Primary central nervous system lymphomas.

Introduction. Up to now PCNSL incidence in the US was presumed to be increasing in all age groups independent of changes in nosology, new diagnostic techniques, and HIV infection. The intent of our study was, firstly, to extend our prior study of PCNSL incidence in the US (Olson et al, Cancer 2002;95:1504-10) with an additional decade of SEER data; and, secondly, to determine time trends during the HAART era in the US. Methods. PCNSL age-adjusted incidence rates from 1973-2007 were obtained from the nine SEER registries used in the Olson et al. study. Similarly, the same exclusion criteria were used to remove PCNSL most likely associated with HIV (never married males and females; persons of unknown marital status; all cases reported in the San Francisco registry). To assess the accuracy of the criteria in removing HIV associated cases, incidence rates of Kaposi sarcoma (KS) were assessed with and without the use of the same exclusion criteria. Results. The incidence of PCNSL in the general population decreased from 1995 to 2000. Following this decrease, the incidence stabilized and is now beginning to increase in the last 5 years. Stratifying the incidence rate by age group and employing the exclusion criteria, PCNSL incidence has remained stable in the 20-64 year old population, but has steadily increased in the 65+ population. Removing the exclusion criteria did not alter the data for the 65+ population but demonstrated a sharp drop in incidence after 1996 for the 20-64 year old population. Applying the same HIV exclusion criteria the incidence of KS resulted in no appreciable change in incidence rates over the same time frame. Conclusion. The incidence rate of PCNSL is increasing. This increase is driven by a continued increase in incidence among the 65+ population while the incidence for those aged 20-64 has stabilized during the same time frame. An effect of HAART on PCNSL incidence in the US is suggested by the decline in the incidence among the 20-64 year old population without the HIV exclusion criteria. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1926. doi:10.1158/1538-7445.AM2011-1926

An excessive increase in the incidence of primary central nervous system lymphoma (PCNSL) has been reported since the mid-1980s in the U.S. and U.K. Clinical studies have shown that radiotherapy and chemotherapy may prolong survival. In the current study, the authors describe the incidence, treatment, and survival of an unselected group of patients with PCNSL in the southern and eastern Netherlands. Data regarding patients diagnosed between 1989-1994 were obtained from 4 population-based regional cancer registries in the southern and eastern Netherlands (n = 86) and the Eindhoven Cancer Registry for 1980-1988 (n = 6). Lymphomas were registered as PCNSL when a tissue diagnosis of CNS lymphoma was established for a patient with neurologic symptoms (i.e., lymphomas were not necessarily restricted to the CNS at the time of diagnosis). Only patients diagnosed during their lifetime with Stage I disease, Stage "IV" disease (i.e., diffuse CNS lymphoma), or disease of unknown stage were included (63 patients, 8 patients, and 15 patients, respectively, between 1989-1994). For 80 patients (93%) follow-up was complete until January 1, 1997. Between 1989-1994, an average World Standardized Rate of 2.3 cases and 1.7 cases per 1 million person-years, respectively, was reported for males and females. The median age of the patients at the time of diagnosis was 62 years, and was 66 years for patients with an unknown disease stage. In the area of the Eindhoven Cancer Registry the occurrence of PCNSL more than doubled from < 2% of all histologically confirmed primary CNS malignancies diagnosed between 1980-1985 to approximately 4% of cases diagnosed between 1986-1994. The median survival of all the patients was 4.1 months; the median survival was 5.8 months for patients with limited (Stage I and Stage IV) disease and was 0.6 months for patients with an unknown stage of disease. Approximately 65% of the patients with limited disease received radiotherapy and approximately 35% of such patients received chemotherapy. Furthermore, chemotherapy was given more often to patients age < 60 years who tended to have a slightly better survival than patients age > or = 60 years. The increase in the incidence of PCNSL in the 1980s may be explained in large part by changes in diagnostics and registration. The relatively high incidence and low survival rate of PCNSL in the southern and eastern Netherlands reported in the 1990s may be due in part to the inclusion of patients with systemic lymphoma and immunodeficiency disorders. However, a significant improvement in the prognosis of patients with PCNSL in the southern and eastern Netherlands diagnosed in the 1990s is unlikely.

