Gliosarcoma with extensive extracranial metastatic spread and familial coincidence: A case report.

Gliosarcoma is a rare histopathological subtype of glioblastoma. Metastatic spreading is unusual. In this report, we illustrate a case of gliosarcoma with extensive extracranial metastases with confirmation of histological and molecular concordance between the primary tumor and a metastatic lesion of the lung. Only the autopsy revealed the extent of metastatic spread and the hematogenous pattern of metastatic dissemination. Moreover, the case bared a familial coincidence of malignant glial tumors as the patient's son was diagnosed with a high-grade glioma shortly after the patient's death. By molecular analysis (Sanger and next generation panel sequencing), we could confirm that both patient's tumors carried mutations in the TP53 gene. Interestingly, the detected mutations were located in different exons. Altogether, this case draws attention to the fact that sudden clinical aggravation could be caused by the rare phenomenon of metastatic spread and should therefore be always taken into consideration, even at an early disease stage. Furthermore, the presented case highlights the contemporary value of autoptic pathological examination.

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.

Discrepancies between biomarkers of primary breast cancer and subsequent brain metastases: an international multicenter study.

PURPOSE: Discordances between the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), expression between primary breast tumors and their subsequent brain metastases (BM) were investigated in breast cancer patients. METHODS: We collected retrospective data from 11 institutions in 8 countries in a predefined-standardized format. Receptor status (positive or negative) was determined according to institutional guidelines (immunohistochemically and/or fluorescence in situ hybridization). The study was subject to each institution's ethical research committee. RESULTS: A total of 167 breast cancer patients with BM were included. 25 patients out of 129 with a complete receptor information from both primary tumor and BM (ER, PR, HER2) available, had a change in receptor status: 7 of 26 (27%) ER/PR-positive/HER2-negative primaries (3 gained HER2; 4 lost expression of ER/PR); 10 of 31 (32%) ER/PR-positive/HER2-positive primaries (4 lost ER/PR only; 3 lost HER2 only; 3 lost both ER/PR and HER2); one of 33 (3%) ER/PR-negative receptor/HER2-positive primaries (gained ER); and 7 of 39 (18%) triple-negative primaries (5 gained ER/PR and 2 gained HER2). CONCLUSIONS: The majority of breast cancer patients with BM in this series had primary HER2-enriched tumors, followed by those with a triple-negative profile. One out of 5 patients had a receptor discrepancy between the primary tumor and subsequent BM. Therefore, we advise receptor status assessment of BM in all breast cancer patients with available histology as it may have significant implications for therapy.

Therapy of leptomeningeal metastasis in solid tumors.

Leptomeningeal metastasis (LM), i.e. the seeding of tumor cells to the cerebrospinal fluid (CSF) and the leptomeninges, is a devastating and mostly late-stage complication of various solid tumors. Clinical signs and symptoms may include cranial nerve palsies, radicular symptoms, signs of increased intracranial pressure such as headache, nausea and vomiting, and cognitive dysfunction. In cases of suspected LM, the highest diagnostic sensitivity is provided by the combination of CSF cytology and contrast-enhanced MRI (cranial as well as complete spine). The therapeutic spectrum includes radiotherapy of the clinically involved region as well as systemic and intrathecal chemotherapy. The choice of treatment modalities depends on the type of LM (non-adherent tumor cells in the CSF vs. nodular contrast-enhancing tumor growth), additional systemic involvement (uncontrolled vs. controlled systemic disease) and additional involvement of the CNS parenchyma (LM as the only CNS involvement vs. LM+parenchymal CNS metastases). Larger contrast-enhancing nodular LM or symptomatic lesions of the spine may be treated with radiotherapy. In case of uncontrolled systemic disease, the treatment regimen should include systemic chemotherapy. The choice of systemic treatment should take into account the histology of the primary tumor. Intrathecal chemotherapy is most important in cases of LM of the non-adherent type. There are three substances for routine use for intrathecal chemotherapy: methotrexate, cytarabine, and thiotepa. Liposomal cytarabine shows advantages in terms of longer injection intervals, a sufficient distribution in the entire subarachnoid space after lumbar administration and improved quality-of-life. The role of new agents (e.g. rituximab and trastuzumab) for intrathecal therapy is still unclear.

