CNS Dissemination Research Articles

STAT1 signaling is essential for protection against Cryptococcus neoformans infection in mice.

Nonprotective immune responses to highly virulent Cryptococcus neoformans strains, such as H99, are associated with Th2-type cytokine production, alternatively activated macrophages, and inability of the host to clear the fungus. In contrast, experimental studies show that protective immune responses against cryptococcosis are associated with Th1-type cytokine production and classical macrophage activation. The protective response induced during C. neoformans strain H99γ (C. neoformans strain H99 engineered to produce murine IFN-γ) infection correlates with enhanced phosphorylation of the transcription factor STAT1 in macrophages; however, the role of STAT1 in protective immunity to C. neoformans is unknown. The current studies examined the effect of STAT1 deletion in murine models of protective immunity to C. neoformans. Survival and fungal burden were evaluated in wild-type and STAT1 knockout (KO) mice infected with either strain H99γ or C. neoformans strain 52D (unmodified clinical isolate). Both strains H99γ and 52D were rapidly cleared from the lungs, did not disseminate to the CNS, or cause mortality in the wild-type mice. Conversely, STAT1 KO mice infected with H99γ or 52D had significantly increased pulmonary fungal burden, CNS dissemination, and 90-100% mortality. STAT1 deletion resulted in a shift from Th1 to Th2 cytokine bias, pronounced lung inflammation, and defective classical macrophage activation. Pulmonary macrophages from STAT1 KO mice exhibited defects in NO production correlating with inefficient inhibition of fungal proliferation. These studies demonstrate that STAT1 signaling is essential not only for regulation of immune polarization but also for the classical activation of macrophages that occurs during protective anticryptococcal immune responses.

357PD - Determinants of Central Nervous System (Cns) Metastases in a Cohort of 620 Early Breast Cancer Patients After 11 Years Follow Up: Role of Disseminated Tumor Cell (Dtc) in Bone Marrow (Bm) Detected at Primary Diagnosis

ABSTRACT Aim: BM DTC detection is known to be a prognostic factor for distant metastasis and overall survival in early breast cancer. However, distant relapses may occur in patients with no DTC detected at time of primary cancer. In this study, we studied the impact of early breast cancer pathological features (including BM DTC status) on the incidence of CNS metastases. Methods: In a cohort (1998-2005) of 620 early breast cancer patients in whom BM DTC were detected using an anti-cytokeratin antibody (A45B/B3), 137 had a later metastatic relapse (median follow up 11y). Chi2 test were performed to compare patient with CNS metastasis and patients with other metastases locations. CNS metastasis survivals were estimated using Kaplan-Meier method and compared by log-rank test. Results: Distant metastases were diagnosed in 137 (22%) patients. In the course of the metastatic disease, 55 of these patients (40%) have been diagnosed with CNS metastases (parenchymal = 30, leptomeningeal = 10, both localizations = 15), as first metastatic or later event. Patients with CNS metastasis were mostly less than 50 years old (60% vs 38%, p = 0.01), pN0 (31% vs 10%, p = 0.002), hormonal receptor status negative (54% vs 30%, p = 0.007) and HER2 status positive (50% vs 22%, p = 0.01). Strikingly, although DTC detection was associated with development of distant metastasis in the whole cohort, the occurrence of CNS metastasis was found to be higher in patients who had no DTC detected at primary diagnosis (p = 0.016). From CNS metastasis, median survival was 7.8 months (8.3 months for parenchymal and 2.4 months for leptomeningeal recurrences). For HER2+ patients, the median survival after diagnosis of CNS metastasis was 16.6 months (N = 15) and 4.1 months for Her2- patients (N = 15). Conclusions: Our study suggests that cancer cells with epithelial differentiation, as detected in the BM, are less prone to CNS dissemination. This study also confirmed previously reported determinants of CNS metastases (age, RH-, HER2+) in the pre-adjuvant trastuzumab era, but also showed that the outcome of HER2+ patients with CNS relapse was longer, probably due to HER2 targeted therapy during metastatic course. Disclosure: All authors have declared no conflicts of interest.

