Stereotactic radiosurgery and radiotherapy for resected brain metastases: current pattern of care in the Radiosurgery and Stereotactic Radiotherapy Working Group of the German Association for Radiation Oncology (DEGRO).

PURPOSE: Preoperative stereotactic radiosurgery (SRS) of brain metastases may achieve similar local control and better leptomeningeal control rates than postoperative fractionated stereotactic radiotherapy (FSRT) in patients treated with elective metastasectomy. To plan a multicentre trial of preoperative SRS compared with postoperative FSRT, a survey of experts was conducted to determine current practice. METHODS: A survey with 15 questions was distributed to the DEGRO Radiosurgery and Stereotactic Radiotherapy Working Group. Participants were asked under what circumstances they offered SRS, FSRT, partial and/or whole brain radiotherapy before or after resection of a brain metastasis, as well as the feasibility of preoperative stereotactic radiosurgery and neurosurgical resection within 6 days. RESULTS: Of 25 participants from 24 centres, 22 completed 100% of the questions. 24 respondents were radiation oncologists and 1 was a neurosurgeon. All 24 centres have one or more dedicated radiosurgery platform and all offer postoperative FSRT. Preoperative SRS is offered by 4/24 (16.7%) centres, and 9/24 (37.5%) sometimes recommend single-fraction postoperative SRS. Partial brain irradiation is offered by 8/24 (33.3%) centres and 12/24 (50%) occasionally recommend whole-brain irradiation. Two centres are participating in clinical trials of preoperative SRS. SRS techniques and fractionation varied between centres. CONCLUSION: All responding centres currently offer postoperative FSRT after brain metastasectomy. Approximately one third offer single-fraction postoperative SRS and four already perform preoperative SRS. With regard to potential co-investigators, 18 were identified for the PREOP­2 multicentre trial, which will randomise between preoperative SRS and postoperative FSRT.

Bevacizumab treatment in malignant meningioma with additional radiation necrosis. An MRI diffusion and perfusion case study.

BACKGROUND AND PURPOSE: Recently two retrospective cohort studies report efficacy of bevacizumab in patients with recurrent atypical and anaplastic meningioma. Another successful therapeutic option of bevacizumab seems to be treatment of cerebral radiation necrosis. However, the antiangiogenic effects in MRI diffusion and perfusion in meningiomas have not been previously described in detail. The objective of this research was to evaluate the clinical and MR imaging effects of bevacizumab in a malignant meningioma patient harboring additional cerebral radiation necrosis. CASE PRESENTATION: We report the case of an 80-year-old woman who underwent bevacizumab therapy (5 mg/kg every 2 weeks for 2 months) for treatment of a symptomatic radiation necrosis in malignant meningiomatosis of World Health Organization (WHO) grade III. The patient was closely monitored with MRI including diffusion and perfusion studies. Upon bevacizumab therapy, the clinical situation was well stabilized over a period of 4 months until the patient unfortunately died due to pneumonia/septicemia probably unrelated to bevacizumab therapy. Consecutive MRI demonstrated 4 important aspects: (1) considerable decrease of the contrast medium (CM)-enhanced radiation necrosis, (2) mixed response with respect to the meningiomatosis with stable and predominantly growing tumor lesions, (3) a new diffusion-weighted imaging (DWI) lesion in a CM-enhanced tumor as described in gliomas, which we did not interpret as a response to bevacizumab therapy, and (4) new thrombembolic infarcts, which are a known side-effect of bevacizumab treatment. CONCLUSION: Bevacizumab is effective in the treatment of radiation necrosis. We could not confirm the potential antitumor effect of bevacizumab in this patient. However, we could describe several new radiographic effects of bevacizumab therapy in malignant meningioma.

Ifosfamide, carboplatin and etoposide in recurrent malignant glioma.

