[Symptomatic tumors in neurofibromatosis type 1: a diagnostic challenge]. / Symptomatische tumoren bij neurofibromatose type 1.

Neurofibromatosis type 1 (NF1) is a hereditary, progressive and unpredictable disease, which can involve many organs. Benign and malignant tumors arise due to unrestrained cell division and cell growth. Recognizing the symptoms of these tumors and using the correct diagnostics is of great importance. In this clinical lesson we show the disease course of 3 patients with NF1. In all 3, the disease course was complicated by a symptomatic tumor. Characteristic in these patients is the relatively long interval between the onset of symptoms and the final tumor diagnosis. In this clinical lesson we examine the causes of this in more detail and we emphasize the importance of the specific knowledge within the Dutch national NF1 care network.

Medulloblastoma in adults: evaluation of the Dutch society for neuro-oncology treatment protocol.

PURPOSE: Medulloblastoma is a rare tumor in adults. The objective of this nationwide, multicenter study was to evaluate the toxicity and efficacy of the Dutch treatment protocol for adult medulloblastoma patients. METHODS: Adult medulloblastoma patients diagnosed between 2010 and 2018 were identified in the Dutch rare tumors registry or nationwide pathology database. Patients with intention to treat according to the national treatment protocol were included. Risk stratification was performed based on residual disease, histological subtype and extent of disease. All patients received postoperative radiotherapy [craniospinal axis 36 Gy/fossa posterior boost 19.8 Gy (14.4 Gy in case of metastases)]. High-risk patients received additional neoadjuvant (carboplatin-etoposide), concomitant (vincristine) and adjuvant chemotherapy (carboplatin-vincristine-cyclophosphamide) as far as feasible by toxicity. Methylation profiling, and additional next-generation sequencing in case of SHH-activated medulloblastomas, were performed. RESULTS: Forty-seven medulloblastoma patients were identified, of whom 32 were treated according to the protocol. Clinical information and tumor material was available for 28 and 20 patients, respectively. The histological variants were mainly classic (43%) and desmoplastic medulloblastoma (36%). Sixteen patients (57%) were considered standard-risk and 60% were SHH-activated medulloblastomas. Considerable treatment reductions and delays in treatment occurred due to especially hematological and neurotoxicity. Only one high-risk patient could complete all chemotherapy courses. 5-years progression-free survival (PFS) and overall survival (OS) for standard-risk patients appeared worse than for high-risk patients (PFS 69% vs. 90%, OS 81% vs. 90% respectively), although this wasn't statistically significant. CONCLUSION: Combined chemo-radiotherapy is a toxic regimen for adult medulloblastoma patients that may result in improved survival.

[Revised guideline 'Brain metastases': More treatment options]. / Herziene richtlijn 'Hersenmetastasen'.

The guideline on brain metastasis from the Netherlands Society of Neurology has been updated. Important changes have been made, particularly with regard to treatment of brain metastases. Treatment of patients with brain metastases is complex and requires a multidisciplinary approach to formulate an optimal, individualized treatment plan. Neurosurgical resection may also be considered in patients with multiple brain metastases and one dominant, symptomatic lesion, if the patient is in good clinical condition. Stereotactic radiosurgery is a treatment option for patients with a maximum of 10 brain metastases, depending on the size and number of metastases. The indication for whole brain radiotherapy is relatively limited. Doctors should be cautious with whole brain radiotherapy in patients with a Karnofsky Performance Status <70. In patients with small, asymptomatic brain metastases, targeted therapy or immune therapy may be considered without locoregional therapy.

Expression-based intrinsic glioma subtypes are prognostic in low-grade gliomas of the EORTC22033-26033 clinical trial.

