Nonprogrammable Shunts for Communicating Hydrocephalus and Three-Dimensional Volumetry: A Retrospective Analysis.

OBJECTIVE: Although the use of different types of valves has been extensively studied in shunt surgery for communicating hydrocephalus (cHC), a consensus about the valve type remains absent. The objective of this study is to evaluate our results with the primary placement of nonprogrammable valves (NPVs) for this indication. METHODS: We retrospectively analyzed all first NPVs implanted between 2014 and 2020 for cHC. We studied the revision rate, clinical outcome described by modified Rankin Scale (mRS), and radiologic evolution using Evans Index (EI) and ventricular volumes three-dimensional semi-automatic segmentation (vv-3DSAS). RESULTS: Forty-one patients were shunted for posthemorrhagic (61%), posttraumatic (24.4%), and tumoral (14.6%) hydrocephalus. Mean age was 65 years (range, 25-89 years). Overall, 59 procedures were performed including 18 revision surgeries in 12 patients (29.3%). The underlying reasons for first shunt revision were valve type related (valve dysfunction, overdrainage, and underdrainage) and nonvalve type related (malpositioning, infection, and shunt migration). The shunt-related revision rate was 17.1%. Twenty-eight patients (68.3%) had an mRS score improvement of 1 or more points. We found a good correlation between ventricle volumes (VV) and EI and a significant reduction in VV measured by EI and vv-3DSAS was observed. However, the mRS improvement was not correlated with a reduction in ventricle volumes. CONCLUSIONS: Overall, our results in terms of shunt revisions as well as clinical and radiologic evolution are comparable to the literature for NPV. vv-3DSAS can be used and could be useful to detect small changes in VV in patients with cHC.

Pituitary carcinoma - case series and review of the literature.

Although pituitary adenomas (PAs) account for 15% of intracranial tumors, pituitary carcinomas (PCs) are a rare entity. Most commonly, PCs evolve from aggressive PAs invading the surrounding structures and eventually leading to metastatic lesions. Due to the low incidence, the diagnosis and treatment remains challenging. We report a case series of five patients with pituitary carcinoma (PC) treated in our center. At first diagnosis 3 patients had an ACTH-producing adenoma, 1 a prolactinoma and 1 a double secreting adenoma (GH and prolactin). The mean time interval from initial diagnosis to diagnosis of PC was 10.7 years (range 5-20 years). All patients underwent multiple surgical resections and radiotherapy. Four patients were treated with temozolomide for metastatic disease. One patient with concomitant radiochemotherapy for local recurrence. Temozolomide led to a stable disease in 2 patients. One patient had a progressive disease after 9 cycles of temozolomide. In absence of standard treatment, immunotherapy was initiated, resulting in a stable disease. We report five cases of PCs. Three patients obtained a stable disease after tailored multidisciplinary treatment. Additionally, one patient was treated with immunotherapy, opening a new treatment option in PCs. Overall, PCs are rare intracranial neoplasms occurring several years after the initial diagnosis of aggressive PAs. Currently, the absence of predictive factors for an aggressive clinical course, provokes a challenging management.

Randomized Trial Comparing Burr Hole Craniostomy, Minicraniotomy, and Twist Drill Craniostomy for Treatment of Chronic Subdural Hematoma.

