Douglas Ney

Combined-Modality Therapy With Radiation and Chemotherapy for Elderly Patients With Glioblastoma in the Temozolomide Era: A National Cancer Database Analysis

IMPORTANCE The optimal management for elderly patients with glioblastoma (GBM) is controversial. Following maximal safe resection or biopsy, accepted treatment paradigms for elderly patients with GBM include combined-modality therapy (CMT) with both radiotherapy (RT) and chemotherapy (CT), RT alone, and CT alone. OBJECTIVE To evaluate the overall survival (OS) outcomes associated with RT, CT, and CMT for elderly patients with GBM in the modern temozolomide era. DESIGN, SETTING, AND PARTICIPANTS In this retrospective cohort study of a prospectively maintained, multi-institutional national cancer registry, the National Cancer Database was queried for elderly patients (≥65 years) with newly diagnosed GBM from January 1, 2005, through December 31, 2011, with complete data sets for RT, CT, tumor resection, Charlson-Deyo comorbidity scores, age, sex, and year of diagnosis. Data analysis was performed from October 2015 through December 2015. INTERVENTIONS Combined-modality therapy, RT, CT. MAIN OUTCOMES AND MEASURES Survival by treatment cohort was estimated using the Kaplan-Meier method and analyzed using the log rank test, univariate and multivariate Cox models, and propensity score-matched analyses. RESULTS A total of 16 717 patients (median [range] age, 73 [65-≥90 y]; 8870 [53%] male) were identified. The median OS by treatment was 9.0 (95% CI, 8.8-9.3) months with CMT (8435 patients), 4.7 (95% CI, 4.5-5.0) months with RT alone (1693 patients), 4.3 (95% CI, 4.0-4.7) months with CT alone (1018 patients), and 2.8 (95% CI, 2.8-2.9) months with no therapy (5571 patients) (P < .001). On multivariate analysis, CMT was superior to both CT alone (hazard ratio, 1.50 [95% CI, 1.40-1.60]; P < .001) and RT alone (hazard ratio, 1.47 [95% CI, 1.39-1.55]; P < .001), whereas no differences were observed between CT alone vs RT alone (P = .60). Propensity score-matched analyses redemonstrated improved OS with CMT over CT alone (P = .002) and RT alone (P < .001); no differences were observed between CT alone vs RT alone (P = .44). On subgroup analyses, a consistent OS advantage was observed with CMT over both CT alone and RT alone across each age stratification (65-69, 70-74, 75-79, and ≥80 years) and among patients treated with or without tumor resection (all P < .001). CONCLUSIONS AND RELEVANCE In this analysis of multimodality therapy for elderly patients with GBM, OS was superior with CMT compared with CT alone and RT alone. Survival was similar between CT alone and RT alone, and both CT alone and RT alone were superior to no therapy. This analysis supports the use of CMT for suitable elderly candidates.

Anti-Ma2 Paraneoplastic Encephalitis in Association with Recurrent Cervical Cancer

Background Paraneoplastic neurological syndromes are rare, and although they are frequently associated with gynecological malignancies, cervical cancer is a rare cause. The symptoms of anti-Ma2 encephalitis are diverse and often present prior to the diagnosis of malignancy. Case Report We report a case of a 37-year-old woman with a history of cervical cancer presenting with unexplained weight gain and vertical supranuclear gaze palsy. Magnetic resonance imaging of the brain revealed lesions within the bilateral hypothalami and midbrain. Anti-Ma2 antibodies were eventually found in the serum, prompting a search for malignancy. Recurrent metastatic cervical cancer was found in the retroperitoneal lymph nodes. Conclusions This is the first report of cervical cancer in association with anti-Ma2 encephalitis, and highlights the need for a high degree of suspicion in patients with a cancer history presenting with neurological symptoms. The symptoms associated with anti-Ma2 encephalitis are diverse and typically precede the diagnosis of cancer in patients, and should trigger a search for an underlying malignancy.