INTRODUCTION: The European Organisation for Research and Treatment of Cancer (EORTC) 22033-26033 clinical trial (NCT00182819) investigated whether initial temozolomide (TMZ) chemotherapy confers survival advantage compared with radiotherapy (RT) in low-grade glioma (LGG) patients. In this study, we performed gene expression profiling on tissues from this trial to identify markers associated with progression-free survival (PFS) and treatment response. METHODS: Gene expression profiling, performed on 195 samples, was used to assign tumours to one of six intrinsic glioma subtypes (IGSs; molecularly similar tumours as previously defined using unsupervised expression analysis) and to determine the composition of immune infiltrate. DNA copy number changes were determined using OncoScan arrays. RESULTS: We confirm that IGSs are prognostic in the EORTC22033-26033 clinical trial. Specific genetic changes segregate in distinct IGSs: most samples assigned to IGS-9 have IDH-mutations and 1p19q codeletion, samples assigned to IGS-17 have IDH-mutations without 1p19q codeletion and samples assigned to other intrinsic subtypes often are IDH-wildtype. A trend towards benefit from RT was observed for samples assigned to IGS-9 (hazard ratio [HR] for TMZ is 1.90, P = 0.065) but not for samples assigned to IGS-17 (HR 0.87, P = 0.62). We did not identify genes significantly associated with PFS within intrinsic subtypes, although follow-up time is limited. We also show that LGGs and glioblastomas differ in their immune infiltrate, which suggests that LGGs are less amenable to checkpoint inhibitor-type immune therapies. Gene expression analysis also allows identification of relatively rare subtypes. Indeed, one patient with a pilocytic astrocytoma was identified. CONCLUSION: IGSs are prognostic for PFS in EORTC22033-26033 clinical trial samples.

Survival of breast cancer patients with synchronous or metachronous central nervous system metastases.

BACKGROUND: Central nervous system (CNS) metastases represent a devastating complication for advanced breast cancer patients. This observational study examines the influence of patient, tumour and treatment characteristics on overall survival after synchronous or metachronous CNS metastases. METHODS: Information on 992 breast cancer patients with CNS metastases (whose primary tumour was diagnosed between 2004 and 2010) was retrieved from the Netherlands Cancer Registry (NCR). Overall survival was calculated from the date of CNS metastatic diagnosis, and the impact of prognostic factors on survival was assessed using univariate and multivariate extended Cox-regression models. RESULTS: We identified 165 patients with synchronous and 827 patients with metachronous CNS metastases. The majority of patients (88%) presented with brain metastases only, 12% had leptomeningeal metastases. Overall median survival was 5.0 months. Non-triple-negative breast cancer and systemic therapy were associated with improved survival in both groups. In patients with synchronous CNS metastases, surgery for the primary tumour and the metastases also improved survival. In patients with metachronous metastases, younger age (<50 years), lower initial tumour stage (I), ductal carcinoma, a prolonged time interval until diagnosis of CNS metastasis (>1 year), and absence of extracranial metastases were associated with improved survival. Metastasectomy and radiation therapy did not provide benefit beyond the first six months. CONCLUSIONS: No difference in survival was established between synchronous and metachronous CNS metastases. Triple-negative disease is prognostically unfavourable in both groups, while those receiving treatment have a better outcome. Metastasectomy and radiotherapy improve survival within the first six months, and additional benefit may be derived from systemic therapy.

[Practice guideline 'Brain metastases' (revision)]. / Richtlijn 'Hersenmetastasen' (revisie).

Improved survival of cancer patients results in an increase in the incidence of brain metastases. In addition, asymptomatic brain metastases are more often detected as a consequence of active screening. In patients with cancer and new neurological symptoms, MRI of the brain is indicated to assess the presence and number of brain metastases. Decisions concerning treatment of brain metastases should take place within a multidisciplinary team. Treatment is in the first instance focused on improvement or preservation of neurological functioning. The main treatment options for patients with brain metastases are whole brain radiotherapy, stereotactic radiosurgery/radiotherapy, and neurosurgical resection. The choice of treatment depends on the number and the location of the brain metastases, the general and neurological condition of the patient, the extent of extracranial tumour activity, and the expected results of treatment. The revised guideline supports the policy of whole brain radiotherapy not being the standard treatment following stereotactic radiosurgery or radiotherapy. In the case of complete resection, confirmed using early postoperative MRI, whole brain radiotherapy does not add to survival benefit, while patients may suffer from radiation-induced toxicity.

IDH1 mutations in low-grade astrocytomas predict survival but not response to temozolomide.