The risk of CNS involvement in aggressive lymphomas in the rituximab era

The risk of CNS dissemination and CNS prophylaxis strategies in aggressive non-Hodgkin lymphoma (NHL) is still debated. CNS dissemination is a rare but fatal event. A CNS prophylaxis is common for Burkitt and B-cell lymphoblastic lymphoma; however, in other NHLs, prophylactic treatments are not systematically warranted. Current risk models showed low sensitivity in predicting CNS involvement, implying overtreatment in roughly 70% of high-risk patients. Risk models in the rituximab era were modulated for the detection of occult CNS disease at diagnosis using flow cytometry. The optimal regimen for CNS prophylaxis in aggressive lymphoma patients has not been established thus far and should be modulated at different levels of ‘intensity’ such as standard intrathecal chemotherapy, ‘active’ intrathecal chemotherapy with liposomal cytarabine or more aggressive systemic treatment with high doses of drugs having good CNS bioavailability reserved for patients who are truly at high risk of CNS dissemination.

Novel Intracranial Xenografts Of CNS Lymphoma Implicate a Role For Cereblon As a Mediator Of Lenalidomide Efficacy

BackgroundCNS manifestations of aggressive non-Hodgkin Lymphoma are associated with serious morbidity and adverse prognosis. Primary CNS lymphomas (PCNSL) exhibit a dichomatous growth pattern, either dissemination within brain, typical at presentation, and/or leptomeningeal spread, common at relapse. Elucidation of the mechanistic basis of CNS lymphoma progression as well as drug resistance requires preclinical models that recapitulate their pathogenesis. MethodsWe developed a novel method to derive cell lines of CNS lymphoma that recapitulate disease phenotypes upon intracranial implantation into mice. We are applying genomics, in vitrochemotaxis, preclinical testing of targeted therapies and neuroimaging to evaluate mechanisms of invasion and resistance. ResultsWe developed 7 CNS lymphoma cell lines; 6 DLBCL (all ABC-type), 1 Burkitt; 5 from secondary CNS lymphoma (SCNSL), and 2 from PCNSL, of which 1 was treatment naïve. Intracranial implantation of lymphoma cells from these tumours within NSG mice provides a reproducible model to dissect the pathogenesis of CNS lymphomas. PCNSL specimens were 10X more efficient in CNS dissemination than SCNSL. High resolution array-CGH demonstrated that intracranial tumour growth was associated with retention of genomic aberrations of the original tumours (e.g. del 6q, gains on 12, etc) and that these were maintained with serial passage in vivo. CNS-infiltrative lymphomas expressed significantly increased levels of MMP-7 and RGS-13 transcripts compared to lymphomas that did not infiltrate brain, while osteopontin and cathepsin D expression by lymphoma cells did not correlate with CNS invasion. Targeted shRNA-mediated knockdown of RGS-13 was performed using lentiviral infection and resulted in significant delay of CNS lymphoma growth in vivo in a xenograft model but had no effect on lymphoma proliferation in culture. Therapeutic response to lenalidomide, minus and plus rituximab, was recapitulated in RAG-/- mice, despite deficient T-cell function and correlated with baseline relative cereblon expression, as quantified using a highly specific immunohistochemical assay. The emergence of resistance to lenalidomide in human CNS lymphoma xenografts also correlated with loss of cereblon protein expression, supporting a role for cereblon in the efficacy of lenalidomide in CNS lymphomas. Notably, significant cereblon protein expression by lymphoma cells was detected by immunohistochemistry in 12/22 diagnostic specimens of aggressive CNS lymphoma. Metabolic imaging of model CNS lymphomas using magnetic resonance spectroscopy demonstrated significant intratumoural lactate production in the microenvironment, detectable before evidence of aberrant T2 signal and reduced diffusion. Lenalidomide reduced tumour expression of lactate dehydrogenase and lactate, as well as RGS-13, consistent with anti-proliferative as well as anti-invasive effects. ConclusionsTo the best of our knowledge we have developed the first panel of patient-derived CNS lymphoma cell lines. We have used these to generate intracranial xenografts that provide a highly reproducible model system to dissect key elements of CNS lymphoma pathogenesis, leading to the elucidation of mechanisms of CNS lymphoma growth and invasion as well as resistance. Our results support a direct, T-cell independent effect of lenalidomide on CNS lymphoma growth and invasion which may be cereblon-dependent. Additional studies are needed to define the role of cereblon as a biomarker and mediator of lenalidomide efficacy in CNS lymphomas. In addition, we are using these models to identify novel genomic and metabolic aberrations predictive of early resistance to lenalidomide and other targeted therapies. Supported by the Lymphoma Research Foundation, Leukemia and Lymphoma Society, and by NIH R01CA139-83-01A1. Disclosures:Heise:Celgene: Employment, Equity Ownership. Rubenstein:Celgene: Research Funding; Genentech: Research Funding. Off Label Use: use of lenalidomide in CNS lymphoma.