After failure of temozolomide, there is no established standard salvage chemotherapy for patients with recurrent glioblastoma (GBM). Two phase II trials combining ifosfamide, carboplatin and etoposide chemotherapy (ICE) showed favorable results. We therefore applied the ICE protocol to 13 patients (10 GBM, 3 anaplastic astrocytomas). Partial or complete remissions were not observed. None of the 13 patients survived progression-free for 6 months. Our retrospective analysis suggests that the ICE regimen is not effective in patients with recurrent high-grade glioma if applied at second or third relapse.

Simultaneous bedside assessment of global cerebral blood flow and effective cerebral perfusion pressure in patients with intracranial hypertension.

BACKGROUND: We examined a bedside technique transcerebral double-indicator dilution (TCID) for global cerebral blood flow (CBF) as well as the concept of effective cerebral perfusion pressure (CPP(eff)) during different treatment options for intracranial hypertension, and compared global CBF and CPP(eff) with simultaneously obtained conventional parameters. METHODS: Twenty-six patients developing intracranial hypertension in the course of traumatic brain injury or subarachnoid hemorrhage were prospectively analyzed using a combined assessment during elevated ventilation (n = 15) or osmotherapy (hypertonic saline or mannitol). For calculation of global CBF, injections of ice-cold indocyanine green boluses were performed and temperature and dye concentration changes were monitored in the thoracic aorta and the jugular bulb. CBF was then calculated according to the mean transit time principle. Estimation of CCP, the arterial pressure at which cerebral blood flow becomes zero, was performed by synchronized registration of corresponding values of blood flow velocity in the middle cerebral artery and arterial pressure and extrapolation to zero-flow velocity. CPP(eff) was calculated as mean arterial pressure minus critical closing pressure (CPP(eff) = MAP(c) - CCP). RESULTS: Elevated ventilation causes a decrease in both ICP (P < 0.001) and CBF (P < 0.001). While CPP(conv) increased (P < 0.001), CPP(eff) decreased during this observation (P = 0.002). Administration of osmotherapeutic agents resulted in a decrease of ICP (P < 0.001) and a temporary increase of CBF (P = 0.052). CPP(conv) and CPP(eff) showed no striking difference under osmotherapy. CONCLUSION: TCID allows repeated measurements of global CBF at the bedside. Elevated ventilation lowered and osmotherapy temporarily raised global CBF. In situations of increased vasotonus, CPP(eff) is a better indicator of blood flow changes than conventional CPP.

Factors of influence upon the SF-36-based health related quality of life of patients following surgery for petroclival and lateral posterior surface of pyramid meningiomas.

OBJECTIVE: To describe the patient's self assessed health related quality of life (saHRQoL) based upon the medical outcome study 36-item short form health survey (SF-36) as well as the factors of influence upon the saHRQoL following surgery for petroclival (PCM) and lateral posterior surface of the pyramid (LPPM) meningiomas. PATIENTS AND METHODS: In a series of 78 patients operated consecutively for PCM (n = 46) or LPPM (n = 32) the preoperative, intraoperative and postoperative data were collected retrospectively. The saHRQoL was obtained by mailing the SF-36 questionnaire to the patients. The SF-36 data of the whole patients group was compared with a healthy population. The SF-36 data of the PCM- and LPPM were compared to each other. The influence of pre-, intra- and postoperative findings upon the SF-36 was assessed by uni- and multifactorial analysis. RESULTS: 58 (69%) out of the 78 patients answered the SF-36 questionnaire at a median postoperative follow-up of 59 months. The patients, who answered the SF-36 questionnaire, had a significant lower perioperative complication rate than those who did not (46% vs. 75%, p = 0.019). The saHRQoL of the LPPM and PCM was reduced on several sub-scales, when compared to the German reference population. The outcome of PCM is, assessed by saHRQoL as well as by conventional neurosurgical grading scales, inferior to that of LPPM. The saHRQoL of LPPM correlated in the uni- and multivariate analysis with the early postoperative KPI on the sub-scales SF1 (physical functioning) and SF5 (vitality). Accordingly, the sub-scale SF2 (role-physical) of PCM correlated with the change of the KPI from preoperative to the last follow up. CONCLUSIONS: The saHRQoL of the evaluable patients was lower than that of the normal population. The saHRQoL score of PCM-patients was lower than that of LPPM-patients. For the future the saHRQol should be assessed routinely; It reflects the patients' perspective upon postoperative outcome and enables the comparison with other treatment modalities of these difficult to treat tumors.