BACKGROUND: Mutations in isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) have been implicated in tumorigenesis of gliomas. Patients with high-grade astrocytomas with IDH1 or IDH2 mutations were reported to have a better survival, but it is unknown if this improved survival also holds for low-grade astrocytoma and whether these mutations predict outcome to specific treatment. METHODS: We retrospectively investigated the correlation of IDH1 and IDH2 mutations with overall survival and response to temozolomide in a cohort of patients with dedifferentiated low-grade astrocytomas treated with temozolomide at the time of progression after radiotherapy. RESULTS: IDH1 mutations were present in 86% of the 49 progressive astrocytomas. No mutations in IDH2 were found. Presence of IDH1 mutations were early events and significantly improved overall survival (median survival 48 vs 98 months), but did not affect outcome of temozolomide treatment. CONCLUSION: These results indicate that IDH1 mutations identify a subgroup of gliomas with an improved survival, but are unrelated to the temozolomide response.

Unusual case of bifocal leptomeningeal melanocytoma in the posterior fossa with seeding in the spinal canal.

A 26-year-old man presented with signs of raised intracranial pressure. CT and MRI of the head demonstrated two separate lesions in the posterior fossa. The radiological differential diagnoses included multiple meningiomas, schwannomas, neurofibromas and subependymomas. Both lesions were surgically resected. Histopathological examination revealed localisations of a leptomeningeal melanocytoma. Leptomeningeal melanocytoma is a rare tumour of the central nervous system. Generally, it has a good prognosis if radical resection can be performed. In cases of subtotal resection, adjuvant radiotherapy should be considered. Local recurrences are common. Less frequently, leptomeningeal metastases and, on rare occasions, distant metastases or progression to malignant melanoma have been described. We describe an unusual case with multiple localisations of melanocytoma in the posterior fossa and spinal canal, with the emphasis being on the radiological findings and diagnosis of this rare tumour. After surgery of the brain, this patient was irradiated on the craniospinal axis.

[Temozolomide, an oral chemotherapeutic agent with potential severe toxicity]. / Temozolomide, een oraal chemotherapeuticum met soms ernstige toxiciteit.

Two patients, a 58-year-old man and a 55-year-old woman, both under treatment for glioblastoma multiforme, were admitted with fever and neutropenia a few weeks after starting to take the oncolytic agent temozolomide. The man died of a cerebral haemorrhage against a background of severe thrombocytopenia and febrile neutropenia, and the woman died of neutropenic sepsis. Temozolomide is an oral alkylating agent that is considered to be a well-tolerated chemotherapeutic agent. It is important to be aware of the potentially life-threatening toxicity of every chemotherapeutic agent, including temozolomide. Therefore, temozolomide should be prescribed only by doctors with sufficient clinical experience with treatment by means of oncolytic agents, and with the recognition of the side effects and treatment of the complications of chemotherapy. In view of the multidisciplinary aspects of the treatment of patients with glioblastoma multiforme, treatment by a specialised team is preferable.

CSF levels of growth factors and plasminogen activators in leptomeningeal metastases.

OBJECTIVE: To investigate the diagnostic value of transforming growth factor beta(1) (TGFbeta(1)), vascular endothelial growth factor (VEGF), urokinase-type plasminogen activator (uPA), and tissue-type plasminogen activator (tPA) in CSF for leptomeningeal metastasis (LM). METHODS: The authors measured concentrations of biomarkers by ELISA in matched samples of CSF and serum, collected from 132 patients with a solid malignancy with LM (n = 19) and without LM (n = 54) and patients with viral (n = 16) and bacterial (n = 16) meningitis and a variety of nonmalignant, noninfectious neurologic disorders (n = 27). Indexes of the biomarkers (CSF/serum value relative to CSF/serum albumin ratios) were calculated to correct for the serum contribution to the CSF marker concentration. RESULTS: CSF VEGF concentration was significantly higher in LM than in all other groups. VEGF indexes were also higher, although not significant. In contrast, the tPA index was significantly decreased in LM compared with all other groups. The combination of the VEGF and tPA indexes resulted in a sensitivity of 100% for LM and a specificity of 73% for the patient group with a primary tumor but without LM. CONCLUSION: Patients with leptomeningeal metastasis have high vascular endothelial growth factor (VEGF) indexes and low tissue-type plasminogen activator (tPA) indexes. As cytologic examination of CSF lacks 100% sensitivity for the diagnosis of leptomeningeal metastasis (LM), the combination VEGF and tPA index analysis may be of additional value in the diagnostic workup of patients suspected of having LM.