Primary pineal tumors: outcome and prognostic factors - a study from the Rare Cancer Network (RCN)

PURPOSE: To better define outcome and prognostic factors in primary pineal tumors. MATERIALS AND METHODS: Thirty-five consecutive patients from seven academic centers of the Rare Cancer Network diagnosed between 1988 and 2006 were included. Median age was 36 years. Surgical resection consisted of biopsy in 12 cases and resection in 21 (2 cases with unknown resection). All patients underwent radiotherapy and 12 patients received also chemotherapy. RESULTS: Histological subtypes were pineoblastoma (PNB) in 21 patients, pineocytoma (PC) in 8 patients and pineocytoma with intermediate differentiation in 6 patients. Six patients with PNB had evidence of spinal seeding. Fifteen patients relapsed (14 PNB and 1 PC) with PNB cases at higher risk (p = 0.031). Median survival time was not reached. Median disease-free survival was 82 months (CI 50 % 28-275). In univariate analysis, age younger than 36 years was an unfavorable prognostic factor (p = 0.003). Patients with metastases at diagnosis had poorer survival (p = 0.048). Late side effects related to radiotherapy were dementia, leukoencephalopathy or memory loss in seven cases, occipital ischemia in one, and grade 3 seizures in two cases. Side effects related to chemotherapy were grade 3-4 leucopenia in five cases, grade 4 thrombocytopenia in three cases, grade 2 anemia in two cases, grade 4 pancytopenia in one case, grade 4 vomiting in one case and renal failure in one case. CONCLUSIONS: Age and dissemination at diagnosis influenced survival in our series. The prevalence of chronic toxicity suggests that new adjuvant strategies are advisable (AU)

High symptom improvement and local tumor control using stereotactic radiotherapy when given early after diagnosis of meningioma. A multicentre study.

PURPOSE: The goal of the present study was to analyze long-term results of fractionated stereotactic radiotherapy (SRT) in patients with a meningioma. METHODS AND MATERIALS: A total of 72 patients treated between 1996 and 2008 in MAASTRO clinic (n = 45) and University Hospital Zurich (n = 27) were included. SRT was given as primary treatment (n = 46), postoperatively (n = 19) or at recurrence (n = 7); 49 tumours (68%) were located in the skull base. Median total dose was 54 Gy. RESULTS: Median follow-up was 4.13 years (range 0.66-11 years). The 3- and 5-year overall survival were 92 and 79% for grade 0 and I meningioma. Progression-free survival for grade 0 and I was 95% at 3 and 5 years, and 40% for grade II and III at 3 years. In 98.4% of patients, clinical symptoms were stable or improved. The majority of symptoms improved within 24 months after SRT. Local control is significantly better if patients are irradiated immediately after diagnosis compared to a watchful waiting policy (p = 0.017). Grade IV toxicity was low (4.2%, n = 3) CONCLUSION: SRT is an effective treatment with high local and clinical control. Early SRT resulted in better outcome than late treatment at progression.

Appropriate end-points for right results in the age of antiangiogenic agents: future options for phase II trials in patients with recurrent glioblastoma.

The progression-free survival rate at 6 months (PFS-6) has long been considered the best end-point for assessing the efficacy of new agents in phase II trials in patients with recurrent glioblastoma. However, due to the introduction of antiangiogenic agents in this setting, and their intrinsic propensity to alter neuroradiological disease assessment by producing pseudoregression, any end-point based on neuroradiological modifications should be reconsidered. Further, statistically significant effects on progression-free survival (PFS) only should not automatically be considered reliable evidence of meaningful clinical benefit. In this context, because of its direct and unquestionable clinical relevance, overall survival (OS) represents the gold standard end-point for measuring clinical efficacy, despite the disadvantage that it is influenced by subsequent therapies and usually takes longer time to be evaluated. Therefore, while awaiting novel imaging criteria for response evaluation and/or new imaging tools to distinguish between 'true' and 'pseudo'-responses to antiangiogenic agents, the measurement of OS or OS rates should be considered primary end-points, also in phase II trials with these agents.

Lhermitte sign and myelopathy after irradiation of the cervical spinal cord in radiotherapy treatment of head and neck cancer.