Risk-Tailored CNS Prophylaxis In 194 Patients With Diffuse Large B-CELL Lymphoma (DLBCL) Treated In The Rituximab ERA: Risk Definition By Clinical Variables and Ontogenic Stratification

BackgroundCNS dissemination is an uncommon but lethal event in non-Hodgkin lymphomas. Early detection of CNS disease and a timely and effective CNS prophylaxis are the main strategies to reduce related mortality. However, both the criteria for recognition of lymphoma patients (pts) with increased risk of CNS involvement and the most effective prophylaxis modality remain important, unmet clinical needs. Some international guidelines recommend intrathecal chemotherapy by lumbar injection as exclusive prophylaxis; however, this strategy results in erratic, short-lived drug bioavailability and does not prevent brain parenchymal relapses. Herein, we report a retrospective analysis of the value of clinical variables and immunohistochemical ontogenic stratification in predicting CNS dissemination and of risk-tailored CNS prophylaxis in a mono-institutional series of 194 pts with DLBCL treated in the rituximab era. MethodsConsecutive HIV- adults with DLBCL without CNS involvement at diagnosis treated with first-line rituximab-CHOP or similar ± radiotherapy were considered. Primary CNS, mediastinal and cutaneous leg-type lymphomas were excluded. ‘High risk' of CNS relapse was defined by the involvement of the testis, spine, skull, orbit, nasopharynx, kidney, and/or breast or by IPI ≥2 (including two among extranodal sites ≥2, advanced stage and high serum LDH). DLBCLs were ontogenically subclassified in ‘germinal-centre B-cell-like' (GCB) and ‘non-germinal-centre B-cell-like' (non-GC) by immunohistochemistry following the Hans algorithm. Results194 patients were analyzed (median age 65, range 18-89; M:F ratio 1.1). Risk of CNS relapse was low in 90 pts and high in 104. Low-risk pt did not receive CNS prophylaxis, while 40/104 (38%) high-risk pts received 3-4 courses of methotrexate 3 g/m2 ± intrathecal (IT) liposomal cytarabine (n=30), cytarabine 16 g/m2 in 4 days (n=2) or IT chemotherapy (n=8). In the high-risk group, IPI ≥2 was more common among pts who did not receive prophylaxis (89% vs. 68%; p=0.006), while “high-risk” extranodal lymphomas were more common among pts who did (88% vs. 33%; p= 0.0001). One hundred and forty-one cases were assessable for Hans algorithm: 74 (52%) were GCB and 67 (48%) were non-GCB DLBCL. GCB DLBCLs were significantly associated with low CNS risk (55% vs. 31%; p= 0.004), and normal LDH levels (57% vs. 36%; p= 0.02); ontogenic stratification was not associated with high-risk extranodal sites, IPI ≥2, bone marrow infiltration, stage and systemic symptoms.After first-line treatment, 160 pts achieved a CR (82%; 95%CI= 77-87%), 34 pts had PD. At a median follow-up of 60 months (13-156), a single low-risk pt and 9 high-risk pts (1% vs. 9%; p= 0.016) experienced CNS relapse (exclusive site in all cases; brain in 5 pts, meninges in 5), with a median TTP of 12 months (7-55). CNS relapses occurred in 3 pts with IPI ≥2, in 1 pt with extranodal disease (testis) and in 5 pts with both features (kidney 3; testis, orbit). Ontogenic stratification was not associated with CNS recurrence, which was 5% for GCB and 6% for non-GCB; these figures were confirmed when analysis was limited to high-risk pts managed without prophylaxis.In the high-risk group, CNS relapses occurred in 7/64 (11%) pts who did not receive prophylaxis, in 2/8 (25%) pts who received only IT chemotherapy, whereas no CNS relapses were detected in the 32 pts treated with intravenous (IV) prophylaxis. CNS relapse rate was 13% for pts treated with “inadequate” prophylaxis (none or IT only) and 0% (p= 0.03) for pts managed with IV prophylaxis.Eight pts with CNS relapses died of lymphoma after 7-37 months (median 12), which represented 28% of all lymphoma-related deaths (n=29) in the high-risk group. Pts treated with IV prophylaxis had a significantly better OS than the other high-risk pts (5-yr: 94 ± 7% vs. 49 ± 6%; p= 0.001). ConclusionsStratification by specific extranodal sites and IPI is superior to ontogenic stratification to recognize CNS risk groups in DLBCL. However, the low sensitivity of predictive clinical variables suggests that molecular studies focused on the predictive and pathogenic role of molecules involved in CNS tropism will contribute to a more accurate definition of lymphoma candidates for CNS-directed strategies. In this context, IV high-dose methotrexate-based prophylaxis may significantly reduce CNS failures in high-risk pts. Disclosures:No relevant conflicts of interest to declare.