BACKGROUND: The mainstay of treatment for symptomatic or large chronic subdural hematoma (CSDH) is surgery, but controversy still exists regarding the best surgical technique. Three different techniques are commonly used: burr hole craniostomy (BHC), minicraniotomy (MC), and twist drill craniostomy (TDC). OBJECTIVE: To determine which surgical technique for drainage of CSDH offers best results. METHODS: We set up a multicenter prospective randomized trial (Comparison of Chronic Subdural Hematoma Treatment [COMPACT] trial) comparing BHC, MC, and TDC for the surgical treatment of CSDH. The primary end point was reoperation rate, and secondary end points included complication rates and clinical outcome. Patients were considered to have good outcome when they did not undergo reoperation, suffered no surgical or medical complication, and had no related mortality. Clinical outcome was also evaluated by evolution of the Markwalder score and the modified Rankin score. RESULTS: Two-hundred forty-five patients were included in the final analysis: 79 BHC, 84 MC, and 82 TDC. Mean duration of surgery was shorter for TDC than for BHC and MC ( P < .001). Reoperation rate was 7.6% for BHC, 13.1% for MC, and 19.5% for TDC ( P = .07). This trend toward better results for BHC was not statistically significant in logistic regression analysis. The proportion of patients with good outcome was 78.5% for BHC group, 76.2% for MC, and 69.5% for TDC ( P = .4). Evolution of the Markwalder score and modified Rankin score were not significantly different between treatment groups. CONCLUSION: All 3 techniques are effective at treating patients with CSDH with eventual 6-month outcome being similar. Although not reaching statistical significance in our study, BHC offers the lowest recurrence rate combined with manageable complication rate.

Quality indicators in neuro-oncology: Review of the literature and development of a new quality indicator set for glioma care through a two-round Delphi survey.

BACKGROUND: Quality Indicators (QIs) are important tools to assess the quality and variability of oncological care. However, their application in neuro-oncology is limited so far. The objective of this study was to develop a set of QIs for glioma, covering process and outcome indicators. METHODS: A systematic review was conducted to identify both QIs in the field of adult glioma care, and guidelines or recommendations that could be translated into QIs. Also reports from national and international healthcare agencies and scientific associations ("grey literature") were taken into account. After conversion of these recommendations into QIs, merging with existing QIs found in the literature and rationalization, a two-round Delphi survey was conducted to gain consensus on relevance for the proposed QIs. RESULTS: In total 240 recommendations and 30 QIs were retrieved from the literature. After conversion, merging and rationalization, 147 QIs were evaluated in the Delphi survey and eventually consensus was gained on 47 QIs in the following 7 domains: Diagnosis and Imaging, Surgery, Pathology, Radio/Chemotherapy, Recurrence, Supportive Treatments (Epilepsy, Thromboembolism, Steroid Use and Rehabilitation) and Survival. CONCLUSION: This study defined a set of 47 QIs for assessing quality of care in adult glioma patients, distributed amongst 7 crucial phases in the patient's care trajectory. These QIs are readily applicable for use in diverse health care systems, depending on the availability of population-based health care data enabling (inter)national benchmarking.

Axitinib plus avelumab in the treatment of recurrent glioblastoma: a stratified, open-label, single-center phase 2 clinical trial (GliAvAx).

BACKGROUND: No treatment demonstrated to improve survival in patients with recurrent glioblastoma (rGB) in a randomized trial. Combining axitinib with the programmed cell death ligand 1 blocking monoclonal antibody avelumab may result in synergistic activity against rGB. METHODS: Adult patients with rGB following prior surgery, radiation therapy and temozolomide chemotherapy were stratified according to their baseline use of corticosteroids. Patients with a daily dose of ≤8 mg of methylprednisolone (or equivalent) initiated treatment with axitinib (5 mg oral two times per day) plus avelumab (10 mg/kg intravenous every 2 weeks) (Cohort-1). Patients with a higher baseline corticosteroid dose initiated axitinib monotherapy; avelumab was added after 6 weeks of therapy if the corticosteroid dose could be tapered to ≤8 mg of methylprednisolone (Cohort-2). Progression-free survival at 6 months (6-m-PFS%), per immunotherapy response assessment for neuro-oncology criteria, served as the primary endpoint. RESULTS: Between June 2017 and August 2018, 54 patients (27 per cohort) were enrolled and initiated study treatment (median age: 55 years; 63% male; 91% Eastern Cooperative Oncology Group Performance Status 0-1). Seventeen (63%) patients treated in Cohort-2 received at least one dose of avelumab. The 6-m-PFS% was 22.2% (95% CI 6.5% to 37.9%) and 18.5% (95% CI 3.8% to 33.2%) in Cohort-1 and Cohort-2, respectively; median overall survival was 26.6 weeks (95% CI 20.8 to 32.4) in Cohort-1 and 18.0 weeks (95% CI 12.5 to 23.5) in Cohort-2. The best objective response rate was 33.3% and 22.2% in Cohort-1 and Cohort-2, respectively, with a median duration of response of 17.9 and 19.0 weeks. The most frequent treatment-related adverse events were dysphonia (67%), lymphopenia (50%), arterial hypertension and diarrhea (both 48%). There were no grade 5 adverse events. CONCLUSION: The combination of avelumab plus axitinib has an acceptable toxicity profile but did not meet the prespecified threshold for activity justifying further investigation of this treatment in an unselected population of patients with rGB.

