Alyx Porter

Del(6)(q22) and BCL6 Rearrangements in Primary CNS Lymphoma Are Indicators of an Aggressive Clinical Course

PURPOSE Primary CNS lymphoma (PCNSL) is an aggressive lymphoma but clinically validated biologic markers that can predict natural history to tailor treatment according to risk are lacking. Several genetic changes including BCL6 rearrangements and deletion of 6q22, containing the putative tumor suppressor gene PTPRK, are potential risk predictors. Herein we determined the prevalence and survival impact of del(6)(q22) and BCL6, immunoglobulin heavy chain (IGH), and MYC gene rearrangements in a large PCNSL cohort treated in a single center. PATIENTS AND METHODS Interphase fluorescence in situ hybridization was performed using two-color probes for BCL6, MYC, IGH-BCL6, and del(6)(q22) on thin sections of 75 paraffin-embedded samples from 75 HIV-negative, immunocompetent patients newly diagnosed with PCNSL. Survival data were analyzed using Kaplan-Meier survival curves, log-rank tests, and proportional hazards regression adjusting for age, deep structure involvement, and high-dose methotrexate (HDMTX) treatment. RESULTS The prevalence of del(6)(q22) and BCL6, IGH, and MYC translocations was 45%,17%, 13%, and 3%, respectively. The presence of del(6)(q22) and/or a BCL6 translocation was associated with inferior overall survival (OS; P = .0097). The presence of either del(6)(q22) alone or a BCL6 translocation alone was also associated with inferior OS (P = .0087). Univariable results held after adjusting for age, deep structure involvement, and HDMTX. CONCLUSION Del (6)(q22) and BCL6 rearrangements are common in PCNSL and predict for decreased OS independent of deep structure involvement and HDMTX. Unlike systemic diffuse large B-cell lymphoma, del(6)(q22) is common and IGH translocations are infrequent and usually involve BCL6 rather than BCL2, suggesting a distinct pathogenesis.

Primary central nervous system lymphoma can be histologically diagnosed after previous corticosteroid use: a pilot study to determine whether corticosteroids prevent the diagnosis of primary central nervous system lymphoma.

The objective is to determine whether corticosteroid administration before biopsy prevents histopathological diagnosis of primary central nervous system lymphoma (PCNSL). A retrospective review was performed of immunocompetent PCNSL patients from 1985 to 2005. A total of 109 patients was identified. Sixty‐eight (63.6%) patients received corticosteroids before diagnosis. Thirteen patients (of 109; 12%) had undergone repeat brain biopsy to confirm PCNSL. These included 8 (of 68) patients who had received corticosteroids (12%), and 5 (of 39) who had not (13%) (p = 1.0). The majority of PCNSL patients who received corticosteroids before diagnosis did not experience significant radiographic change or require second biopsy for diagnosis. Ann Neurol 2008;63:662–667

Spinal cord astrocytoma presenting as “idiopathic” intracranial hypertension

Increased intracranial pressure is rarely seen in association with spinal tumors. We describe a young, non-obese man who presented with increased intracranial pressure, papilledema and visual obscuration. Multiple cerebrospinal fluid (CSF) examinations with normal or minimally elevated CSF protein lead to the initial diagnosis of idiopathic intracranial hypertension. After a lumboperitoneal shunt placement a progressive thoracic myelopathy developed 7 months after onset of symptoms. The spinal MRI showed a low cervical-upper thoracic intramedullary tumor. Open biopsy confirmed a grade 3 fibrillary astrocytoma. The suspected mechanisms of spinal tumors causing increased intracranial pressure are reviewed as well as three other cases of spinal astrocytomas previously reported in the literature that presented with papilledema and increased intracranial pressure without hydrocephalus. This case illustrates that increased intracranial pressure may in exceptional cases of spinal tumors precede the more typical myelopathic presentation by months and mimic idiopathic intracranial hypertension.

Treatment of Glioma in the 21st Century: An Exciting Decade of Postsurgical Treatment Advances in the Molecular Era

Abstract The past decade has brought about major changes in the way we classify and have begun to approach patients with high‐grade glioma. As we trend toward personalized medicine, we are now able to utilize the molecular characteristics of each individuals tumor in order to tailor their treatment, particularly if the patient is elderly or has a poor performance status at baseline. We address the state of the practice as of 2016 in regard to chemotherapy, immunotherapy, and tumor‐treating fields. The goal of this review is to enhance readers’ understanding of the nuances that are allowing clinicians to tailor the treatment of high‐grade glioma more specifically.