Alternating intra‐arterial and intravitreal chemotherapy for advanced intraocular retinoblastoma: First successful results without systemic chemotherapy

AbstractPurpose Background: To describe the efficacy of intra‐arterial chemotherapy combined with intravitreal chemotherapy for the treatment of advanced stage retinoblastomaMethods The Authors report the medical records of four patients who presented with unilateral retinoblastoma, (Reese‐Ellsworth stage Vb/ group D of ABC Classification in the affected eye). They underwent clinical and ophthalmoscopic evaluation and MRI to exclude local and CNS dissemination. All 4 patients received 2 cycles (six infusions) of intrarterial chemotherapy (4‐5 mg of melphalan/0.3‐0.4 mg of topotecan), and from 7 up to 9 melphalan injections into the vitreous (10‐30μg in 0.05 mL).Results Successful control of tumor masses and vitreous seeds was achieved in all cases at long‐term (> 6 months) follow‐up. Tumor control was 100% in all cases. Complications included: posterior lens opacities, acute ischemic papillitis, transient hypotonia, vitreous hemorrhage. There were no cases of orbital tumor recurrence or metastasis (follow‐up range, 6 – 12 months).Conclusion Sequential intra‐arterial chemotherapy and intravitreal melphalan for advanced retinoblastoma allowed to provide retinal and vitreous seed control

The role of Notch signaling in host defenses to Cryptococcus neoformans (P3310)

Abstract Cryptococcus neoformans (C. neoformans) is a major opportunistic fungal pathogen in individuals with impaired T cell-mediated immunity. Notch pathway is an important signaling component of immunological synapse during APC/T-cell engagement. Little is known about the role of Notch signaling in fungal infections. We sought to determine the role of Notch signaling in C. neoformans infection. Wild-type C57BL/6 (WT) and CD4-Cre+×ROSA DNMAML (DNMAML) mice were infected intratracheally infected with C. neoformans. The fungal burden, leukocyte recruitment, and cytokine profile were assessed at 3 and 6 weeks post-infection (wpi). A 50-fold greater fungal burden was detected in both lungs and brains of DNMAML mice compared to those in the WT mice at 6 wpi. Although, equivalent fungal burdens were found at 3 wpi in WT and DNMAML groups, the production of IFN-γ, IL-4, and IL-13 was significantly decreased in lung leukocytes of DNMAML mice. In contrast, an equivalent induction of IL-17 was observed in both WT and DNMAML mice at this time. Notch signaling plays a crucial role in the host defense against C. neoformans. Notch signaling contributes to control of pulmonary fungal growth and inhibition of CNS dissemination by promoting cytokine induction. This is the first demonstration of the importance of Notch signaling in cryptococcal infection. The mechanisms by which Notch signaling regulate the immune response against cryptococcal infection are under investigation.

Immune Modulation Mediated by Cryptococcal Laccase Promotes Pulmonary Growth and Brain Dissemination of Virulent Cryptococcus neoformans in Mice

C. neoformans is a leading cause of fatal mycosis linked to CNS dissemination. Laccase, encoded by the LAC1 gene, is an important virulence factor implicated in brain dissemination yet little is known about the mechanism(s) accounting for this observation. Here, we investigated whether the presence or absence of laccase altered the local immune response in the lungs by comparing infections with the highly virulent strain, H99 (which expresses laccase) and mutant strain of H99 deficient in laccase (lac1Δ) in a mouse model of pulmonary infection. We found that LAC1 gene deletion decreased the pulmonary fungal burden and abolished CNS dissemination at weeks 2 and 3. Furthermore, LAC1 deletion lead to: 1) diminished pulmonary eosinophilia; 2) increased accumulation of CD4+ and CD8+ T cells; 3) increased Th1 and Th17 cytokines yet decreased Th2 cytokines; and 4) lung macrophage shifting of the lung macrophage phenotype from M2- towards M1-type activation. Next, we used adoptively transferred CD4+ T cells isolated from pulmonary lymph nodes of mice infected with either lac1Δ or H99 to evaluate the role of laccase-induced immunomodulation on CNS dissemination. We found that in comparison to PBS treated mice, adoptively transferred CD4+ T cells isolated from lac1Δ-infected mice decreased CNS dissemination, while those isolated from H99-infected mice increased CNS dissemination. Collectively, our findings reveal that immune modulation away from Th1/Th17 responses and towards Th2 responses represents a novel mechanism through which laccase can contribute to cryptococcal virulence. Furthermore, our data support the hypothesis that laccase-induced changes in polarization of CD4+ T cells contribute to CNS dissemination.