The Impact of Adjuvant Radiation Therapy for High-Grade Gliomas by Histology in the United States Population

PURPOSE To compare the survival impact of adjuvant external beam radiation therapy (RT) for malignant gliomas of glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO), and mixed anaplastic oligoastrocytoma (AOA) histology. METHODS AND MATERIALS The Surveillance, Epidemiology, and End Results (SEER) database was queried from 1998 to 2007 for patients aged ≥18 years with high-grade gliomas managed with upfront surgical resection, treated with and without adjuvant RT. RESULTS The primary analysis totaled 14,461 patients, with 12,115 cases of GBM (83.8%), 1312 AA (9.1%), 718 AO (4.9%), and 316 AOA (2.2%). On univariate analyses, adjuvant RT was associated with significantly improved overall survival (OS) for GBMs (2-year OS, 17% vs 7%, p<.001), AAs (5-year OS, 38% vs 24%, p<.001), and AOAs (5-year OS, 55% vs 44%, p=.026). No significant differences in OS were observed for AOs (5-year OS, with RT 50% vs 56% without RT, p=.277). In multivariate Cox proportional hazards models accounting for extent of resection, age, sex, race, year, marital status, and tumor registry, RT was associated with significantly improved OS for both GBMs (HR, 0.52; 95% CI, 0.50-0.55; P<.001) and AAs (HR, 0.57; 95% CI, 0.48-0.68; P<.001) but only a trend toward improved OS for AOAs (HR, 0.70; 95% CI, 0.45-1.09; P=.110). Due to the observation of nonproportional hazards, Cox regressions were not performed for AOs. A significant interaction was observed between the survival impact of RT and histology overall (interaction P<.001) and in a model limited to the anaplastic (WHO grade 3) histologies. (interaction P=.024), characterizing histology as a significant predictive factor for the impact of RT. Subgroup analyses demonstrated greater hazard reductions with RT among patients older than median age for both GBMs and AAs (all interaction P≤.001). No significant interactions were observed between RT and extent of resection. Identical patterns of significance were observed for cause-specific survival and OS across analyses. CONCLUSIONS In this large population-based cohort, glioma histology represented a significant predictor for the survival impact of RT. Adjuvant RT was associated with improved survival for AAs, with benefits comparable to those observed for GBMs over the same 10-year interval. No survival advantage was observed with adjuvant RT for AOs.

Intraventricular Meningioma After Cranial Irradiation for Childhood Leukemia

Meningiomas are among the most common brain tumors in adults. They are most commonly located over the cerebral convexities and are infrequently found in an intraventricular location. Ionizing cranial radiation is a risk factor for late occurrence of meningiomas within the radiation field. While pathologic grading of meningiomas is straightforward, significant variability often exists between pathologists in applying standard grading criteria. This has implications for prognosis. Radiation-induced meningiomas may also have predilection to recur. The authors describe a case of an intraventricular meningioma occurring 23 years after cranial irradiation for childhood acute lymphoblastic leukemia.

Primary CNS plasmablastic lymphoma in an HIV/EBV negative patient: A case report.

