Adília Hormigo

Long-Term Follow-Up of High-Dose Methotrexate-Based Therapy With and Without Whole Brain Irradiation for Newly Diagnosed Primary CNS Lymphoma

PURPOSE We previously reported a series of patients treated with high-dose methotrexate (MTX) -based chemotherapy, with or without whole brain radiotherapy. The purpose of this report is to update the initial results and provide long-term data regarding overall survival, patterns of relapse, and the risk of treatment-related neurotoxicity. PATIENTS AND METHODS Fifty-seven patients with an average age of 65 and median Karnofsky performance score of 70 were treated; all patients have been observed longitudinally with serial magnetic resonance imaging scans and neurologic examinations. RESULTS The overall median survival was 51 months with a median follow-up of 115 months for surviving patients. Twenty-five patients relapsed or developed progressive disease; median progression-free survival was 129 months. Seventeen patients developed treatment-related neurotoxicity; all but one had received whole brain radiotherapy as a component of treatment. Seventy-four percent of patients younger than 60 years who received both MTX-based chemotherapy and whole brain radiotherapy were alive at last follow-up. Median survival for patients older than 60 years was 29 months regardless of whether or not they received whole brain radiotherapy. CONCLUSION Long-term follow-up of our initial cohort confirms the observation of excellent overall survival, particularly for those patients younger than age 60 at diagnosis. For older patients, it appears to be reasonable to defer whole brain radiotherapy in an effort to minimize treatment-related neurotoxicity.

Randomized Phase II Trial of Chemoradiotherapy Followed by Either Dose-Dense or Metronomic Temozolomide for Newly Diagnosed Glioblastoma

PURPOSE Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM. PATIENTS AND METHODS Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m(2) days 1 to 7 and 15 to 21) or metronomic (50 mg/m(2) continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. RESULTS Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm). CONCLUSION Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.

Ocular presentation of primary central nervous system lymphoma: diagnosis and treatment.

Primary ocular lymphoma (POL), a lymphoma of the globe, is a restricted form of primary central nervous system lymphoma (PCNSL) that often progresses to the brain and meninges; frequently it is misdiagnosed until central nervous system (CNS) lymphoma develops. The optimal treatment has not yet been identified. We retrospectively reviewed the course and the treatment of POL in 31 patients. Seventeen patients were treated for isolated POL (group A) and 14 were treated only after CNS disease was diagnosed (group B). The treatment in both groups consisted of systemic chemotherapy, chemotherapy plus radiotherapy (RT) or RT alone. In group A, nine patients (53%) developed CNS progression and five (29%) had ocular recurrence. In group B, seven (50%) had CNS progression and three (21%) ocular relapse. To control for diagnostic lead time, median survival was calculated from initial ocular symptoms and was 60 months in group A and 35 months in group B (P < 0·05). Ocular lymphoma responds to a variety of therapies but treatment with chemotherapy and/or ocular radiotherapy (ORT) failed to prevent CNS progression. Patients whose ocular disease was identified and treated before CNS progression had a significantly improved survival.

Nuclear localization of anti-Hu antibody is not associated with in vitro cytotoxicity

IgG fractions of sera containing anti-Hu antibodies or control sera were incubated with Hu-positive and Hu-negative cell lines. Anti-Hu IgG specifically localized in the nucleus of Hu-positive cells. Anti-Hu-positive and control sera were incubated with Hu-positive cells and human complement or peripheral blood mononuclear cells. Hu antibody caused neither complement-mediated lysis nor augmented antibody-dependent cell-mediated cytotoxicity. Anti-Hu IgG did not affect proliferation of Hu-positive cells. Anti-Hu antibodies may not play a direct role in tissue injury in patients with paraneoplastic encephalomyeloneuropathy and anti-Hu antibodies.