Final results of a multicenter trial addressing role of CSF flow cytometric analysis in NHL patients at high risk for CNS dissemination

AbstractThis prospective study compared diagnostic and prognostic value of conventional cytologic (CC) examination and flow cytometry (FCM) of baseline samples of cerebrospinal fluid (CSF) in 174 patients with newly diagnosed aggressive non-Hodgkin lymphoma (NHL). FCM detected a neoplastic population in the CSF of 18 of 174 patients (10%), CC only in 7 (4%; P < .001); 11 patients (14%) were discordant (FCM+/CC−). At a median follow-up of 46 months, there were 64 systemic progressions and 10 CNS relapses, including 2 patients with both systemic and CNS relapses. Two-year progression-free and overall survival were significantly higher in patients with FCM− CSF (62% and 72%) compared with those FCM+ CSF (39% and 50%, respectively), with a 2-year CNS relapse cumulative incidence of 3% (95% confidence interval [CI], 0-7) versus 17% (95% CI, 0-34; P = .004), respectively. The risk of CNS progression was significantly higher in FMC+/CC− versus FCM−/CC− patients (hazard ratio = 8.16, 95% CI, 1.45-46). In conclusion, FCM positivity in the CSF of patients with high-risk NHL is associated with a significantly higher CNS relapse risk and poorer outcome. The combination of IV drugs with a higher CNS bioavailability and intrathecal chemotherapy is advisable to prevent CNS relapses in FCM+ patients.

Lapatinib efficacy according to metastatic sites in trastuzumab pretreated patients with HER2-positive metastatic breast cancer: An analysis form IntERB registry in the Czech Republic.

e11072 Background: Lapatinib is an oral dual tyrosin kinase inhibitor of EGFR and HER2 and compared to trastuzumab penetrates to CNS. We evaluated efficacy and safety of lapatinib treatment according to different metastatic sites involvement using data from IntERB registry that has been initiated and run by Czech Society for Oncology and Institute of Biostatistics and Analyses at Masaryk University, Brno, Czech Republic. Methods: An analysis included 213 patients with HER2 positive metastatic breast cancer treated from January 2007 to September 2011. Lapatinib was mostly administered orally 1250mg/day with capecitabine (2000mg/m2 D1-14), 16 patients received lapatinib in monotherapy. All patients had experienced progression during prior trastuzumab based therapy. Results: Median age was 56 years (range 23 – 78). Median duration of lapatinib therapy was 20.6 weeks (range 1–146). Complete response was achieved in 13 patients (6.1%), partial response in 31 (14.6%), stable disease in 118 (55.4%). In 26 disease have progressed (12.2%); response could not be assessed in 25 patients (11.7%). PFS for whole group was 7.1 months (95% CI 5.9-8.5). Overall survival was 17.2m (95% CI 15.8-18.6), probability of 6m OS was 80.3% and 1-year OS was 64%. Metastatic sites specific survival was evaluated in 103 patients. CNS dissemination was initially diagnosed in 31 patients (30.1%), PFS in this group was 6.2m (95% CI 3.3-9.1), OS was not reached, 6-m OS was 67.3%. In non-CNS group (skeletal metastasis in 49.5%, lung 38.8%, hepatic 36.9%, lymphatic 17.5%, other 15.5%) was PFS 6.3m (95% CI 1.6-11.1), OS 22.0m (95% CI 15.3-28.8) and 6-m OS was 88.2%. Most common toxicities were diarrhea in 11.7% patients, rash/skin toxicity in 10.8%, nausea/vomitus in 5.2% and hepatotoxicity in 2.3%. No cardiac toxicity was reported. Therapy was discontinued due toxicity in 9.0%. Conclusions: Lapatinib in combination with capecitabine proved its efficacy in trastuzumab pretreated HER2 positive metastatic breast cancer. Even in patients with CNS involvement was achieved a notable PFS and OS, comparable to non-CNS group of patients. Therapy was well tolerated.