Dear Editor, A 39-year-old Hispanic man without a significant past medical history was admitted to the hospital with a 6-day history of progressive left hemiparesis. He reported persistent headaches during the prior six months. On admission, the patient was alert and oriented. His physical examination was significant for hyper-reflexia and mild left side weakness without other associated neurological symptoms. Contrast-enhanced brain magnetic resonance imaging (MRI) revealed a right frontal lobe enhancing mass, measuring 40 mm 3 24 mm 3 24 mm with surrounding edema (Fig. 1A). He was taken to surgery where the H&E-stained imprint cytology and frozen section of intraoperative specimen revealed the presence of large tumor cells with morphologic features of plasmablast with eosinophilic cytoplasm and eccentric large nuclei with prominent nucleoli (Fig. 1B). Immunophenotypic studies of brain biopsy, using flow cytometry (FACSCanto ll flow cytometer (BDB), and Infinicyt software program (Cytognos, V1.4)) detected 92% of Lambda-restricted B-cells (Fig. 1C) that were CD202 (Fig. 1D), CD52, CD32, CD381 (Fig. 1E), CD101, CD451, CD191, BCL21. A diagnosis of plasmablastic lymphoma was then considered. The formalin-fixed paraffin-embedded tissue sections showed diffuse infiltration by cells with similar morphological characteristics of the intraoperative specimen (Fig. 1F). Immunohistochemical analysis revealed that tumor cells were CD20 (Fig. 1G) and ALK negative and showed strong positivity with CD138, MUM-1, CD38, CD10, MYC, and p53, (Figs. 1H–K), with a high index of proliferation of 80% (Fig. 1L) confirming plasmablastic lymphoma (PBL). Immunostains for HHV-8, cytomegalovirus, Simian virus 40, and in situ hybridization for Epstein– Barr virus (EBV) were negative (Fig. 1M). Fluorescence in situ hybridization (FISH) for MYC/IGH t (8;14) (q24;q32) was positive in tumor cells (Fig. 1N) and translocation t(14; 18) (q32; q21) was not detected (Vysis-Abbott) (Fig. 1O). Cerebrospinal fluid (CSF) cytology showed the presence of plasmablastic tumor cells (Fig. 1P) and flow cytometry stabilized with Transfix CSF identified 83.8% (98 cells/mL) of monoclonal B-cell population with immunophenotypic similar characteristics of the tumor cells of brain biopsy (Figs. 1Q–T). Staging with 18-FDG PET/CT (fluorodeoxyglucose positron emission tomography/computer tomography) was negative for other sites of involvement. Bone marrow histological examination and flow cytometry did not show involvement by lymphoma. HIV testing was negative. Serologies for hepatitis B, C, and Cytomegalovirus, were negative. The final diagnosis was a primary central nervous system plasmablastic lymphoma (PCNSPBL) in an immunocompetent patient. The patient received five cycles of systemic high-dose methotrexate (HD-MTX) with leucovorin rescue, cytarabine, and intrathecal methotrexate followed by whole brain radiation therapy. After 11 months the patient was alive, without neurological deficits. The MRI and CSF cytology were negative at this time (Fig. 1U); although the CFS flow cytometry showed 1.7% (0.1 cells/uL) of Lambda-restricted B-cells, CD202, CD451, CD381,CD191, CD101 (Figs. 1V–Y). Primary central nervous system lymphoma (PCNSL) is a rare brain tumor that accounts for 2–3% of all cases of non-Hodgkin’s lymphoma. It is limited to the brain parenchyma, intraocular compartment, cranial nerves, leptomeninges, and spinal cord. It is associated with a poor prognosis with a median survival of 14 and 2 months for immunocompetent and HIV-positive patients respectively. Approximately, 95% of PCNSL tumors are diffuse large B-cell lymphoma (DLBCL); and less commonly T-cell, *Correspondence to: Martha Romero, Fundaci on Santa Fe de Bogot a, Calle 119 No. 7-75, Bogot a, Colombia. E-mail: sanmalili@yahoo.com.ar § Both authors contributed equally to this work. Received 26 March 2015; Revised 21 August 2015; Accepted 24 September 2015 DOI: 10.1002/dc.23374 Published online 15 October 2015 in Wiley Online Library (wileyonlinelibrary.com).