BACKGROUND AND PURPOSE: The goal of this work was to examine toxicity and risk factors after irradiation of the cervical spinal cord. PATIENTS AND METHODS: A total of 437 patients irradiated for a laryngeal and oropharyngeal carcinoma were eligible (median follow-up 27 months). Spinal cord contouring was defined differently over time as anatomically defined spinal cord area (SCA) and the spinal cord on CT (SC) with a margin of 3 or 5 mm (SCP3/SCP5). RESULTS: None developed chronic progressive radiation myelopathy (CPRM) (maximum spinal dose 21.8-69 Gy); 3.9% (17/437) developed a Lhermitte sign (LS) with a median duration of 6 months (range 1-30 months) and was reversible in all patients. Risk factors for developing LS were younger age (52 vs. 61 years, p < 0.001), accelerated RT (12/17 patients, p < 0.005), and dose-volume relationships for SCA with ≥ 45 Gy of 14.15 cm(3) and 7.9 cm(3) for patients with and without LS, respectively. CONCLUSION: LS is more frequently observed in younger patients and in patients treated with accelerated radiotherapy. A dose-volume relationship was seen for V45 in the case of SCA. For higher doses, no clear dose-volume relationships were observed.

Relocatable fixation systems in intracranial stereotactic radiotherapy. Accuracy of serial CT scans and patient acceptance in a randomized design.

PURPOSE: The goal was to provide a quantitative evaluation of the accuracy of three different fixation systems for stereotactic radiotherapy and to evaluate patients' acceptance for all fixations. METHODS: A total of 16 consecutive patients with brain tumours undergoing fractionated stereotactic radiotherapy (SCRT) were enrolled after informed consent (Clinical trials.gov: NCT00181350). Fixation systems evaluated were the BrainLAB® mask, with and without custom made bite-block (fixations S and A) and a homemade neck support with bite-block (fixation B) based on the BrainLAB® frame. The sequence of measurements was evaluated in a randomized manner with a cross-over design and patients' acceptance by a questionnaire. RESULTS: The mean three-dimensional (3D) displacement and standard deviations were 1.16 ± 0.68 mm for fixation S, 1.92 ± 1.28 and 1.70 ± 0.83 mm for fixations A and B, respectively. There was a significant improvement of the overall alignment (3D vector) when using the standard fixation instead of fixation A or B in the craniocaudal direction (p = 0.037). Rotational deviations were significantly less for the standard fixation S in relation to fixations A (p = 0.005) and B (p = 0.03). EPI imaging with off-line correction further improved reproducibility. Five out of 8 patients preferred the neck support with the bite-block. CONCLUSION: The mask fixation system in conjunction with a bite-block is the most accurate fixation for SCRT reducing craniocaudal and rotational movements. Patients favoured the more comfortable but less accurate neck support. To optimize the accuracy of SCRT, additional regular portal imaging is warranted.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Guidelines on management of low-grade gliomas: report of an EFNS-EANO Task Force.

BACKGROUND: Diffuse infiltrative low-grade gliomas of the cerebral hemispheres in the adult are a group of tumors with distinct clinical, histological and molecular characteristics, and there are still controversies in management. METHODS: The scientific evidence of papers collected from the literature was evaluated and graded according to EFNS guidelines, and recommendations were given accordingly. RESULTS AND CONCLUSIONS: WHO classification recognizes grade II astrocytomas, oligodendrogliomas and oligoastrocytomas. Conventional MRI is used for differential diagnosis, guiding surgery, planning radiotherapy and monitoring treatment response. Advanced imaging techniques can increase the diagnostic accuracy. Younger age, normal neurological examination, oligodendroglial histology and 1p loss are favorable prognostic factors. Prophylactic antiepileptic drugs are not useful, whilst there is no evidence that one drug is better than the others. Total/near total resection can improve seizure control, progression-free and overall survival, whilst reducing the risk of malignant transformation. Early post-operative radiotherapy improves progression-free but not overall survival. Low doses of radiation are as effective as high doses and better tolerated. Modern radiotherapy techniques reduce the risk of late cognitive deficits. Chemotherapy can be useful both at recurrence after radiotherapy and as initial treatment after surgery to delay the risk of late neurotoxicity from large-field radiotherapy. Neurocognitive deficits are frequent and can be caused by the tumor itself, tumor-related epilepsy, treatments and psychological distress.