Interinstitutional variance of postoperative radiotherapy and follow up for meningiomas in Germany: impact of changes of the WHO classification.

OBJECTIVE: To document and critically analyse the impact of the revised WHO 2000 histological classification for meningiomas on postoperative radiotherapy/radiosurgery indications and MRI follow up protocols. METHODS: The current (2000) WHO classification was used to grade 57 meningiomas treated surgically at one institution. These had been reviewed previously in 1999. All German neurosurgical departments carrying out intracranial microsurgery were asked to detail their guidelines for radiation therapy and follow up for meningiomas of different WHO grades. RESULTS: Use of the current criteria downgraded seven of 15 atypical meningiomas (WHO grade II, MII) to grade I (MI), and four of six anaplastic tumours (WHO grade III, MIII) to grade II. Indications for radiotherapy/radiosurgery and MRI follow up protocols varied substantially with the histological grade and between institutions--for example, after an incomplete resection, radiotherapy/radiosurgery recommendations differed between MI and MII in 30 of 58 units (52%), and between MII and MIII in 34 of 56 units (61%). CONCLUSIONS: Correlative studies combining treatment and outcome data with a standardised histopathological analysis are warranted to define properly the indications for radiotherapy/radiosurgery and follow up protocols after surgery for meningiomas of different histological grades. The use of changing grading paradigms during recent years renders decision making based on local and published experience difficult. The relatively large number of meningiomas classified as atypical/WHO grade II in current practice would argue against an uncritically aggressive approach to these tumours.

Amplification and overexpression of the MDM4 (MDMX) gene from 1q32 in a subset of malignant gliomas without TP53 mutation or MDM2 amplification.

We have previously reported on the amplification and overexpression of the MDM2 proto-oncogene in a subset of malignant gliomas without TP53 mutation (G. Reifenberger et al, Cancer Res., 53: 2736-2739, 1993). Here, we show that the MDM4 (MDMX) gene located on 1q32 is a further target for amplification in malignant gliomas. MDM4 codes for a Mdm2-related protein that can bind to p53 and inhibits p53-mediated transcriptional transactivation. We investigated a series of 208 gliomas (106 glioblastomas, 46 anaplastic gliomas, and 56 low-grade gliomas) and identified 5 tumors (4 glioblastomas and 1 anaplastic oligodendroglioma) with MDM4 amplification and overexpression. Several other genes from 1q32 were found to be coamplified with MDM4, such as GAC1 in five tumors, REN in four tumors, and RBBP5 in three tumors. Additional analyses revealed that the malignant gliomas with MDM4 amplification and overexpression carried neither mutations in conserved regions of the TP53 gene nor amplification of the MDM2 gene. Taken together, our data indicate that amplification and overexpression of MDM4 is a novel molecular mechanism by which a small fraction of human malignant gliomas escapes p53-dependent growth control.

Mutation of the PTEN (MMAC1) tumor suppressor gene in a subset of glioblastomas but not in meningiomas with loss of chromosome arm 10q.