MicroRNA Analysis in the Cerebrospinal Fluid and Blood Serum of Lymphoma Patients At Diagnosis and in Response to Therapy,

Abstract 3663MicroRNAs are non-coding RNAs (19–23nt) that negatively regulate expression by interference with the translation or RNA stability of up to hundreds of targets. Tumors including leukemias and lymphomas are associated with deregulated expression of microRNAs (Volinia et al. 2010). Several microRNAs including miR-17-92 cluster members and miR-155 are overexpressed in lymphomas and showed promise in predicting relapse (Fabbri M et al. 2011). Unlike longer species of RNA, microRNAs are preserved and detectable in human fluids including serum, plasma and cerebrospinal fluid (CSF) (Baraniskin A. et al. 2011). We investigated abundance of microRNAs in the CSF and sera and tested whether their levels are associated with diagnosis or treatment of lymphomas. We studied patients with primary central nervous system lymphomas (PCNSL) (N=3) and systemic lymphomas either with CNS dissemination (N=3) or without (N=11). Histological type was predominantly diffuse large B cell lymphoma - DLBCL (N=13). Sera of a control group were also used. 200 uL of CSF and sera (both cell free) were used for total RNA isolation followed by PCR and the data were adjusted to levels of control microRNAs (miR-let-7a or miR-24). Our data demonstrate that the microRNAs of the miR-17-92 cluster (miR-19a, miR-20a, miR-92a) and miR-106b-25 cluster (miR-106b, miR-25) and miR-155 are detectable (unlike miR-106a, miR-18a) in both the CSF and sera. Particularly, miR-17-92 and miR-106b-25 are increased in CSF of the PCNSL and the systemic lymphomas with CNS involvement compared with systemic lymphomas without CNS involvement. Conversely, in the sera, expression of miR-17-92 is increased in systemic lymphomas compared to PCNSL and the control group. Next, we investigated the levels of these microRNAs in a patient with systemic DLBCL with CNS dissemination during the treatment (R-CHOP alternating with RMPV) resulting in complete remission. Analysis of the CSF and also of the sera (at 9 different time points within three months) revealed a gradual decrease (∼6 fold) of the levels of miR-19a, miR-20a, miR-92a, miR-106b, and miR-25. However, the levels of these microRNAs in the sera at the stage of complete remission were still 2 fold higher compared to controls. We conclude that measurement of microRNAs in both CSF and sera represents novel sensitive tool, additional to other approaches, for tumor detection and/or for estimation of the therapy efficacy. (Grants: NT10310-3/2009, MPO FR-TI2/509, NPVII 2B06077, MSM 0021620806, LC 06044, SVV-2011-262507) Disclosures:No relevant conflicts of interest to declare.

Strain-dependent CNS dissemination in guinea pigs after Mycobacterium tuberculosis aerosol challenge

Clinical reports suggest an association of distinct Mycobacterium tuberculosis strains with CNS disease. We therefore examined CNS dissemination by different laboratory strains (two M. tuberculosis H37Rv, one CDC1551) in a guinea pig aerosol infection model. Although all strains grew exponentially in lungs, with similar bacterial burdens at the time of extrapulmonary dissemination, M. tuberculosis CDC1551 disseminated to the CNS significantly more than the H37Rv strains. No CNS lesions were observed throughout the study, with only a modest cytokine response. These data suggest that M. tuberculosis may have virulence factors that promote CNS dissemination, distinct from those required for pulmonary TB.

Role of high‐dose chemotherapy (HDCT) in treatment of atypical teratoid/rhabdoid tumors (AT/RTs)

Atypical teratoid/rhabdoid tumors (AT/RTs) of the CNS have been recently characterized as a distinct clinicopathologic entity with an unusually poor prognosis and with the highest incidence in the first 2 years of life. It often arises in the posterior fossa and its distinctive immunohistochemical (negative stain for INI-1) and cytogenetic features (monosomy or deletion of chromosome 22) permit an adequate diagnosis in most of cases. AT/RT of the CNS is a usually fatal disease virtually unresponsive to chemotherapy (CT) and radiotherapy (RT). Rapid progression and CNS dissemination are commonly reported. Whether combined regimens including high-dose CT are able to prolong survival or change the natural history of this tumor are under evaluation.