Is there a place for radiotherapy in low-grade gliomas?

The optimal management of supratentorial low-grade glioma remains controversial, and only limited definitive data is available to guide recommendations. Treatment decisions have to take into account both the management of symptoms and of tumour control, and must balance the benefits against the potential for treatment-related complications. Overall outcome is more dependent on patient and tumour-related characteristics such as age, tumour grade, histology and neurological function than treatment. From the pooled analysis of 2 randomized EORTC trials a prognostic score has been derived, median survival is varying from 3.2 to 7.8 years. Radiation therapy is usually the primary treatment modality; however its benefit on initial tumour control may be outweighed by potential late toxicity. To date only 4 large randomized trials in patients with low-grade glioma have been reported. It allows concluding that early radiotherapy does not improve overall survival and supports an initially expectative approach. Similarly, higher radiation doses above 45-50 Gy (fractions of 1.8-2.0 Gy) do not confer a better outcome but may be associated with increased toxicity. The adjuvant use of PCV-chemotherapy in high-risk patients also failed to improve progression-free and overall survival. An ongoing large randomized EORTC/NCIC trial is investigating the primary treatment with temozolomide chemotherapy versus standard radiotherapy in patients "at need for treatment". Tumour material will be collected in all patients, which ultimately may allow identifying on a molecular basis patients for whom one or another treatment strategy may fit best. Irrespective of new chemotherapeutic agents, radiotherapy is also evolving. Highly conformal techniques based on modern imaging as co-registered MRI scans, limiting the amount of normal tissue irradiated without compromising tumour control, will be the future approach in order to reduce neurotoxicity.

Effectiveness of temozolomide for primary glioblastoma multiforme in routine clinical practice.

Temozolomide has been used as a standard therapy for the treatment of newly diagnosed glioblastoma multiforme since 2005. To assess the effectiveness of temozolomide in routine clinical practice, we conducted an observational study at Maastricht University Medical Centre (MUMC). Data of patients receiving radiotherapy and temozolomide between January 2005 and January 2008 were retrieved from a clinical database (radiochemotherapy group), as were data of patients in a historical control group from the period before 2005 treated with radiotherapy only (radiotherapy group). The primary endpoint was overall survival. A total of 125 patients with GBM were selected to form the study cohort. Median survival benefit was 4 months: the median overall survival was 12 months (95% CI, 9.7-14.3) in the group with radiochemotherapy with temozolomide, versus 8 months (95% CI, 5.3-10.7) in the group with only radiotherapy. Progression-free survival was 7 months (95% CI, 5.5-8.5) in the radiochemotherapy group and 4 months (95% CI, 2.9-5.1) in the group with only radiotherapy. The two-year survival rate was 18% with radiochemotherapy with temozolomide against 4% with radiotherapy alone. Concomitant treatment with radiotherapy and temozolomide followed by adjuvant temozolomide resulted in grade III or IV haematological toxic effects in 9% of patients. The addition of temozolomide to radiotherapy in routine clinical practice for newly diagnosed glioblastoma resulted in a clinically meaningful survival benefit with minimal haematological toxicity, which confirms the experience of previous trials and justifies the continued use of temozolomide in routine clinical practice.

A novel technique using customised templates for the application of fractionated interstitial HDR brachytherapy to the tumour bed in soft-tissue sarcomas located in the extremities.

AIMS: Postoperative interstitial brachytherapy of limbs is challenging, because it is difficult to deliver a conformal dose to the tumour bed. We developed and assessed a new surgical fixation system for positioning guiding tubes in interstitial brachytherapy in order to achieve favourable geometry. MATERIALS AND METHODS: A 28-year-old patient was treated with postoperative interstitial brachytherapy boost followed by external radiotherapy after the 11th recurrence of a desmoid tumour in the forearm. On the basis of preoperative imaging data, customised resorbable templates made of polydioxanone (PDS) were cut to fit in the space left by the resected tumour. These were strategically positioned in the tumour bed during surgery. In order to hold the brachytherapy-guiding tubes parallel for the duration of treatment, they were passed through a series of holes bored into the templates. RESULTS: Fixing the guiding tubes with PDS templates resulted in a fixed geometry, and thus in an optimal dose distribution with only little additional dose optimisation needed by the brachytherapy treatment planning system. An optimised dose to the tumour bed, and a reduction of dose to critical normal tissues, is achievable with this template system for sarcomas located between osseous structures. CONCLUSION: The PDS templates offer a more rigid fixation of the guiding tubes in relation to the surrounding anatomy even after the operation cavity has been closed. A tailored dose distribution can be achieved, thus reducing possible side-effects. Additionally, because of the self-resorbable nature of the material, a re-operation for template removal is not necessary. The potential advantages of this method are being further investigated.