Phase II Study of Bevacizumab, Temozolomide and Hypofractionated Stereotactic Radiotherapy for Newly Diagnosed Glioblastoma

Purpose: Bevacizumab is associated with decreased vascular permeability that allows for more aggressive radiotherapy schedules. We conducted a phase II trial in newly diagnosed glioblastoma utilizing a novel hypofractionated stereotactic radiotherapy (HFSRT) schedule combined with temozolomide and bevacizumab. Experimental Design: Patients with tumor volume ≤60 cc were treated with HFSRT (6 × 6 Gy to contrast enhancement and 6 × 4 Gy to FLAIR hyperintensity with dose painting) combined with concomitant/adjuvant temozolomide and bevacizumab at standard doses. Primary endpoint was 1-year overall survival (OS): promising = 70%; nonpromising = 50%; α = 0.1; β = 0.1. Results: Forty patients were enrolled (median age: 55 years; methylated MGMT promoter: 23%; unmethylated: 70%). The 1-year OS was 93% [95% confidence interval (CI), 84–100] and median OS was 19 months. The median PFS was 10 months, with no pseudo-progression observed. The objective response rate (ORR) was 57%. Analysis of The Cancer Genome Atlas glioblastoma transcriptional subclasses (Nanostring assay) suggested patients with a proneural phenotype (26%) fared worse (ORR = 14%, vs. 77% for other subclasses; P = 0.009). Dynamic susceptibility-contrast perfusion MRI showed marked decreases in relative cerebral blood volume over time (P < 0.0001) but had no prognostic value, whereas higher baseline apparent diffusion coefficient (ADC) ratios and persistent hypermetabolism at the 6-month FDG-PET predicted poor OS (P = 0.05 and 0.0001, respectively). Quality-of-life (FACT-BR-4) and neuropsychological test scores were stable over time, although some domains displayed transient decreases following HFSRT. Conclusions: This aggressive radiotherapy schedule was safe and more convenient for patients, achieving an OS that is comparable with historical controls. Analysis of advanced neuroimaging parameters suggests ADC and FDG-PET as potentially useful biomarkers, whereas tissue correlatives uncovered the poor prognosis associated with the proneural signature in non–IDH-1–mutated glioblastoma. Clin Cancer Res; 20(19); 5023–31. ©2014 AACR.

Serum YKL-40 is a marker of prognosis and disease status in high-grade gliomas

The objective of this study was to evaluate whether longitudinal levels of serum YKL-40 correlate with disease status or survival in adults with gliomas. Patients with histologically confirmed gliomas were eligible for this longitudinal study. Serum samples were collected prospectively and concurrently with MRI scans at multiple time points during the course of the disease. YKL-40 levels determined by ELISA were correlated with radiographic disease status and survival. We performed a multivariate survival analysis including well-known prognostic factors such as age, performance status, and extent of surgical resection. Three hundred and forty-three patients with gliomas (41 low-grade, 105 anaplastic, and 197 glioblastoma) were accrued. Two-year survival from registration was 29% for glioblastomas, 62% for anaplastic gliomas, and 83% for low-grade gliomas. A total of 1740 serum samples were collected, and 95.6% of samples had matching MRI scans. Serum YKL-40 level was significantly lower in patients with no radiographic disease compared with patients with radiographic disease in both the anaplastic glioma (P= .0008) and the glioblastoma (P= .0006) cohorts. Serum levels of YKL-40 in patients with low-grade gliomas were not associated with radiographic disease status. Increases in YKL-40 were independently associated with worse survival in anaplastic gliomas (hazard ratio [HR] = 1.4, P= .01) and glioblastomas (HR = 1.4, P< .0001). Longitudinal increases in serum YKL-40 are associated with increased risk of death in patients with glioblastomas and anaplastic gliomas. YKL-40 is also a putative indicator of disease status in these patients.

YKL-40 and MMP-9 as serum markers for patients with primary central nervous system lymphoma

To evaluate YKL‐40 and MMP‐9 proteins as tumor biomarkers in serum samples from patients with primary central nervous system lymphoma (PCNSL).

Gemcitabine induced myositis in patients with pancreatic cancer: case reports and topic review

Gemcitabine potential myotoxicity has been described in several cases of radiation recall and in patients treated with gemcitabine alone or in combination with other chemotherapy agents. We report two cases of gemcitabine related myositis identified at our institution, and perform a literature review of cases which meet the criteria for gemcitabine induced myositis associated to either radiation therapy or chemotherapy alone.

A target for antiangiogenic therapy: vascular endothelium derived from glioblastoma.