Focal radiation necrosis of the brain in patients with melanoma brain metastases treated with pembrolizumab.

INTRODUCTION: Up to 60% of patients with metastatic melanoma develop melanoma brain metastasis (MBM) during the course of their disease. Surgery, radiosurgery (SRS), stereotactic radiotherapy (SRT), and whole-brain radiation therapy (WBRT) or combinations of these are commonly used local treatment modalities. Inhibitory monoclonal antibodies against the CTLA-4 and PD-1 immune checkpoint receptors significantly improved the survival of metastatic melanoma patients, including patients with MBM. This prolonged survival, and potentially also the immunostimulatory mechanisms, may expose patients to a higher risk for long-term complications such as focal postradiation necrosis of the brain (RNB). METHODS: We analyzed the incidence of pseudotumoral RNB in a single institution cohort of 142 melanoma patients that were prospectively followed after starting treatment with pembrolizumab in an expanded access program. RESULTS: Of the 142 patients, 43 (30.7%) patients had MBM at initiation pembrolizumab. Of these, 31 (72.1%) were treated with SRS, 8 (18.6%) with WBRT while 4 (9.3%) had no prior local therapy. Of patients treated with RT, 28 (71.1%) received RT before the initiation of pembrolizumab. 5 (12.8%) patients developed a new symptomatic pseudotumoral lesion at a median time of 11.15 months (range 8-46) after the RT. In all patients, the diagnosis of RNB was radiologically confirmed. The RNB was treated with corticosteroids in two patients, bevacizumab in two patients, and surgery in three symptomatic patients. The diagnosis was histologically confirmed in the patients treated with surgery. CONCLUSION: Melanoma patients with MBM treated with radiosurgery and showing a beneficial response to pembrolizumab are at risk for late RNB. In case of suspected isolated progression at the site of a previously irradiated MBM, the diagnosis of RNB should be considered.

Early-Onset Creutzfeldt-Jakob Disease Mimicking Immune-Mediated Encephalitis.

OBJECTIVES: The objective of this study is to explore the clinical, radiological, and pathological manifestations of a rare subtype of prion disease and their implication for differential diagnosis in case of an early onset neuropsychiatric deterioration. METHODS: We discuss a patients' clinical history, as well as the string of investigations and symptomatological evolution that finally led to a pathological diagnosis. RESULTS: Our patient had the extremely rare VV1 type sporadic Creutzfeldt-Jakob disease (sCJD). We explain the differential diagnosis of progressive encephalomyelitis with rigidity and myoclonus and its implications for treatment. CONCLUSION: sCJD, especially the VV1 subtype, can present at an early age with an insidious psychiatric onset. Classical findings of prion disease-14-3-3 protein, PSWC on electroencephalography, and magnetic resonance imaging patterns-are not always present. The presence of neural autoantibodies does not always implicate pathogenicity in the presence of other neurological/neurodegenerative conditions.

Meningoencephaloradiculitis following infection with tick borne encephalitis virus: case report and review of the literature.

Tick borne encephalitis (TBE) is an infectious zoonotic disease caused by an RNA virus that is endemic to Central and Eastern Europe, Russia, and large parts of Asia. The tick borne encephalitis virus (TBEV) is transmitted through the saliva of infected ticks and infected goat milk. In the vast majority of cases, an infection with TBEV has a subclinical course. However, in some cases, it leads to neurological symptoms due to meningitis, meningoencephalitis, meningoencephalomyelitis, or meningoencephaloradiculitis. Here, we present the first case of meningoencephaloradiculitis in Belgium.