Clinical results of BNCT for malignant brain tumors in children

It is very difficult to treat the patients with malignant brain tumor in children, especially under 3 years, because the conventional irradiation cannot be applied due to the damage of normal brain tissue. However, boron neutron capture therapy (BNCT) has tumor selectivity such that it can make damage only in tumor cells. We evaluated the clinical results and courses in patients with malignant glioma under 15 years. Among 183 patients with brain tumors treated by our group using BSH-based intra-operative BNCT, 23 patients were under 15 years. They included 4 patients under 3 years. There were 3 glioblastomas (GBM), 6 anaplastic astrocytomas(AAS), 7 primitive neuroectodermal tumors (PNET), 6 pontine gliomas and 1 anaplastic ependymoma. All GBM and PNET patients died due to CSF and/or CNS dissemination without local tumor regrowth. All pontine glioma patients died due to regrowth of the tumor. Four of 6 anaplastic astrocytoma and 1 anaplastic ependymoma patients alive without tumor recurrence. BNCT can be applied to malignant brain tumors in children, especially under 3 years instead of conventional radiation. Although it can achieve the local control in the primary site, it cannot prevent CSF dissemination in patients with glioblastoma.

Phase I Study of Intraventricular Administration of Rituximab in Patients With Recurrent CNS and Intraocular Lymphoma

We previously determined that intravenous administration of rituximab results in limited penetration of this agent into the leptomeningeal space. Systemic rituximab does not reduce the risk of CNS relapse or dissemination in patients with large cell lymphoma. We therefore conducted a phase I dose-escalation study of intrathecal rituximab monotherapy in patients with recurrent CNS non-Hodgkin's lymphoma (NHL). The protocol planned nine injections of rituximab (10 mg, 25 mg, or 50 mg dose levels) through an Ommaya reservoir over 5 weeks. The safety profile of intraventricular rituximab was defined in 10 patients. The maximum tolerated dose was determined to be 25 mg and rapid craniospinal axis distribution was demonstrated. Cytologic responses were detected in six patients; four patients exhibited complete response. Two patients experienced improvement in intraocular NHL and one exhibited resolution of parenchymal NHL. High RNA levels of Pim-2 and FoxP1 in meningeal lymphoma cells were associated with disease refractory to rituximab monotherapy. These results suggest that intrathecal rituximab (10 to 25 mg) is feasible and effective in NHL involving the CNS.

AFP/β-HCG Secreting CNS Germ Cell Tumors: Long-Term Outcome with Respect to Initial Symptoms and Primary Tumor Resection. Results of the Cooperative Trial MAKEI 89

The aim of the present study was to evaluate survival and factors influencing long-term outcome of patients with AFP/beta-HCG secreting (non-seminomatous) central nervous system germ cell tumors (secCNSGCT), who were prospectively collected in the cooperative MAKEI (German: maligne Keimzelltumoren) 89 protocol. Between January 1989 and January 1994, 28 patients with secCNS GCT were registered and treated according to the MAKEI 89 protocol. The protocol recommended, after a clinically or histologically proven diagnosis and cisplatin-based chemotherapy, a resection of residual tumor and craniospinal irradiation (30 Gy) with a tumor boost (20 Gy). The estimated (Kaplan-Meier) event-free survival (EFS) of protocol patients is 0.57 +/- 0.09 (n = 28) and the relapse-free survival (RFS) is 0.67 +/- 0.10 (at five and ten years). With respect to long-term survival, the combination of marked neurological symptoms at diagnosis along with primary tumor resection seem to be the main negative prognostic risk factors (Fisher exact test p < 0.05). CNS dissemination at diagnosis can also be considered as a negative risk factor as 3 of 5 patients with primary dissemination died of the disease. Cisplatin-based three agent chemotherapy followed by resection of the residual tumor and craniospinal irradiation (CSI) with tumor boost is a successful and well-tolerated treatment for secCNSGCTs. The possibility of a clinical diagnosis based on MRI and tumor markers together with the use of modern neurosurgical techniques gives us the chance to postpone or even avoid major surgery. This gives an additional chance to reduce acute morbidity and further decrease late effects.

Ocular manifestation of primary nervous system lymphoma: what can be expected from imaging?