Glioblastoma is the most frequent primary brain tumor in the adult, accounting for 53.8% of all gliomas (http://www.cbtrus.org), and it is one of the most deadly among all human tumors. Despite aggressive treatment at diagnosis, consisting of resection followed by radiation with concurrent and subsequent adjuvant chemotherapy with temozolomide, the tumor almost invariably recurs or progresses, with a patient median survival of 14.6 mo (1). The hallmark of glioblastoma that distinguishes it from all of the other glial tumors is microvascular proliferation in conjunction with necrosis. Therefore, treatment with antiangiogenic agents holds great promise to block the growth of this most vascularized tumor. The best-known antiangiogenic agents are inhibitors of VEGF-A, an indispensable angiogenic factor during developmental organogenesis and growth of numerous tumors. However, treatment with bevacizumab, a neutralizing antibody to VEGF-A, at relapse only confers transient benefit and a marginal increase in survival, indicating at tumor progression a VEGF-independent angiogenic mechanism of glioblastoma resistance (2). Several mechanisms have been implicated in angiogenesis. One is the sprouting of capillaries from preexisting blood vessels by endothelial proliferation (3). Another is the cooption of preexisting blood vessels by tumor cells, leading to expression of angiopoietin-2 by those vessels’ endothelial cells and tumor cell proliferation, followed later by involution of preexisting vessels in the core of the tumor, massive tumor cell apoptosis, organization of remaining tumor cells into pseudopalisading that resides around areas of necrosis, and tumor rescue at the margins by angiogenesis (4, 5). Expression of HIF-1α and up-regulation of VEGF-A have been identified in hypoxic perinecrotic pseudopalisading tumor cells (4–6). Hypoxia induces elevated levels of VEGF-A (6) and VEGF-A receptors that appear up-regulated in tumor endothelial cells but not in normal brain (7). Another mechanism is the release of angiogenic factors by the tumor that recruit bone marrow-derived endothelial progenitors, hematopoietic stem and progenitor cells that participate in vessel formation (8–10). In PNAS, Soda, Verma, and colleagues reveal a new paradigm for glioblastoma angiogenesis whose main contribution is transdifferentiation of glioblastoma cells into endothelial cells (11) (Fig. 1). Notably, these tumor-derived endothelial cells (TDECs) are refractory to inhibition of both VEGF-A and basic fibroblast growth factor (bFGF, FGF-2) pathways. By mapping GFP+ p53-deficient glioblastoma established in glial-specific Cre mice (GFAP-Cre) (12), Soda et al. find that tumor cells can directly transdifferentiate into CD31+CD34+ endothelial cells that lack VEGF-A receptors (VEGFR), constituting over 20% of total CD31+CD34+ tumor endothelial population. These TDECs are capable of forming patent vessels. Moreover, further analysis by hypoxyprobe unraveled their preferential localization in deep hypoxic areas of the tumors. The hypoxic-associated distribution of TDECs and elevated expression of HIF-1α, a hypoxia-induced transcription factor, indicate the role of hypoxia as the key determinant in forcing putative glioma cells to differentiate into endothelial-like cells.

Internalization of anti-Hu IgG is not Fc gamma receptor mediated

Patients with paraneoplastic subacute sensory neuronopathy or encephalomyelitis associated with small cell lung cancer cells (SCLC) frequently harbor anti-Hu antibodies (also called antineuronal nuclear antibodies type 1) in serum and CSF. [1] These antibodies react with a family of nuclear proteins, with apparent molecular mass ranging from 35 to 45 kD, expressed in neurons and SCLC cells. [2] Anti-Hu antibodies are one example of ANA associated with autoimmune disease. ANA occur in a variety of autoimmune disorders, most classically systemic lupus erythematosus. The ability of these antibodies to interact with nuclear antigens in living cells has been questioned and the relevance of the antibodies to disease production doubted. However, several groups have demonstrated that autoantibodies can penetrate living cells. [3] Anti-Hu IgG penetrates viable Hu-positive SCLC cells and localizes in the nucleus. [4] How this IgG internalizes into the cell and translocates to the nucleus is unknown. Immunocytochemistry, immunoprecipitation, and flow cytometry show no Hu antigen on the cell surface (Lieberman and Hormigo, unpublished data; Posner, personal communication). Alternatively, internalization may be mediated by receptors that recognize the Fc portion of immunoglobulin molecules, the Fc gamma receptors (Fc gamma Rs). Fc gamma Rs comprise a family of molecules within the immunoglobulin superfamily. There are three main classes: Fc gamma RI, Fc gamma RII, and Fc gamma RIII. [5] For example, the internalization of …