Combined VEGFR and CTLA-4 blockade increases the antigen-presenting function of intratumoral DCs and reduces the suppressive capacity of intratumoral MDSCs.

Melanoma brain metastases (MBM) occur in 10% to 50% of melanoma patients. They are often associated with a high morbidity and despite the improvements in the treatment of advanced melanoma, including immunotherapy, patients with MBM still have a poor prognosis. Antiangiogenic treatment was shown to reduce the immunosuppressive tumor microenvironment. Therefore we investigated the effect of the combination of VEGFR- and CTLA-4 blockade on the immune cells within the tumor microenvironment. In this study we investigated the effect of the combination of axitinib, a TKI against VEGFR-1, -2 and -3, with therapeutic inhibition of CTLA-4 in subcutaneous and intracranial mouse melanoma models. The combination of axitinib with αCTLA-4 reduced tumor growth and increased survival in both intracranial and subcutaneous models. Investigation of the splenic immune cells showed an increased number of CD4+ and CD8+ T cells after combination treatment. Moreover, combination treatment increased the number of intratumoral dendritic cells (DCs) and monocytic myeloid-derived suppressor cells (moMDSCs). When these immune cell populations were sorted from the subcutaneous and intracranial tumors of mice treated with axitinib+αCTLA-4, we observed an increased antigen-presenting function of DCs and a reduced suppressive capacity of moMDSCs on a per cell basis. Our results suggest that the combination of antiangiogenesis and checkpoint inhibition can lead to an enhanced antitumor effect leading to increased survival. We found that this effect is in part due to an enhanced antitumor immune response generated by an increased antigen-presenting function of intratumoral DCs in combination with a reduced suppressive capacity of intratumoral moMDSCs.

Bone Marrow Metastases from a 1p/19q Co-deleted Oligodendroglioma - A Case Report.

BACKGROUND: Metastasis of oligodendroglioma outside of the central nervous system (CNS) is a very rare event. CASE: We describe in detail the clinical story of a 50-year-old woman diagnosed with profound pancytopenia and signs of extramedullary hematopoiesis caused by diffuse bone marrow replacement by a metastatic oligodendroglioma. RESULTS: Upon development of pancytopenia, a diagnostic bone marrow examination revealed the presence of metastatic oligodendroglial cells. No others sites of malignant dissemination were found outside the CNS. Despite best supportive care, the patient died three weeks after diagnosis of myelophthisis. CONCLUSION: Extracranial metastases from CNS oligodendroglioma are a very rare event but can be the cause of bone marrow failure.

Disease progression in recurrent glioblastoma patients treated with the VEGFR inhibitor axitinib is associated with increased regulatory T cell numbers and T cell exhaustion.

BACKGROUND: Recurrent glioblastoma is associated with a poor overall survival. Antiangiogenic therapy results in a high tumor response rate but has limited impact on survival. Immunotherapy has emerged as an efficient treatment modality for some cancers, and preclinical evidence indicates that anti-VEGF(R) therapy can counterbalance the immunosuppressive tumor microenvironment. METHODS: We collected peripheral blood mononuclear cells (PBMC) of patients with recurrent glioblastoma treated in a randomized phase II clinical trial comparing the effect of axitinib with axitinib plus lomustine and analyzed the immunophenotype of PBMC, the production of cytokines and expression of inhibitory molecules by circulating T cells. RESULTS: PBMC of 18 patients were collected at baseline and at 6 weeks after initiation of study treatment. Axitinib increased the number of naïve CD8(+) T cells and central memory CD4(+) and CD8(+) T cells and reduced the TIM3 expression on CD4(+) and CD8(+) T cells. Patients diagnosed with progressive disease on axitinib had a significantly increased number of regulatory T cells and an increased level of PD-1 expression on CD4(+) and CD8(+) T cells. In addition, reduced numbers of cytokine-producing T cells were found in progressive patients as compared to patients responding to treatment. CONCLUSION: Our results suggest that axitinib treatment in patients with recurrent glioblastoma has a favorable impact on immune function. At the time of acquired resistance to axitinib, we documented further enhancement of a preexisting immunosuppression. Further investigations on the role of axitinib as potential combination partner with immunotherapy are necessary.

