesis, the homing and engraftment of bone marrow-derived vascular progenitors, remain undefined. We hypothesized that tumor cell-secreted factors regulate vasculogenesis. We studied vasculogenic and nonvasculogenic intracranial murine gliomas. A PCR screen identified stromal-derived factor-1 (SDF-1/CXCL12) and vascular endothelial growth factor (VEGF) expression by vasculogenic glioma cells and spontaneously arising vasculogenic tumors in NF1+/-:Trp53+/- mice, but not by nonvasculogenic glioma cells. Enforced SDF-1, not VEGF, expression in nonvasculogenic cells caused vasculogenesis. Combined SDF-1 and VEGF expression augmented vasculogenesis over SDF-1 expression alone. Blocking SDF-1 receptor CXCR4 reduced short-term homing and long-term engraftment of vascular progenitors. Implanting tumor cells secreting SDF-1 was therefore necessary and sufficient to incorporate marrow-derived precursors into tumor endothelium. SDF-1 seemed to exert these effects by acting locally intratumorally and did not cause an efflux of marrow-derived progenitors into circulation. Tumor microenvironment determined additional fates of marrow-derived cells. Hypoxia, observed with ectopic s.c. murine tumors at levels approximating that of intracranial human glioblastoma, interacted with tumor-secreted SDF-1 to expand engrafted vascular progenitor differentiated phenotypes to include pericytes as well as endothelium. In contrast, less hypoxic orthotopic intracranial murine gliomas contained only marrow-derived endothelium without marrow-derived pericytes. Furthermore, we found that vasculogenesis is significant for tumors because it generates endothelium with a higher mitotic index than endothelium derived from local sources. Although CXCR4 blockade selectively targeted endothelium generated by vasculogenesis, completely inhibiting vessel formation may require combination therapy targeting locally derived and marrow-derived endothelium.

Publication Types:

• Research Support, N.I.H., Extramural
• Research Support, Non-U.S. Gov't

PMID: 16982747 [PubMed - indexed for MEDLINE]

 

33: Clin Cancer Res. 2006 Sep 15;12(18):5336-45.

 
Protein kinase C as a therapeutic target.

Teicher BA.

Genzyme Corporation, Framingham, Massachusetts 01701-9322, USA. Beverly.Teicher@Genzyme.com

Publication Types:

• Review

PMID: 17000666 [PubMed - indexed for MEDLINE]

 

34: Eur J Cancer. 2006 Oct;42(15):2499-503. Epub 2006 Aug 17.

 
1p/19q loss within oligodendroglioma is predictive for response to first line temozolomide but not to salvage treatment.

Kouwenhoven MC, Kros JM, French PJ, Biemond-ter Stege EM, Graveland WJ, Taphoorn MJ, Brandes AA, van den Bent MJ.

Department of Neuro-Oncology, Daniel den Hoed Oncology Center, P.O. Box 5201, 3008AE Rotterdam, The Netherlands.

BACKGROUND: Combined loss of 1p/19q predicts an almost 100% response rate to first line procarbazine, CCNU and vincristine chemotherapy (PCV) chemotherapy in oligodendroglial tumours. We assessed the impact of 1p and 19q loss on the outcome to first line temozolomide (TMZ) chemotherapy and to second line PCV or TMZ in progressive oligodendroglial tumours. MATERIALS AND METHODS: Tumour samples from patients included in two prospective EORTC studies on first line and second line TMZ chemotherapy in recurrent oligodendroglioma were used for this study. Most patients in the first line TMZ trial received PCV at further progression. Loss of 1p and 19q was assessed on paraffin embedded tumour samples by fluorescent in situ hybridisation with locus specific probes for 1p36 and 19q13. RESULTS: Losses of 1p and 19q were mainly observed in morphologically classical oligodendrogliomas (OD). Thirteen out of 18 patients with 1p loss (72%) responded to first line temozolomide (p<0.01). Both response to second line salvage PCV or to second line temozolomide was limited, even in patients with combined 1p/19q loss. Patients with tumours with 1p loss treated with salvage PCV had improved PFS (p<0.05). More patients with 1p loss were alive at 60 and 120 months after initial surgery (p<0.001). CONCLUSION: Combined 1p/19q loss is mainly observed in classical OD. Responses to first line temozolomide are strongly correlated to loss of 1p. Response to second line alkylating treatment is modest even in tumours with 1p/19q loss. For further improvement of outcome in OD novel treatments are needed.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 16914310 [PubMed - indexed for MEDLINE]

 

35: J Clin Oncol. 2006 Nov 20;24(33):5223-33.

