Morten Lund-Johansen

Vestibular schwannomas: clinical results and quality of life after microsurgery or gamma knife radiosurgery.

OBJECTIVE:The aim of the present study was to evaluate the overall treatment efficacy (tumor control, facial nerve function, complications) and quality of life for patients treated primarily for unilateral vestibular schwannomas of 30 mm or less, either by microsurgery or by gamma knife (GK) radiosurgery. The results for the two treatment groups are compared with each other, with main emphasis on the long-term quality of life. METHODS:This is a retrospective study of 189 consecutive patients, 86 treated by microsurgery and 103 by gamma knife. The mean observation time was 5.9 years. All patients had a magnetic resonance imaging scan and clinical evaluation performed toward the end of the study. To evaluate the quality of life, we used two standardized questionnaires, the Glasgow Benefit Inventory and Short-Form 36. The questionnaires were sent to the 168 living patients. The reply rate was 83.3%. RESULTS:A total of 79.8% of the patients in the microsurgery group and 94.8% of the GK patients had a good facial nerve function (House-Brackmann Grade 1–2). Hearing was usually lost after microsurgery, whereas the GK patients had preserved hearing, which often became reduced over the years after the treatment. The treatment efficacy, defined as no need for additional treatment, was similar for the two treatment modalities. Quality of life was reduced compared with normative data, being most reduced in the microsurgery group. Some of the quality of life questions showed an association with facial nerve function and sex. CONCLUSION:Posttreatment facial nerve function, hearing, complication rates, and quality of life were all significantly in favor of GK radiosurgery.

Vestibular schwannoma: surgery or gamma knife radiosurgery? A prospective, nonrandomized study.

OBJECTIVETo conduct a prospective, open, nonrandomized study of treatment-associated morbidity in patients undergoing microsurgery or gamma knife radiosurgery (GKRS) for vestibular schwannomas. METHODSNinety-one patients with vestibular schwannomas with a maximum tumor diameter of 25 mm in the cerebellopontine angle were treated according to a prospective protocol either by GKRS (63 patients) or open microsurgery (28 patients) using the suboccipital approach. Primary end points included hearing function, according to the Gardner-Robertson scale, and facial nerve function, according to the House-Brackmann scale at 2 years. Clinical data included a balance platform test, score for tinnitus and vertigo using a visual analog scale, and working ability. Patients responded to the quality-of-life questionnaires Short-Form 36 and Glasgow Benefit Inventory. RESULTSThree elderly GKRS patients withdrew; all remaining patients were followed for 2 years. Both primary end points were highly significant in favor of GKRS (P < 0.001). Evidence of reduced facial nerve function (House-Brackmann grade 2 or poorer) at 2 years was found in 13 of 28 open microsurgery patients and 1 of 60 GKRS patients. Thirteen of 28 patients who underwent surgery had serviceable hearing (Gardner-Robertson grade A or B) preoperatively, but none had serviceable hearing postoperatively. Twenty-five of 60 GKRS patients had serviceable hearing before treatment, and 17 (68%) of them had serviceable hearing 2 years after treatment. The tinnitus and vertigo visual analog scale score, as well as balance platform tests, did not change significantly after treatment, and working status did not differ between the groups at 2 years. Quality of life was significantly better in the GKRS group at 2 years, based on the Glasgow Benefit Inventory questionnaire. One GKRS patient required operative treatment within the 2-year study period. CONCLUSIONThis is the second prospective study to demonstrate better facial nerve and hearing outcomes from GKRS than from open surgery for small- and medium-sized vestibular schwannomas.

Preoperative Octreotide Treatment in Newly Diagnosed Acromegalic Patients with Macroadenomas Increases Cure Short-Term Postoperative Rates: A Prospective, Randomized Trial

CONTEXT Surgery is the primary treatment of acromegaly. However, it often fails to cure the patient. New strategies that improve surgical outcome are needed. OBJECTIVE Our objective was to investigate whether 6-month preoperative treatment with octreotide improves the surgical outcome in newly diagnosed acromegalic patients. PATIENTS During a 5-yr period (1999-2004), all newly diagnosed acromegalic patients between 18 and 80 yr of age in Norway were screened and invited to participate in the study. A total of 62 patients was included in the Preoperative Octreotide Treatment of Acromegaly study. RESEARCH DESIGN AND METHODS After a baseline evaluation, patients were randomized directly to transsphenoidal surgery (n = 30) or pretreatment with octreotide (n = 32) 20 mg im every 28th day for 6 months before transsphenoidal surgery. Cure was evaluated 3 months postoperatively primarily by IGF-I levels. RESULTS According to the IGF-I criteria, 14 of 31 (45%) pretreated patients vs. seven of 30 (23%) patients with direct surgery were cured by surgery (P = 0.11). In patients with microadenomas (< or = 10 mm), one of five (20%) pretreated vs. three of five (60%) with direct surgery were cured (P = 0.52). In patients with macroadenomas, 13 of 26 (50%) pretreated vs. four of 25 (16%) with direct surgery were cured (P = 0.017). CONCLUSIONS Six-month preoperative octreotide treatment might improve surgical cure rate in newly diagnosed acromegalic patients with macroadenomas. These results have to be confirmed in future studies.