Intratumoral Delivery of TriMix mRNA Results in T-cell Activation by Cross-Presenting Dendritic Cells.

Modulating the activity of tumor-infiltrating dendritic cells (TiDC) provides opportunities for novel cancer interventions. In this article, we report on our study of the uptake of mRNA by CD8α(+) cross-presenting TiDCs upon its intratumoral (i.t.) delivery. We exploited this property to deliver mRNA encoding the costimulatory molecule CD70, the activation stimuli CD40 ligand, and constitutively active Toll-like receptor 4, referred to as TriMix mRNA. We show that TiDCs are reprogrammed to mature antigen-presenting cells that migrate to tumor-draining lymph nodes (TDLN). TriMix stimulated antitumor T-cell responses to spontaneously engulfed cancer antigens, including a neoepitope. We show in various mouse cancer models that i.t. delivery of TriMix mRNA results in systemic therapeutic antitumor immunity. Finally, we show that the induction of antitumor responses critically depends on TiDCs, whereas it only partially depends on TDLNs. As such, we provide a platform and a mechanistic rationale for the clinical testing of i.t. administration of TriMix mRNA.

Sunitinib Malate plus Lomustine for Patients with Temozolomide-refractory Recurrent Anaplastic or Low-grade Glioma.

Tyrosine kinase signaling through the vascular endothelial growth factor receptor 2 (VEGFR2), platelet-derived growth factor receptor- α (PDGFR-α) and KIT cell surface receptors mediates neo-angiogenesis and contributes to cancer cell survival in recurrent anaplastic and low-grade glioma. Thirteen patients with temozolomide-refractory recurrent anaplastic or low-grade glioma were treated with sunitinib malate, a small-molecule tyrosine kinase inhibitor of the VEGFR, PDGFR, and KIT receptors, in combination with lomustine. The most frequent grade 3 and 4 adverse events were fatigue, thrombocytopenia, neutropenia and lymphopenia. The best objective tumor response by Response Assessment in Neuro-Oncology (RANO) criteria was one complete response, one unconfirmed partial response and three cases of stable disease. The median progression-free survival was 1.8 months (95% confidence interval=1.0-2.7 months) with 6-month progression-free survival of 15% (95% confidence interval=0-35%). The median overall survival was 6.7 months (95% confidence interval=0.7-12 months). The investigated combination regimen of sunitinib and lomustine is well-tolerated but insufficiently active to warrant further investigation in an unselected population of patients with temozolomide-refractory recurrent anaplastic and low-grade glioma.

Axitinib increases the infiltration of immune cells and reduces the suppressive capacity of monocytic MDSCs in an intracranial mouse melanoma model.

Melanoma patients are at a high risk of developing brain metastases, which are strongly vascularized and therefore have a significant risk of spontaneous bleeding. VEGF not only plays a role in neo-angiogenesis but also in the antitumor immune response. VEGFR-targeted therapy might not only have an impact on the tumor vascularization but also on tumor-infiltrating immune cells. In this study, we investigated the effect of axitinib, a small molecule TKI of VEGFR-1, -2, and -3, on tumor growth and on the composition of tumor-infiltrating immune cells in subcutaneous and intracranial mouse melanoma models. In vivo treatment with axitinib induced a strong inhibition of tumor growth and significantly improved survival in both tumor models. Characterization of the immune cells within the spleen and tumor of tumor-bearing mice respectively showed a significant increase in the number of CD3+CD8+ T cells and CD11b+ cells of axitinib-treated mice. More specifically, we observed a significant increase of intratumoral monocytic myeloid-derived suppressor cells (moMDSCs; CD11b+Ly6ChighLy6G-). Interestingly, in vitro proliferation assays showed that moMDSCs isolated from spleen or tumor of axitinib-treated mice had a reduced suppressive capacity on a per cell basis as compared to those isolated from vehicle-treated mice. Moreover, MDSCs from axitinib-treated animals displayed the capacity to stimulate allogeneic T cells. Thus, treatment with axitinib induces differentiation of moMDSC toward an antigen-presenting phenotype. Based on these observations, we conclude that the impact of axitinib on tumor growth and survival is most likely not restricted to direct anti-angiogenic effects but also involves important effects on tumor immunity.