Distinct Phenotypic Clusters of Glioblastoma Growth and Response Kinetics Predict Survival

PURPOSE Despite the intra- and intertumoral heterogeneity seen in glioblastoma multiforme (GBM), there is little definitive data on the underlying cause of the differences in patient survivals. Serial imaging assessment of tumor growth allows quantification of tumor growth kinetics (TGK) measured in terms of changes in the velocity of radial expansion seen on imaging. Because a systematic study of this entire TGK phenotype-growth before treatment and during each treatment to recurrence -has never been coordinately studied in GBMs, we sought to identify whether patients cluster into discrete groups on the basis of their TGK. PATIENTS AND METHODS From our multi-institutional database, we identified 48 patients who underwent maximally safe resection followed by radiotherapy with imaging follow-up through the time of recurrence. The patients were then clustered into two groups through a k-means algorithm taking as input only the TGK before and during treatment. RESULTS There was a significant survival difference between the clusters ( P = .003). Paradoxically, patients among the long-lived cluster had significantly larger tumors at diagnosis ( P = .027) and faster growth before treatment ( P = .003) but demonstrated a better response to adjuvant chemotherapy ( P = .048). A predictive model was built to identify which cluster patients would likely fall into on the basis of information that would be available to clinicians immediately after radiotherapy (accuracy, 90.3%). CONCLUSION Dichotomizing the heterogeneity of GBMs into two populations-one faster growing yet more responsive with increased survival and one slower growing yet less responsive with shorter survival-suggests that many patients who receive standard-of-care treatments may get better benefit from select alternative treatments.

Connecting Patterns of Tumor Growth with Sex Differences in Extreme Survivorship for Primary Glioblastoma Patients

Purpose: Patient sex is recognized as a significant determinant of outcome but the relative prognostic importance of molecular, imaging, and other clinical features of GBM has not yet been thoroughly explored for male versus female patients. Combining multi-modal MR images and patient clinical information, this investigation assesses which pretreatment MRI-based and clinical variables impact sex-specific survivorship in glioblastoma patients. Methods: We considered the multi-modal MRI and clinical data of 494 patients newly diagnosed with primary glioblastoma (299 males and 195 females). Patient MR images (T1Gd, T2, and T2-FLAIR) were segmented to quantify imageable tumor volumes for each MR sequence. Cox proportional hazard (CPH) models and Student’s t-tests were used to assess which variables were significantly associated with survival outcomes. We used machine learning algorithms to develop pruned decision trees to integrate the impact of these variables on patient survival. Results: Among males, tumor (T1Gd) radius was a significant predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p<0.001). Female extreme survivors had significantly smaller tumors (T1Gd) (p=0.010 t-test), but tumor size was not significantly correlated with female overall survival (p=0.955 CPH). Both male and female extreme survivors had significantly lower tumor cell net proliferation rates than patients in other survival groups (M p=0.004, F p=0.001, t-test). Age at diagnosis was a significant predictive factor for overall survival length for both males and females (M HR= 1.030, F HR=1.022). Additional variables like extent of resection, tumor laterality, and IDH1 mutation status were also found to have sex-specific effects on overall survival. Conclusion: The results indicated that some variables, like the tumor cell diffuse invasion rate and tumor size, had sex-specific implications for survival, while other variables, such as age at diagnosis and tumor cell proliferation rate, impacted both sexes in the same way. Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes. The sex differences in the predictive value of these and other variables emphasizes the importance of considering sex as a biological factor when determining patient prognosis and treatment approach.Background Sex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences. Methods Combining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients. Pretreatment MR images of 494 glioblastoma patients (299 males and 195 females) were segmented to quantify tumor volumes. Cox proportional hazard (CPH) models and Student’s t-tests were used to assess which variables were associated with survival outcomes. Results Among males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, p Conclusion Despite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes, which emphasizes the importance of considering sex as a biological factor when determining patient prognosis and treatment approach.

Neuroimaging abnormalities in patients with Cowden syndrome: Retrospective single-center study