The PTEN (MMAC1) gene, which has been identified as a tumor suppressor gene at 10q23.3, is mutated in multiple malignant tumors, including glioblastomas [J. Li et al., Science (Washington DC), 275: 1943-1947, 1997; P. A. Steck et al., Nat. Genet., 15: 356-362, 1997]. Among tumors of the central nervous system, loss of 10q is not restricted to glioblastomas but is also common in atypical and anaplastic meningiomas. Therefore, we have investigated 36 glioblastomas and 34 meningiomas (2 benign, 17 atypical, and 15 anaplastic meningiomas) for loss on 10q, as well as deletion, mutation, and expression of PTEN. Analysis of eight microsatellites from 10q revealed loss of heterozygosity (LOH) in 25 of 36 glioblastomas (69%). Twenty-three of these tumors demonstrated LOH at all informative loci. Two glioblastomas showed LOH restricted to markers located distally to PTEN, with breakpoints mapping telomeric to D10S541 and D10S185. One glioblastoma demonstrated evidence of homozygous deletion of PTEN by differential PCR analysis. PTEN mutations were detected in 9 of 36 glioblastomas (25%). Seven of these tumors showed LOH at all informative loci from 10q, indicating complete loss of wild-type PTEN. Although loss of 10q was detected by comparative genomic hybridization and/or LOH analysis in 14 of the 34 meningiomas investigated (41%), none of these tumors showed evidence of PTEN mutations or homozygous gene deletions. Our findings corroborate that PTEN is inactivated in a subset of glioblastomas. However, the lack of detectable PTEN alterations in a considerable fraction of glioblastomas and all meningiomas with 10q loss strongly supports the hypothesis that at least one additional tumor suppressor gene is located on 10q.

hMYH and hMTH1 cooperate for survival in mismatch repair defective T-cell acute lymphoblastic leukemia.

hMTH1 is an 8-oxodGTPase that prevents mis-incorporation of free oxidized nucleotides into genomic DNA. Base excision and mismatch repair pathways also restrict the accumulation of oxidized lesions in DNA by removing the mis-inserted 8-oxo-7,8-dihydro-2'-deoxyguanosines (8-oxodGs). In this study, we aimed to investigate the interplay between hMYH DNA glycosylase and hMTH1 for cancer cell survival by using mismatch repair defective T-cell acute lymphoblastic leukemia (T-ALL) cells. To this end, MYH and MTH1 were silenced individually or simultaneously using small hairpin RNAs. Increased sub-G1 population and apoptotic cells were observed upon concurrent depletion of both enzymes. Elevated cell death was consistent with cleaved caspase 3 accumulation in double knockdown cells. Importantly, overexpression of the nuclear isoform of hMYH could remove the G1 arrest and partially rescue the toxicity observed in hMTH1-depleted cells. In addition, expression profiles of human DNA glycosylases were generated using quantitative reverse transcriptase-PCR in MTH1 and/or MYH knockdown cells. NEIL1 DNA glycosylase, involved in repair of oxidized nucleosides, was found to be significantly downregulated as a cellular response to MTH1-MYH co-suppression. Overall, the results suggest that hMYH and hMTH1 functionally cooperate for effective repair and survival in mismatch repair defective T-ALL Jurkat A3 cells.

Identification of two distinct deleted regions on the short arm of chromosome 1 and rare mutation of the CDKN2C gene from 1p32 in oligodendroglial tumors.

Oligodendroglial tumors frequently show allelic losses on the short arm of chromosome 1. To narrow down the putative tumor suppressor gene site(s) on 1p, we have investigated 35 oligodendrogliomas and 10 mixed gliomas (oligoastrocytomas) for loss of heterozygosity (LOH) at 21 highly polymorphic loci on chromosome 1 (19 loci on 1p and 2 loci on 1q). LOH at loci on 1p was found in 30 of the 45 tumors (67%). Two distinct regions of common allelic loss were identified: a distal region between D1S76 and D1S253 at 1p36.3, and a proximal region between D1S482 and D1S2743 at 1p34-p35. We also analyzed our tumor series for genetic alterations and expression of the cyclin dependent kinase inhibitor gene CDKN2C (p18INK4c) from 1p32. We found 1 recurrent anaplastic oligodendroglioma that carried a somatic CDKN2C mutation at codon 113 (GAA ==> TAA: Glu ==> Stop). The remaining 44 tumors of our series showed neither coding sequence mutations nor homozygous deletions of CDKN2C. Investigation of 35 tumors by differential reverse transcription-PCR revealed expression of CDKN2C transcripts in all instances. Our data thus provide evidence for more than a single oligodendroglioma-associated tumor suppressor gene on 1p and implicate CDKN2C as a candidate tumor suppressor gene altered in a low fraction of oligodendroglial tumors.