 
Identification of tumor-specific molecular signatures in intracranial ependymoma and association with clinical characteristics.

Modena P, Lualdi E, Facchinetti F, Veltman J, Reid JF, Minardi S, Janssen I, Giangaspero F, Forni M, Finocchiaro G, Genitori L, Giordano F, Riccardi R, Schoenmakers EF, Massimino M, Sozzi G.

Unit of Molecular Cytogenetics, Istituto Nazionale per lo Studio e la Cura dei Tumori, Milano, Italy. piergiorgio.modena@istitutotumori.mi.it

PURPOSE: To delineate clinically relevant molecular signatures of intracranial ependymoma. MATERIALS AND METHODS: We analyzed 24 primary intracranial ependymomas. For genomic profiling, microarray-based comparative genomic hybridization (CGH) was used and results were validated by fluorescent in situ hybridization and loss of heterozygosity mapping. We performed gene expression profiling using microarrays, real-time quantitative reverse transcriptase polymerase chain reaction, and methylation analysis of selected genes. We applied class comparison analyses to compare both genomic and expression profiling data with clinical characteristics. RESULTS: A variable number of genomic imbalances were detected by array CGH, revealing multiple regions of recurrent gain (including 2q23, 7p21, 12p, 13q21.1, and 20p12) and loss (including 5q31, 6q26, 7q36, 15q21.1, 16q24, 17p13.3, 19p13.2, and 22q13.3). An ependymoma-specific gene expression signature was characterized by the concurrent abnormal expression of developmental and differentiation pathways, including NOTCH and sonic hedgehog signaling. We identified specific differentially imbalanced genomic clones and gene expression signatures significantly associated with tumor location, patient age at disease onset, and retrospective risk for relapse. Integrated genomic and expression profiling allowed us to identify genes of which the expression is deregulated in intracranial ependymoma, such as overexpression of the putative proto-oncogene YAP1 (located at 11q22) and downregulation of the SULT4A1 gene (at 22q13.3). CONCLUSION: The present exploratory molecular profiling study allowed us to refine previously reported intervals of genomic imbalance, to identify novel restricted regions of gain and loss, and to identify molecular signatures correlating with various clinical variables. Validation of these results on independent data sets represents the next step before translation into the clinical setting.

Publication Types:

• Research Support, Non-U.S. Gov't

PMID: 17114655 [PubMed - indexed for MEDLINE]

 

36: J Natl Cancer Inst. 2006 Nov 1;98(21):1528-37.

 
Comment in:

• J Natl Cancer Inst. 2006 Nov 1;98(21):1510-1.

New primary neoplasms of the central nervous system in survivors of childhood cancer: a report from the Childhood Cancer Survivor Study.

Neglia JP, Robison LL, Stovall M, Liu Y, Packer RJ, Hammond S, Yasui Y, Kasper CE, Mertens AC, Donaldson SS, Meadows AT, Inskip PD.

Department of Pediatrics, University of Minnesota School of Medicine, Minneapolis, MN, USA. jneglia@umn.edu

BACKGROUND: Subsequent primary neoplasms of the central nervous system (CNS) have frequently been described as late events following childhood leukemia and brain tumors. However, the details of the dose-response relationships, the expression of excess risk over time, and the modifying effects of other host and treatment factors have not been well defined. METHODS: Subsequent primary neoplasms of the CNS occurring within a cohort of 14,361 5-year survivors of childhood cancers were ascertained. Each patient was matched with four control subjects by age, sex, and time since original cancer diagnosis. Tumor site-specific radiation dosimetry was performed, and chemotherapy information was abstracted from medical records. Conditional logistic regression was used to estimate odds ratios (ORs), to calculate 95% confidence intervals (CIs), and to model the excess relative risk (ERR) as a function of radiation dose and host factors. For subsequent gliomas, standardized incidence ratios (SIRs) and excess absolute risks (EARs) were calculated based on Surveillance, Epidemiology, and End Results data. RESULTS: Subsequent CNS primary neoplasms were identified in 116 individuals. Gliomas (n = 40) occurred a median of 9 years from original diagnosis; for meningiomas (n = 66), it was 17 years. Radiation exposure was associated with increased risk of subsequent glioma (OR = 6.78, 95% CI = 1.54 to 29.7) and meningioma (OR = 9.94, 95% CI = 2.17 to 45.6). The dose response for the excess relative risk was linear (for glioma, slope = 0.33 [95% CI = 0.07 to 1.71] per Gy, and for meningioma, slope = 1.06 [95% CI = 0.21 to 8.15] per Gy). For glioma, the ERR/Gy was highest among children exposed at less than 5 years of age. After adjustment for radiation dose, neither original cancer diagnosis nor chemotherapy was associated with risk. The overall SIR for glioma was 8.7, and the EAR was 19.3 per 10,000 person-years. CONCLUSIONS: Exposure to radiation therapy is the most important risk factor for the development of a new CNS tumor in survivors of childhood cancers. The higher risk of subsequent glioma in children irradiated at a very young age may reflect greater susceptibility of the developing brain to radiation.