Background We retrospectively reviewed the neuroimaging findings of patients with Cowden syndrome and determined their frequency in a single cohort. Methods Electronic medical records were queried from January 1999 to January 2017 to identify patients who fit the clinical criteria for diagnosis of Cowden syndrome with or without a documented PTEN mutation. Patients with brain MRI examinations were then identified. Results We retrospectively identified 44 patients with Cowden syndrome, 22 of whom had neuroimaging for review. Eleven (50%) had Lhermitte-Duclos disease, 4 (18.1%) had meningiomas, 13 (59.1%) had at least one developmental venous anomaly, 3 had cavernous malformations, 2 had evidence of dural arteriovenous fistula, 7 had increased white matter signal abnormalities relative to age (31.8%), 4 had prominent perivascular spaces, cerebellar tonsillar ectopia was present in 7 of 21 (33.3%), and 1 had cortical malformation. Conclusions It is important to recognize that in addition to Lhermitte-Duclos disease, other intracranial findings such as multiple venous anomalies, meningiomas, greater than expected white matter signal abnormality, prominent perivascular spaces, and cortical malformations may warrant a thorough evaluation for Cowden syndrome in the appropriate clinical setting. We further recommend that this broader spectrum of intracranial abnormalities be considered for addition to the Cowden syndrome diagnostic criteria at the time of next revision.

CAR-T cell therapy in neuro-oncology: applications and toxicity

A new era for cancer treatment has been ushered in with the field of cancer immunotherapy. After initial success with systemic malignancies, several of these promising treatments are being investigated for efficacy with primary and secondary brain tumors. Chimeric antigen receptor (CAR) T cells are being studied, both with systemic infusion and direct administration to the tumor and into the cerebrospinal fluid, with promising early results. Systemic CAR-T treatment can have serious systemic and neurological toxicities that are important for the practicing neurologist and neuro-oncologist to know and understand. This review aims to discuss adoptive cell therapies with a focus on CAR-T treatment. We review use of this therapy in brain cancers, particularly malignant glioma, and provide an overview of the toxicity of CAR-T treatment and its appropriate management.

Malignant glial neuronal tumors after west nile virus neuroinvasive disease

West Nile virus (WNV) is a single-stranded RNA flavivirus with tropism for the central nervous system (CNS). On a molecular level, WNV infection results in elevations of pro-inflammatory and tumorigenic protein biomarkers, including S100 calcium binding protein B (S100B), an astrocytic signaling protein affecting intracellular and extracellular functions, and high-mobility group box-1 (HMGB1), a versatile protein with nuclear and extracellular functions.1,2 The effects of S100B and HMGB1 on neurons are transduced by the receptor for advanced glycation end products (RAGE). The pro-inflammatory and tumor-promoting effects of RAGE and its ligands have been reported in many cancers, and have been associated with poor prognosis and tumor aggressiveness.3 The phosphoglycoprotein osteopontin (OPN), a cancer biomarker, may also be elevated in patients with WNV infection.4 OPN has been highlighted in pathways that facilitate tumor cells in resisting apoptosis, evading growth suppressors, avoiding immune destruction, and increasing angiogenesis, resulting in increased tumor aggressiveness.5 These findings suggest interplay between the neurotropic WNV and resulting pro-inflammatory and tumorigenic alteration of cellular signaling pathways.

Analysis of MRI volumetric changes after hypofractionated stereotactic radiation therapy for benign intracranial neoplasms

Purpose To quantitatively assess volumetric changes after hypofractionated stereotactic radiation therapy (HFSRT) in patients treated for vestibular schwannomas and meningiomas. Methods and materials We retrospectively reviewed records of patients treated with HFSRT at our institution from 2002 to 2014. Patients received a median dose of 25 Gy in 5 fractions. After treatment, they underwent clinical and radiologic follow-up with magnetic resonance imaging (MRI) at 3- to 12-month intervals. Gross tumor volume was outlined on each thin slice of contrast-enhanced T1 series before and on each scan after HFSRT. Volumetric changes were calculated and compared with neuroradiologist interpretations. Results Forty-three patients underwent 182 MRI scans. Tumor types included vestibular schwannoma (n = 34) and meningioma (n = 9). Median follow-up time was 29 months. Median gross tumor volume was 3.1 cm3. Local control was 81.4% for the entire cohort at the time of last follow-up. Transient volume expansion was noted in 17 patients (50%) with vestibular schwannoma and 2 (22%) with meningioma. For all patients, transient volume expansion and subsequent regression occurred at a median time of 5.5 and 12 months, respectively. Neuroradiologist agreement with regard to tumor regression, progression, or stability occurred in 155 of 182 total reports (85%). The largest discordance identified was a stable finding on the MRI interpretation when the measured volumetric change exceeded 20% (n = 24 [13%]). Conclusions HFSRT is associated with excellent local control and a low incidence of toxicity. With volumetric MRI measurement, transient volume expansion was a common finding and was associated with temporary adverse effects. Although the neuroradiologist’s interpretation generally agreed with the volumetric MRI measurement, the overall 15% discordance rate emphasizes the potential benefit of considering volumetric measurements, which may help clinicians correlate posttreatment symptoms with MRI findings.