AZD1480 delays tumor growth in a melanoma model while enhancing the suppressive activity of myeloid-derived suppressor cells.

AZD1480 is a potent, competitive small-molecule inhibitor of JAK1/2 kinase which inhibits STAT3 phosphorylation and tumor growth. Here we investigated the effects of AZD1480 on the function of different immune cell populations in a melanoma model. When MO4 tumor-bearing mice were treated with AZD1480 we observed a strong inhibition of tumor growth as well as a prolonged survival. Moreover, a significant decrease in the percentage of myeloid-derived suppressor cells (MDSCs) was observed after treatment with AZD1480. However, AZD1480 enhanced the suppressive capacity of murine MDSCs while at the same time impairing the proliferative as well as the IFN-γ secretion capacity of murine T cells. The addition of AZD1480 to co-cultures of human MDSCs and T cells does not affect the suppressive activity of MDSCs but it does reduce the IFN-γ secretion and the proliferative capacity of T cells. We showed that although AZD1480 has the ability to delay the tumor growth of MO4 tumor-bearing mice, this drug has detrimental effects on several aspects of the immune system. These data indicate that systemic targeting of the JAK/STAT pathway by JAK1/2 inhibition can have divergent effects on tumor growth and anti-tumor immune responses.

Symptomatic Histologically Proven Necrosis of Brain following Stereotactic Radiation and Ipilimumab in Six Lesions in Four Melanoma Patients.

Four cases previously treated with ipilimumab with a total of six histologically confirmed symptomatic lesions of RNB without any sign of active tumour following stereotactic irradiation of MBM are reported. These lesions were all originally thought to be disease recurrence. In two cases, ipilimumab was given prior to SRT; in the other two ipilimumab was given after SRT. The average time from first ipilimumab to RNB was 15 months. The average time from SRT to RNB was 11 months. The average time from first diagnosis of MBM to last follow-up was 20 months at which time three patients were still alive, one with no evidence of disease. These cases represent approximately three percent of the total cases of melanoma and ten percent of those cases treated with ipilimumab irradiated in our respective centres collectively. We report this to highlight this new problem so that others may have a high index of suspicion, allowing, if clinically warranted, aggressive surgical salvage, possibly resulting in increased survival. Further studies prospectively collecting data to understand the denominator of this problem are needed to determine whether this problem is just the result of longer survival or whether there is some synergy between these two modalities that are increasingly being used together.

Single-center experience with ipilimumab in an expanded access program for patients with pretreated advanced melanoma.

Ipilimumab, a CTLA-4-blocking monoclonal antibody, improved the overall survival (OS) of advanced melanoma patients treated in prospective clinical trials. We here report a study on the outcome of patients with pretreated advanced melanoma offered ipilimumab (at its licensed dose of 3 mg/kg, every 3 wk for a total of 4 doses) in an expanded access program at a single-center university hospital. Of the 50 patients initiating ipilimumab, 31 patients completed induction therapy and 9 patients were offered reinduction therapy. Most immune-related adverse events were mild and reversible. The best objective response rate by mWHO-criteria included 1 complete response and 4 partial responses (best objective response rate of 10%). Two additional patients obtained a partial response by immune-related response criteria. Median OS was 7 months, with a 1- and 2-year survival rate of 45.2% and 28.8%, respectively. Long-term disease control with ipilimumab was observed in 7 patients of which 4 received reinduction. Baseline serum C-reactive protein (CRP) and the absolute lymphocyte count (ALC) measured on week 6 significantly correlated with OS. In conclusion, in this single-center experience with ipilimumab for advanced pretreated melanoma patients, clinical outcome was comparable with the results of published prospective studies. Reinduction therapy was of importance for maintaining long-term disease control in the majority of responding patients. Baseline CRP and ALC at week 6 deserve further prospective evaluation as prognostic and/or predictive (surrogate) markers.