Survival and prognostic factors in patients with brain metastases from malignant melanoma.

AIM: We wanted to determine the factors influencing survival in a retrospective review of patients with melanoma brain metastases to permit more specific recommendations regarding therapy. PATIENTS AND METHODS: We reviewed the data of 100 patients treated at the Department of Dermatology and Radiation Oncology, University of Zurich, and the Klinik im Park, Zurich. Information on potential prognostic factors (age, sex, location of the primary tumor, Clark level, Breslow index, histological type, number of brain metastases, stage at initial diagnosis, location of brain metastases, and therapy) was collected from the medical records of 100 patients treated between 1966 and 2002. Univariate and multivariate analyses were performed to identify significant prognostic factors. RESULTS: The overall median survival time was 4.8 months, with 6-month, 1-year and 2-year survival percentages of 36, 14 and 5%, respectively. Univariate analysis indicated that survival correlated significantly with radiotherapy (partial and whole brain), surgery, stereotactic radiosurgery, chemotherapy, Clark level and Breslow index. Treatment with temozolomide (p = 0.052) and number of brain metastases (p = 0.07) failed to be statistically significant. Multivariate analysis confirmed radiotherapy (partial and whole brain), surgery, stereotactic radiosurgery, chemotherapy and the location of brain metastases as independent and significant prognostic factors of survival. The remaining factors did not reach statistical significance in multivariate analysis. CONCLUSION: Radiotherapy, chemotherapy and especially surgery and stereotactic radiosurgery seem to significantly prolong survival, as shown by multivariate analysis. Treatment with temozolomide will possibly play an important role in the future management of patients with brain metastases from cutaneous melanoma, but further prospective studies to verify this assumption are urgently needed.

A comparison of dose distributions of proton and photon beams in stereotactic conformal radiotherapy of brain lesions.

PURPOSE: Micromultileaf collimators (mMLC) have recently been introduced to conform photon beams in stereotactic irradiation of brain lesions. Proton beams and stereotactic conformal radiotherapy (SCRT) can be used to tailor the dose to nonspherical targets, as most tumors of the brain are irregularly shaped. Comparative planning of brain lesions using either proton or stereotactically guided photon beams was done to assess the institution's clinically available modality for three-dimensional conformal radiotherapy. METHODS AND MATERIALS: For the photon treatment, multiple stereotactically guided uniform intensity beams from a linear accelerator were used, each conformed to a projection of the planning target volume (PTV) by a mMLC. Proton beams were delivered from an isocentrically mounted gantry, using the spot-scanning technique and energy modulation. Seven patients were scanned in a stereotactic frame; target volumes and organs at risk (OAR) were delineated with the help of MR images. Four different lesions were selected: (1) concave, (2) ellipsoid isolated, (3) superficial and close to an organ at risk, and (4) irregular complex. Dose distributions in the PTV and critical structures were calculated using three-dimensional treatment-planning systems, followed by both a quantitative (by dose--volume histogram and conformity index) and qualitative (visual inspection) assessment of the plans. RESULTS: A high degree of conformation was achieved with a mMLC and stereotactic uniform intensity beams with comparable conformity indices to protons for 5 out of 7 plans, especially for superficial or spherical lesions. In the cases studied, the conformity index was better for protons than for photons for complex or concave lesions, or when the PTV was in the neighborhood of critical structures. CONCLUSION: The results for the cases studied, show that for simple geometries or for superficial lesions, there is no advantage in using protons. However, for complex PTV shapes, or when the PTV is in the vicinity of critical structures, protons seem to be potentially better than the fixed-field photon technique.