Three-dimensional reconstruction of tumor microvasculature: simultaneous visualization of multiple components in paraffin-embedded tissue.

Three-dimensional (3D) visualization of microscopic structures may provide useful information about the exact 3D configuration, and offers a useful tool to examine the spatial relationship between different components in tissues. A promising field for 3D investigation is the microvascular architecture in normal and pathological tissue, especially because pathological angiogenesis plays a key role in tumor growth and metastasis formation. This paper describes an improved method for 3D reconstruction of microvessels and other microscopic structures in transmitted light microscopy. Serial tissue sections were stained for the endothelial marker CD34 to highlight microvessels and corresponding images were selected and aligned. Alignment of stored images was further improved by automated non-rigid image registration, and automated segmentation of microvessels was performed. Using this technique, 3D reconstructions were produced of the vasculature of the normal brain. Also, to illustrate the complexity of tumor vasculature, 3D reconstructions of two brain tumors were performed: a hemangioblastoma and a glioblastoma multiforme. The possibility of multiple component visualization was shown in a 3D reconstruction of endothelium and pericytes of normal cerebellar cortex and a hemangioblastoma using alternate staining for CD34 and alpha-smooth muscle actin in serial sections, and of a GBM using immunohistochemical double staining. In conclusion, the described 3D reconstruction procedure provides a promising tool for simultaneous visualization of microscopic structures.

Cerebral venous and sinus thrombosis with cerebrospinal fluid circulation block after the first methotrexate administration by lumbar puncture.

We report a patient treated for small lymphocytic lymphoma/leukemia with cerebral venous and sinus thrombosis (CVST) after lumbar puncture with intrathecal administration of methotrexate (MTX). He also developed a cerebrospinal fluid flow block. This is the first report of an association between lumbar puncture and intrathecally administered MTX and the development of CVST. Intrathecal treatment in this patient was discontinued and he was successfully treated with high-dose low-molecular-weight heparin subcutaneously.

[The treatment of brain metastases]. / De behandeling van hersenmetastasen.

Patients with cancer have a 15 to 30% risk of developing symptomatic brain metastases. The prognosis is extremely poor then: the median survival period is less than one year. Treatment strategies aim to guarantee an optimal quality of life. Curative treatment can only be given in just a few unique cases. Besides the previous standard treatment of whole-brain radiotherapy, the efficacy of other treatment modalities as surgery, radiosurgery, and systemic chemotherapy has been demonstrated to have additional value for certain indications. Important factors that play a role in the decision to give a specific treatment are the age and performance status of the patient, the number of brain metastases and their location, the systemic tumour activity, and the radiosensitivity and chemosensitivity of the primary tumour. A multidisciplinary approach is necessary to guarantee an optimal treatment plan.

Primary central nervous system T-cell lymphoma.

Most primary CNS lymphomas (PCNSL) are B-cell neoplasms; T-cell lymphomas are quite rare. The authors report two young patients with T-cell PCNSL who had a complete response to chemo- and radiotherapy but developed recurrent disease and died 11 and 13 months from diagnosis. The prognosis of T-cell PCNSL may be worse than that of comparable B-cell tumors.

Characteristic chromosomal aberrations in sporadic cerebellar hemangioblastomas revealed by comparative genomic hybridization.

Hemangioblastomas (HBs) of the central nervous system are benign tumors and occur as sporadic (sp) tumors (75%) or as a manifestation of the von Hippel-Lindau (VHL) disease (25%). VHL-disease is an autosomal dominant disorder characterized by HBs of the central nervous system and retina, renal cell carcinoma (RCC), phaeochromocytoma (PHEO), islet tumors of the pancreas, and endolympatic sac tumors as well as cysts and cystadenoma in the kidney, pancreas and epididymis. In VHL patients a large spectrum of germline mutations in the VHL gene has been detected. In spHBs VHL alleles are reported to be inactivated in up to 50% of the tumors. To our knowledge the involvement of other genes in spHBs has not been investigated. To elucidate the oncogenesis of spHBs, we performed CGH on 10 spHBs to screen for chromosomal imbalances throughout the entire tumor genome. Aberrations most frequently detected are losses of chromosomes 3 (70%), 6 (50%), 9 (30%), and 18q (30%) and a gain of chromosome 19 (30%). Based on these frequencies and the co-occurrence of these aberrations in the analyzed tumors we hypothesize that loss of chromosome 3 (harboring the VHL gene) is an early event in the oncogenesis of spHBs, followed by loss of 6, and then losses of chromosomes 9, 18q and gain of chromosome 19. Comparison of the chromosomal imbalances in spHBs to those previously reported in RCCs and PHEOs reveals that the pathway of spHBs shows similarities to both the RCCs and PHEOs.