Primitive neuroectodermal tumors of the cerebral hemispheres in two siblings with TP53 germline mutation.

AWe report on two siblings (brother and sister) who developed cerebral PNETs at the age of 5 years and 6 months, respectively. Both children were treated by operation followed by polychemotherapy. The brother also received cranio-spinal irradiation. Nevertheless, the children died about 12 months and 24 months post-operatively due to extensive cerebral tumor recurrences. Shortly after having lost both of her children, the mother developed an intra-abdominal tumor, which was resected and histologically diagnosed as ovarian carcinoma. Because of this unusual familial clustering of tumors and a positive history of brain tumors and other cancers in several maternal relatives, we analyzed DNA isolated from both PNETs and the ovarian carcinoma as well as constitutional (leukocyte) DNA from the whole family for mutation of the TP53 tumor suppressor gene. This analysis revealed that all tumors were homozygous for a missense mutation at codon 213 (CGA => TGG) resulting in an amino acid exchange from arginine to tryptophane. The same mutation was present in one TP53 allele in the constitutional DNA of the mother and the children, indicating that the mother had transmitted a TP53 germline mutation to both of her children. Analysis of loss of heterozygosity at microsatellite markers from 17p confirmed deletion of the paternal (wild-type) allele in both PNETs. Further investigation of the PNETs by comparative genomic hybridization revealed multiple chromosomal abnormalities. Interestingly, some genomic changes were common to both PNETs, while many others were not, a finding suggesting substantial genomic instability, probably as a consequence of p53 inactivation.

Allelic losses on chromosome arm 10q and mutation of the PTEN (MMAC1) tumour suppressor gene in primary and metastatic malignant melanomas.

Malignant melanomas frequently show loss of alleles on the long arm of chromosome 10. The PTEN (MMAC1) gene has been identified as a tumour suppressor gene at 10q23.3 that is mutated in various types of advanced human cancers. We have investigated a series of 40 sporadic melanomas from 37 patients (15 primary cutaneous melanomas and 25 melanoma metastases) for allelic losses on chromosome 10, as well as for deletion and mutation of the PTEN gene. Microsatellite analysis revealed loss of heterozygosity at loci located on 10q in tumours from 15 of 34 patients investigated (44%). Somatic PTEN mutations were identified in melanomas from 4 of 37 patients (11%), all of whom had metastatic disease. In two of these patients, the tumours had additionally lost one PTEN allele, indicating complete loss of wild-type PTEN in the tumour cells. Our findings corroborate that loss of heterozygosity on chromosome 10 is a frequent aberration in malignant melanomas and implicate PTEN as a tumour suppressor gene inactivated by somatic mutation in a fraction of these tumours.

Primary glioblastoma multiforme of the oculomotor nerve. Case report.

Tumors of the oculomotor nerve are rare and most instances reported have been schwannomas. The authors present clinical, neuroradiological, and neuropathological findings in a 70-year-old woman with a glioblastoma multiforme (GBM) growing primarily in the proximal part of the left oculomotor nerve. The patient presented with a 1-month history of transient diplopia. Neurological examination revealed an incomplete left-sided oculomotor nerve palsy with no further signs of neurological dysfunction. Cranial computerized tomography and magnetic resonance imaging showed a tumor of the left oculomotor nerve without any obvious signs of penetration into the midbrain or upper pons. Following subtotal removal of the tumor, neuropathological examination of the operative specimen revealed a GBM that had grown diffusely within peripheral nerve tissue. Six weeks after surgery, the patient suddenly died of pulmonary thromboembolism. Postmortem examination of the brain confirmed a large leptomeningeal GBM at the left pontomesencephalic junction with complete destruction of the left oculomotor nerve. To the authors' knowledge, this represents the first case of a GBM of the oculomotor nerve, probably originating from glial cells within the most proximal part of the nerve or the adjacent leptomeninges.