Primary ocular lymphoma, which affects the posterior parts of the eye, is an ocular manifestation of primary central nervous system lymphoma (PCNSL). It used to be the ocular disease with the shortest time of survival, even worse than ocular melanoma. Death ensues by CNS dissemination. Unfortunately, ocular lymphoma may be the initial manifestation of PCNSL and diagnosis is frequently difficult, even if vitreal biopsy is performed. Therefore, it should be determined whether cross sectional imaging may be helpful in detection and differential diagnosis of ocular lymphoma. MRI of seven patients (female = 6, male = 1, median age 62 years) with biopsy proven ocular lymphoma were retrieved from the files of our hospital and of a multicenter PCNSL study. In four patients, ocular lymphoma was the first manifestation of PCNSL, in three a cerebral lesion had occurred in the first place. Progression to cerebral lymphoma was seen in three of the four patients with initial eye manifestation. Imaging was performed using a dedicated thin section protocol in four patients. An intraocular abnormality was found in four cases, always in T1-weighted images after contrast injection. Differential diagnosis from uveitis or ocular melanoma was not possible by imaging alone. The examination was falsely negative in the remaining three patients.Hence, imaging has a low sensitivity for ocular lymphoma and does not facilitate differential diagnosis against uveitis or ocular melanoma.

Intramedullary Spinal Cord Metastases in Breast Carcinoma: Report of Two Cases and Review of the Literature

Intramedullary spinal cord metastases (ISCM) are usually the result of rapidly progressing systemic malignancy. Breast cancer is one of the most common solid tumors with a high propensity of CNS dissemination. In the present report we describe two new cases with advanced breast cancer developing ISCM after a variable disease course. One of these patients had brain metastases at presentation, while at relapse developed leptomeningeal carcinomatosis which was treated successfully, but followed shortly, as a terminal event, by ISCM and parenchymal brain recurrence. The other patient was treated initially for locally advanced breast cancer and after multiple locoregional relapses, she developed liver metastases and subsequent ISCM and asymptomatic parenchymal brain deposits. Both patients experienced a rather rapidly evolving disease course leading to death 2 and 4 months, respectively, after widespread neuraxis dissemination of their cancer. Both these cases, added to the list of the anecdotally reported cases of ISCM after breast cancer, undermine the ominous prognosis and limited treatment options available for this disease manifestation, and an extensive literature review and discussion of similar cases is provided.

Medulloblastoma/Primitive Neuroectodermal Tumor in 45 Adults

Medulloblastoma/primitive neuroectodermal tumor (PNET) is an uncommon tumor in adults. We reviewed the medical records of 45 patients, 15 years or older, with medulloblastoma/PNET. Most patients presented with symptoms referable to the posterior fossa, and 31 of 45 patients had disease limited to the posterior fossa at the time of diagnosis. Despite initial favorable response to surgical resection, radiation, and chemotherapy, one-half had recurrence 10 to 76 months after initial treatment. Only two of these patients had local recurrence; the remainder had CNS dissemination, systemic metastasis, or both. The recommended approach to medulloblastoma/PNET in adults is similar to that in children, and includes initial staging evaluation, systemic and focal therapy (ie, neuraxis irradiation with posterior fossa boost and chemotherapy), and long-term follow-up to detect late and distant recurrence.

Carcinoma of the choroid plexus: A pediatric experience

Carcinoma of the choroid plexus (CCP) is a rare tumor of the central nervous system which occurs more frequently in patients under 3 years of age. We report 10 cases of CCP in children. There were 5 males and 5 females, aged 5 to 84 months at diagnosis (median 32 months). Eight CCP were located in the lateral ventricle and 2 in the fourth ventricle. All patients underwent initial surgery, with complete resection in 5 cases. Postoperative treatment included radiotherapy alone in 4 patients, chemotherapy alone in 4, both in 1 patient, and no further treatment in one patient. Six patients remain in first continuous complete remission with a follow-up of 12 to 156 months (mean 34 months). Five of these six patients had a complete surgical resection of their tumor and 4 of them received chemotherapy alone. A comparison with the series in the literature suggests that total resection of the tumors is the major prognostic factor for survival. Recourse to additional treatments to prevent local relapses and CNS dissemination seems necessary. In our opinion, radiotherapy should be avoided as far as possible because of its deleterious effect in very young children. As some of the long term survivors did not receive radiation treatment, we conclude that CCP can be treated post operatively using chemotherapy protocols designed for infants with malignant brain tumors.