Expression of extracellular matrix components in a highly infiltrative in vivo glioma model

Abstract. This work demonstrates the expression of extracellular matrix (ECM) components in a highly infiltrative brain tumor model developed by simple inoculation of spheroids from five human glioma biopsy tissues directly into the brains of immunodeficient rats. Non-invasive tumors derived from one glioblastoma biopsy specimen and two glioma cell lines (D-54MG and U-251MG) were also included in this study. The extent of tumor cell infiltration was studied using a pan-human monoclonal anti-vimentin antibody. The cellular origin for several of these ECM components was identified using human-specific monoclonal antibodies and polyclonal antibodies detecting epitopes from both species. Immunostaining revealed a diffuse parenchymal staining of glioma-produced tenascin, whereas vitronectin was produced mainly by the invading glioma cells. ECM components such as laminin, fibronectin and collagen type IV were most probably produced by the host and were mainly associated with the blood vessels in the tumors. However, some parenchymal staining with regional variations was observed. The expression pattern of these components was different in cell lines tumors as compared to the biopsy specimen tumors. The α3 and β1 integrin subunits were mainly observed in areas of tumor cell invasion in the invasive tumors. In conclusion, the observed staining patterns clarify the cellular origin and indicate the possible biological function of tenascin, vitronectin, laminin, fibronectin and collagen type IV in these highly invasive malignant tumors of glial origin.

Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma.

L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, 13C–glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes.

Deletion-mutant epidermal growth factor receptor in human gliomas: Effect of type II mutation on receptor function

Malignant human glioma D-298 MG amplifies a rearranged epidermal growth factor receptor (EGFR) gene (c-erbB proto-oncogene), resulting in an in-frame deletion of 83 amino acids in domain IV of the extracellular domain of the EGFR. EGF and transforming growth factor-a (TGF-a) bound to the mutant EGFR with high affinity and enhanced the intrinsic mutant EGFR kinase activity. The mutant EGFR was capable of transducing EGF-stimulated glioma cell proliferation and invasiveness in an in vitro three-dimensional spheroid model. The deletion-mutant EGFR in D-298 MG is capable of being activated by growth factor; this suggests that overexpression of this mutant EGFR protein rather than structural alteration may be the more significant biologic event.

Treatment of chronic subdural hematoma by burr-hole craniostomy in adults: influence of some factors on postoperative recurrence.

SummaryBackground. The study was conducted to determine the causative factors in the postoperative recurrence (PR) of chronic subdural haematomas (CSDHs) and to evaluate the efficacy of surgery in adults enrolled in this trial. Methods. 99 patients with 121 CSDHs, who were operated on between January 1999 and December 2001, were studied. We evaluated the PR rate related to anamnestic, clinical, surgical and neuroradiological imaging variables. In addition, we reviewed the number and the type of repeated operations, complications of surgery and the outcomes at one, three and 12 months. Findings. 82.6% of lesions were successfully treated following the initial evacuation, and 95.9% of lesions following a second procedure. The PR rate was 14.9%.A significantly high PR rate was found to be associated with separated type, frontal base type, a midline displacement >5 mm and the presence of acute subdural clots in cranial base type on CT scans obtained within four days postsurgery. The interval from head trauma to initial surgery <60 days, the maximum width of subdural space >10 mm and massive collection of air in the subdural space tended to give a high PR rate. The PR rate associated with the homogeneous type of CSDHs was significantly low.Age, sex, cause of CSDH, anticoagulant therapy, preoperative neurological presentation, concomitant disease, variables on preoperative CT scans, and surgical factors such as the extent of the surgical procedure, use of drainage, duration and volume of drainage were not significantly associated with PR rate. Conclusions. It is important to identify factors leading to a high or a low PR rate in the treatment of CSDHs because this may help to select appropriate surgical procedures and postoperative management to treat this condition efficiently.