Publication Types:

• Multicenter Study
• Research Support, N.I.H., Extramural
• Research Support, N.I.H., Intramural
• Research Support, Non-U.S. Gov't

PMID: 17077355 [PubMed - indexed for MEDLINE]

 

37: J Natl Cancer Inst. 2006 Nov 1;98(21):1510-1.

 
Comment on:

• J Natl Cancer Inst. 2006 Nov 1;98(21):1528-37.

Childhood cancer--treatment at a cost.

Ron E.

Publication Types:

• Comment
• Editorial

PMID: 17077348 [PubMed - indexed for MEDLINE]

 

38: J Neurochem. 2006 Dec 1; [Epub ahead of print]

 
Overexpression of midkine contributes to anti-apoptotic effects in human meningiomas.

Tong Y, Mentlein R, Buhl R, Hugo HH, Krause J, Mehdorn HM, Held-Feindt J.

Department of Neurosurgery, University Medical Center Schleswig-Holstein, Kiel, Germany.

Meningiomas are the second most common intracranial tumours. Most meningiomas grow slowly; however, atypical and anaplastic meningiomas show an aggressive biological behaviour. Overexpression of growth factors is considered to be a cause of carcinogenesis. Midkine and pleiotrophin are heparin-binding growth factors that promote growth, survival, migration and differentiation of various target cells. Both molecules are highly expressed during human embryogenesis but are rarely seen in the adult. We show that in relation to normal dura and arachnoid tissues, midkine was overexpressed in meningiomas on the mRNA and protein level, whereas pleiotrophin was not. Thereby, not only the intact but also the truncated form of midkine could be observed. The expression of midkine receptors was variable in different samples. Midkine stimulation of cultured meningioma cells induced phosphorylation of Akt, whereas no increase in phosphorylation of p42/44 MAPK or p38 MAPK could be detected. Midkine did not influence the proliferation of meningioma cells in vitro, but it did protect meningioma cells from camptothecin-mediated apoptotic cell death through reduction in the amounts of active caspase-3. These findings provide evidence for the overexpression of midkine in meningiomas which contributes to protection from cell death in these second most common intracranial tumours.

PMID: 17181554 [PubMed - as supplied by publisher]

 

39: J Neurochem. 2006 Nov;99(3):989-99.

 
TAp73 isoforms antagonize Notch signalling in SH-SY5Y neuroblastomas and in primary neurones.

Hooper C, Tavassoli M, Chapple JP, Uwanogho D, Goodyear R, Melino G, Lovestone S, Killick R.

King's College London, MRC Centre for Neurodegenerative Research, Institute of Psychiatry, London, UK.

p73, like Notch, has been implicated in neurodevelopment and in the maintenance of the mature central nervous system. In this study, by the use of reporter-gene assays, we demonstrate that C-promoter binding factor-1 (CBF-1)-dependent gene transcription driven by the Notch-1 intracellular domain (N1(ICD)) is potently antagonized by exogenously expressed transactivating (TA) p73 splice variants in SH-SY5Y neuroblastomas and in primary neurones. Time course analysis indicated that the inhibitory effects of TAp73 are direct and are not mediated via the product of a downstream target gene. We found that endogenous TAp73 stabilized by either c-Abl or cisplatin treatment also potently antagonized N1(ICD)/CBF-1-dependent gene transcription. Furthermore, western blotting revealed that exogenous TAp73 suppressed endogenous hairy and enhancer of split-1 (HES-1) protein levels and antagonized the increase in HES-1 protein induced by exogenous N1(ICD) expression. Evidence of a direct physical interaction between N1(IC