Quality improvement in neurology: Neuro-oncology quality measurement set

Over 78,000 new CNS tumors are diagnosed each year in the United States, nearly one-third of which are primary malignant brain tumors,1 and the US prevalence of primary brain tumors is approximately 688,000.2 While primary CNS neoplasms represent only 1.4% of new cancer diagnoses, approximately 2.7% of cancer deaths are related to CNS neoplasms,3 and it is estimated that 16,947 deaths will result from primary CNS tumors in 2017.1 Population-based studies have shown that socioeconomic disparities are present within the neuro-oncology community,4–7 highlighting the need for a unified system of quality metrics in this growing field. Toward this end, several authors have published work on quality-based practice and on the inclusion of patient-reported outcomes in brain tumor care.8–12

Prominent Vascular and Perivascular Eosinophilic Infiltrates Heralding CNS Mycosis Fungoides

Brain parenchymal involvement of mycosis fungoides (MF) is very rare. This study reports a patient with known cutaneous MF (under treatment) who presented with a CNS syndrome and multiple brain lesions. Brain biopsy demonstrated massive eosinophilic infiltrates but no MF cells. Despite treatment, new lesions developed and the patient died. At autopsy, there was massive involvement MF cells, suggesting that the eosinophilic infiltrates presaged the severe involvement of the CNS by MF.

The Neurologic Assessment in Neuro-Oncology (NANO) Scale as an Assessment Tool for Survival in Patients With Primary Glioblastoma

BACKGROUND The Neurologic Assessment in Neuro-Oncology (NANO) scale is a standardized objective metric designed to measure neurological function in neuro-oncology. Current neuroradiological evaluation guidelines fail to use specific clinical criteria for progression. OBJECTIVE To determine if the NANO scale was a reliable assessment tool in glioblastoma (GBM) patients and whether it correlated to survival. METHODS Our group performed a retrospective review of all patients with newly diagnosed GBM from January 1, 2010, through December 31, 2012, at our institution. We applied the NANO scale, Karnofsky performance score (KPS), Eastern Cooperative Oncology Group (ECOG) scale, Macdonald criteria, and the Response Assessment in Neuro-Oncology (RANO) criteria to patients at the time of diagnosis as well as at 3, 6, and 12 mo. RESULTS Initial NANO score was correlated with overall survival at time of presentation. NANO progression was correlated with decreased survival in patients at 6 and 12 mo. A decrease in KPS was associated with survival at 3 and 6 mo, an increase in ECOG score was associated only at 3 mo, and radiological evaluation (RANO and Macdonald) was correlated at 3 and 6 mo. Only the NANO scale was associated with patient survival at 1 yr. NANO progression was the only metric that was linked to decreased overall survival when compared to RANO and Macdonald at 6 and 12 mo. CONCLUSION The NANO scale is specific to neuro-oncology and can be used to assess patients with glioma. This retrospective analysis demonstrates the usefulness of the NANO scale in glioblastoma.

Quality improvement in neurology: Neuro-Oncology Quality Measurement Set

Over 78,000 new central nervous system (CNS) tumors are diagnosed each year in the United States, nearly one-third of which are primary malignant brain tumors,1 and the US prevalence of primary brain tumors is approximately 688,000.2 While primary CNS neoplasms represent only 1.4% of new cancer diagnoses, approximately 2.7% of cancer deaths are related to CNS neoplasms,3 and it is estimated that 16,947 deaths will result from primary CNS tumors in 2017.1 Population-based studies have shown that socioeconomic disparities are present within the neuro-oncology community,4–7 highlighting the need for a unified system of quality metrics in this growing field. Toward this end, several authors have published work on quality-based practice and on the inclusion of patient reported outcomes in brain tumor care.8–12 During the launch of AAN’s Axon Registry®, the American Academy of Neurology (AAN) requested that subspecialty societies identify gaps in subspecialty care amenable to clinical quality measure development, and work to identify ways the AAN could help meet those needs. Thereafter, the AAN and the Society for Neuro-oncology (SNO) identified a small work group to determine neuro-oncological gaps in care, to evaluate supporting evidence for clinical practice standards, and to develop feasible clinical quality measures to address these areas. The hope is that these measures will help drive clinical practice improvement and better patient outcomes.