Mononeuropathy multiplex as the initial manifestation of neurofibromatosis type 2.

The authors report a patient with neurofibromatosis type 2 (NF2) presenting with an axonal mononeuropathy multiplex. Sural nerve biopsy showed small scattered groups of Schwann cells transformed into irregular branching cells with abnormal cell-cell contacts. The authors hypothesize that defective Schwann cell function, due to inactivation of the NF2 gene product merlin, leads to changes in morphology, cell-cell contact, and growth, and finally to degeneration of axons.

Cyclosporine neurotoxicity: a review.

Cyclosporin A (CsA) induces neurological side effects in up to 40% of patients. A reversible posterior leukoencephalopathy syndrome is the most serious complication. Symptoms include headache, altered mental functioning, seizures, cortical blindness, and other visual disturbances, with hypertension. Neuroimaging studies show white matter changes in the posterior regions of the brain. Other neurological side effects of CsA include tremor, diffuse encephalopathy, cerebellar syndrome, extrapyramidal syndrome, pyramidal weakness, and peripheral neuropathy. Hypertension, hypomagnesemia, hypocholesteremia, and the vasoactive agent endothelin may all play a role in the pathogenesis of CsA neurotoxicty. Neurotoxicity is more frequent with high CsA blood levels, but levels may be within the therapeutic range. Dose reduction or withdrawal of CsA usually results in resolution of clinical symptoms and of neuroimaging abnormalities.

Different types of plasminogen activator activity in human brain tumours: relation with peritumoral oedema?

In 20 tissue samples from human brain tumours the concentrations were measured of (1) total plasminogen activator activity, (2) tissue-type plasminogen activator (t-PA) activity, (3) urokinase-type plasminogen activator (u-PA) activity, and (4) t-PA antigen. Most tumours contained a considerable amount of t-PA, but a high interindividual and in a few cases even an intra-individual variability was observed. A weak but significant negative correlation was found between t-PA concentration and the oedema/tumour ratio, as calculated from the preoperative computerized tomography (CT) brain scanning. No correlation was found with u-PA activity. It is concluded that t-PA and u-PA are probably not important factors in the production of peritumoral cerebral oedema, but a correlation between locally different amounts of t-PA or u-PA and the locally different extent of surrounding oedema has not yet been excluded.

Surgery for intracranial meningiomas in elderly patients.

Ninety-three patients above 60 years of age underwent craniotomy for intracranial meningioma removal between 1980 and 1990 at the University Hospital Rotterdam. Sixty-four patients were 60-70 years of age, 29 were 70 years or older. Retrospectively, operative mortality, morbidity and outcome on discharge from hospital and at 6 months were assessed and correlated with age, sex, size and location of the tumor and preoperative neurological status. Seven patients (7.5%) had no or only minor symptoms, 68 (73%) had moderate neurological symptoms (able to live at home with some assistance) and 18 patients (19.5%) had severe symptoms and were dependent on assistance. Surgical mortality was 14%; after 6 months 17% of patients had died. Postoperative complications (surgical, medical or neurological) occurred in 41%. Neurological status 6 months after surgery was improved in 35 patients (38%), unchanged in 38 patients (41%) and worsened in 20 patients (21%), 16 of whom had died. Outcome on discharge from hospital and after 6 months correlated significantly with preoperative neurological status. There was no significant correlation with age, sex, size or location of the tumor. Removal of intracranial meningiomas in the elderly is associated with a high morbidity and mortality rate. However, a large number of elderly patients benefit from surgery for intracranial meningiomas, especially those patients with a good neurological preoperative status.