Patterns of response in patients with pretreated metastatic melanoma who received ipilimumab 3 mg/kg in a European expanded access program: five illustrative case reports.

Ipilimumab 3 mg/kg was the first agent to improve survival of pretreated advanced melanoma patients. Nonconventional response patterns to ipilimumab have been reported widely, but most of these data were from studies with ipilimumab 10 mg/kg. Here, case reports from five patients treated within an expanded access program (EAP) with ipilimumab at its licensed dose of 3 mg/kg illustrate the efficacy of ipilimumab in an expanded access setting and the range of different tumor response patterns encountered. The durable clinical benefit seen in these patients despite the observed atypical response patterns highlights the necessity for comprehensive clinical decision making.

Correlation of EGFR, IDH1 and PTEN status with the outcome of patients with recurrent glioblastoma treated in a phase II clinical trial with the EGFR-blocking monoclonal antibody cetuximab.

Mutation and gene amplification of the epithelial growth factor receptor (EGFR) is one of the most common genetic alterations in glioblastoma (GB). EGFR is, therefore, an attractive molecular target for the treatment of GB. EGFR-targeted therapies however have been largely ineffective in clinical trials. In this study, we investigated the correlation between the EGFR gene amplification status, expression of the EGFR variant III (EGFRvIII) and EGFR variant IV (EGFRvIV) mutations, expression of the phosphatase and tensin homologue gene on chromosome 10 (PTEN) and mutation of the isocitrate dehydrogenase 1 (IDH1) gene and the survival of patients suffering from recurrent glioblastoma who were treated with the EGFR-targeted monoclonal antibody cetuximab in a prospective phase II clinical trial. EGFR amplification was detected in 19 out of 35 GB (54%), EGFRvIII expression in 11 (31.4%) and EGFRvIV expression in 7 (20%). The EGFRvIII and EGFRvIV mutations were exclusively found in GB with EGFR amplification and were almost mutually exclusive with IDH1 mutation (EGFRvIII mutation was found in 1 out of 11 GB with an IDH1 mutation). Patients with an EGFR amplification lacking EGFRvIII expression had a significantly superior progression free survival (PFS) and a numerical better overall survival (OS) following treatment with cetuximab [median PFS 3.03 vs. 1.63 months (p=0.006); median OS 5.57 vs. 3.97 months (p=0.12)]. Within the subgroup of patients with EGFR amplification, patients with EGFRvIII positive glioblastoma had a worse survival [median PFS 1.63 vs. 3.03 months (p=0.01); median OS 3.27 vs. 5.57 months (p=0.08)]. Our observations indicate that the type of EGFR mutation may determine the outcome of GB patients treated with cetuximab. Prospective investigation of both the EGFR amplification and mutation status in clinical trials with EGFR-targeted therapies for GB is indicated.

Radiation necrosis of the brain in melanoma patients successfully treated with ipilimumab, three case studies.

Metastasis to the brain is a frequent event in patients with advanced melanoma. Despite treatment with neurosurgery, pancranial irradiation and high-precision conformal radiotherapy, the prognosis of patients suffering from melanoma brain metastasis has remained very poor. Ipilimumab is a new effective immunotherapy for the treatment of advanced melanoma and has demonstrated activity against brain metastases. We report three patients successfully treated with ipilimumab who subsequently developed focal necrosis of the brain following prior radiotherapy of their melanoma brain metastases. As new active systemic treatment options become available that improve the survival of patients with melanoma brain metastases, adequate diagnosis and management of the late sequela from radiation to the brain is likely to gain importance in the management of these patients.