Multiple intracranial juvenile xanthogranulomas. Case report.

The authors report on an 11-year-old boy in whom proptosis of the eye caused by a benign intraosseous xanthofibroma of the left orbital wall became clinically apparent at the age of 4 years. Two years later he developed bilateral papilledema, at which time computerized tomography and magnetic resonance studies revealed multiple enhancing intracranial lesions. The largest mass was located in the left middle fossa; other lesions were located at the tentorium cerebelli, in both lateral ventricles, near the superior sagittal sinus, and extracranially near the left jugular vein. The mass in the left middle fossa was resected and diagnosed as juvenile xanthogranuloma (JXG). Thirty months later, the patient again became symptomatic, exhibiting behavioral abnormalities and a decrease in mental powers. At that time, the two remaining lesions in both lateral ventricles had grown enough to cause trapping of the temporal horns and raised intracranial pressure. These lesions were successively resected and histopathologically confirmed to be JXGs. However, resection of the second intraventricular lesion was complicated by postoperative bilateral amaurosis, presumably caused by postdecompression optic neuropathy. According to a review of the literature, fewer than 20 patients with JXG involving the central nervous system have been reported. The patient described in this report is the first in whom multiple intracranial JXGs developed in the absence of cutaneous manifestations. Although JXGs are biologically benign lesions, the treatment of patients with multifocal and/or progressive intracranial manifestations is problematic.

Learning needs of hospitalized and recently discharged patients.

Patients' perceptions about the importance of health information they receive during hospitalization and their satisfaction with this information was investigated in a study of hospitalized and recently discharged patients. Results show that information about medications, treatment and complications, and enhancing quality of life are most valued by hospitalized patients followed by information concerning activities of living, community follow-up, skin care, and feelings about condition. For recently discharged patients, the importance of most health information increases, rather than diminishes. These recently discharged patients show high levels of satisfaction with the information they received during hospitalization. These results suggest that hospital-based nurses prioritize patient learning needs and diversify teaching strategies to address patient knowledge deficits both in the hospital and immediately post-discharge.

Early determinants of required nursing care hours in the acute care setting.

This study was conducted to evaluate how patients' requirements for nursing care are related to physician and nurse practice and hospital and patient characteristics. Data available in the first 24 hours of hospitalization were collected for more than 5,000 patients admitted to a 600-bed tertiary care hospital and discharged in one of 20 DRGs. Average daily nursing care hours and total nursing care hours were best predicted by the amounts of specific types of nursing care required on the first day of hospitalization.

Predictors of nurses' involvement in research activities.

Practicing nurses who have special expertise concerning clinical problems generally have minimal involvement in clinical nursing research. As a step toward increasing their research participation and, therefore, the relevancy of clinical studies, this study surveyed 1,217 nurses employed at nine health care agencies concerning their research attitudes, work environment, and research involvement. Descriptive statistics indicated that nurses value nursing research and want more time for research-related activities. Discriminant function analysis revealed that prior research instruction, awareness of support for research, and positive attitudes toward research were predictive of nurses' participation in research activities.

Multiple health care contracts: changing the rules for hospital staff and systems.

Contracting has become a major factor for health care institutions across the country. In this study, researchers at a university-affiliated teaching hospital investigated the day-to-day impact of multiple health care contracts, including their cost in time and inefficiency. The research also identified benefits achieved in improved operations, enhanced data systems, and reductions in unnecessary hospitalizations.

Impact of physician practice on nursing care.

In this study, the effect of physician practice on hours of required nursing care was examined. Although patient diagnosis and severity of illness explained much of the variation in required hours of care, physician practice preferences explained an additional 6% to 38% of variance.