Gamma knife stereotactic radiosurgery for acromegaly

BACKGROUND Gamma knife radiosurgery (GKR) is an adjuvant treatment for acromegaly if surgery fails to normalize GH hypersecretion. OBJECTIVE To examine the effect of GKR on tumor growth and hypersecretion, and to characterize the adverse effect of this treatment. DESIGN Cross-sectional follow-up study. First, retrospective data pre- and post-GKR were collected. PATIENTS then underwent a predefined survey including radiological, endocrinological, ophthalmological, and neurosurgical evaluation. SETTING Norwegian National Center for gamma knife treatment. PATIENTS Sixty-one patients treated with GKR for acromegaly. Out of 55, 53 living patients underwent a detailed survey. The mean follow-up was 5.5 years. No patient was lost to follow-up. RESULTS Tumor growth was stopped in all patients. At 3, 5, and 10 years after GKR, 45, 58, and 86% of patients had normal IGF-I levels. Consecutive hormone value analysis showed that patients receiving GH-suppressive medication had a more rapid decline in hypersecretion than those who did not receive such medication. Evaluated by survey baseline values alone, non-elevated IGF-I and GH levels below 5 mIU/l were found in 38%. GH-suppressive medication was terminated in 16 out of 40 patients following GKR. Nine out of 53 surveyed patients (17%) had normal IGF-I and GH nadir below 2.6 mIU/l at glucose tolerance tests, while not on hormone-suppressive medication. Two patients developed minor visual field defects. Eight patients started hormone substitution therapy during the follow-up period. CONCLUSION GKR is an effective adjuvant treatment for residual acromegaly, carrying few side effects.

Stimulation of extracellular matrix components in the normal brain by invading glioma cells

Malignant gliomas are characterized by an extensive invasion of tumor cells into the normal brain parenchyma. A substantial amount of data indicates that cell movement in general is regulated by specific interactions between extracellular matrix components and specific cell‐surface receptors. In the present work, multicellular spheroids from 4 human glioma cell lines (U‐373Mg, A‐172Mg, U‐251Mg and HF‐66) were confronted with normal rat brain cell aggregates in vitro, which resulted in a progressive invasion of tumor cells into the brain aggregates. The co‐cultures were then sectioned and immuno‐stained for specific extracellular matrix components (laminin, fibronectin and collagen type IV) and for specific cell‐surface receptors which bind to these components (integrins β1, β4, α3, α6). In addition, flow‐cytometric measurements and Northern blot analyses showed expression of several different integrins within the cell lines. The α3 subunit was expressed strongly in all cell lines. Whereas the β1 subunit was expressed weakly in exponentially growing monolayer cultures, it showed a pronounced expression in multicellular spheroids, indicating that the integrin expression may vary depending on the micro‐environment within a tumor. Furthermore, normal brain tissue was able to produce laminin when confronted with the glioma cells, which also was observed for fibronectin and collagen type IV. The relevance of our observations to the in vivo situation was investigated further by immuno‐staining 5 human glioma biopsy samples for laminin. In some areas of the tumors, specific deposits of laminin were observed. In conclusion, we have shown that normal brain tissue has the ability to produce extracellular matrix components, such as laminin, collagen type IV and fibronectin, when confronted with invading glioma cells. Our results show that the glioma cells express specific integrins which can interact with these extracellular matrix components. Such interactions may facilitate tumor cell migration and invasion. Int. J. Cancer 75:864–872, 1998.

Expression of the progenitor marker NG2/CSPG4 predicts poor survival and resistance to ionising radiation in glioblastoma

Glioblastoma (GBM) is a highly aggressive brain tumour, where patients respond poorly to radiotherapy and exhibit dismal survival outcomes. The mechanisms of radioresistance are not completely understood. However, cancer cells with an immature stem-like phenotype are hypothesised to play a role in radioresistance. Since the progenitor marker neuron-glial-2 (NG2) has been shown to regulate several aspects of GBM progression in experimental systems, we hypothesised that its expression would influence the survival of GBM patients. Quantification of NG2 expression in 74 GBM biopsies from newly diagnosed and untreated patients revealed that 50% express high NG2 levels on tumour cells and associated vessels, being associated with significantly shorter survival. This effect was independent of age at diagnosis, treatment received and hypermethylation of the O6-methylguanine methyltransferase (MGMT) DNA repair gene promoter. NG2 was frequently co-expressed with nestin and vimentin but rarely with CD133 and the NG2 positive tumour cells harboured genetic aberrations typical for GBM. 2D proteomics of 11 randomly selected biopsies revealed upregulation of an antioxidant, peroxiredoxin-1 (PRDX-1), in the shortest surviving patients. Expression of PRDX-1 was associated with significantly reduced products of oxidative stress. Furthermore, NG2 expressing GBM cells showed resistance to ionising radiation (IR), rapidly recognised DNA damage and effectuated cell cycle checkpoint signalling. PRDX-1 knockdown transiently slowed tumour growth rates and sensitised them to IR in vivo. Our data establish NG2 as an important prognostic factor for GBM patient survival, by mediating resistance to radiotherapy through induction of ROS scavenging enzymes and preferential DNA damage signalling.