Phase 1 investigation of lenalidomide/rituximab plus outcomes of lenalidomide maintenance in relapsed CNS lymphoma

Primary CNS lymphoma (PCNSL) has been increasing in incidence among both immunocompetent and immunocompromised patients. Today there is no uniform approach to the treatment of this disease. Whole brain irradiation (WBI) has been standard treatment, resulting in complete remission in the majority of patients, but with most patients relapsing and dying of their disease within 2 years after treatment. The addition of chemotherapy to WBI appears to prolong survival for patients younger than 60 years with median survival reaching a plateau at approximately 40 months. The issue of the best treatment for older patients remains controversial. Prospective studies will be needed, as it is impossible to draw conclusions from the nonrandomized small series published so far. This is because the prognostic variables of age and performance status to date have affected outcome more than therapy. In this review, some of the questions regarding the management of PCNSL are addressed. Since the role of radiotherapy remains unclear, we designed a new randomized multicenter study (G-PCNSL-SG-1 trial) to investigate the optimal timing of WBI after high-dose methotrexate (HD-MTX) chemotherapy.

Purpose: Lack of standard treatment of Primary Central Nervous System Lymphoma (PCNSL) was acknowledged in phase III intergroup study (HOVON 105/ALLG NHL 24). PCNSL incidence is increasing for unknown reasons, particularly among persons over 65 years of age. The major limitation of successful treatment of PCNSL is the blood-brain barrier (BBB), which prevents drug delivery into the brain. Our novel treatment employs nano immunoconjugates (NICs) that cross BBB and activate brain lymphoma immunity. These NICs specifically block c-Myc expression and induce CD20 crosslinking. The NICs, in combination with αPD1, were systemically delivered to the lymphoma mice and this treatment led to a local and systemic broad-spectrum immune response by activation of IFN-γ that is an important anti-tumor M1 macrophage activator. Methods: Polymer nanoconjugate based on biodegradable poly(N-(2-hydroxypropyl) methacrylamide) (PHPMA)-P was used for treatment of BALB/C mice with intracranially inoculated murine A20 lymphoma. PHPMA-based nanoconjugates have defined synthesis strategy for BBB transcytosis, tumor targeting, and cancer cell killing. Nano-immunodrug P/AP-2/CD20 Fab'or c-Myc inhibitor (anti-sense oligonucleotides)/H6 conjugate contains multiple AP-2 peptides for efficient delivery across the BBB and Fab' fragments of αCD20 Ab (mouse specific) for CD20 receptor crosslinking on PCNSL cells. c-Myc inhibitor bound via a disulfide bond is transferred to the cytoplasm followed by cleavage; this is facilitated by (His)6 peptide-mediated endosome disruption. The nanoconjugate was examined for the ability to cross BBB in vivo by live imaging. The therapeutic efficacy and survival were evaluated together with spectral flow cytometry (FC) and RNA-seq bioinformatic analysis of tumor tissues. Results: NIC was able to penetrate BBB and accumulate in brain parenchyma. The best survival results were obtained from the combination groups with CD20 Fab' crosslinking CD20 receptors resulting in apoptosis and c-Myc antisense inhibition in combination with αPD-1 checkpoint inhibitor. Survival compared to PBS-treated controls was significant (P=0.0006, P=0.0034, respectively, by ANOVA). FC analysis of A20 brain lymphoma tissue after treatment with NICs demonstrated reduction of Tregs, associated with downregulation of IL-10 and IL-1β in plasma. Spectral flow cytometry revealed activation of tumor infiltrating T lymphocytes and the M1 macrophages in lead treatment groups. RNA-seq data correlated with flow cytometry results indicating the activation of genes linked to IFN-γ pathway important for anti-tumor response and M1 macrophage activation. Immunostaining confirmed a marked increase of M1-specific iNOS expression in the nanodrug-treated tumors. Conclusion: The PCNSL treatment results demonstrate for the first time that the BBB delivery of NICs modified brain tumor microenvironment and activated brain local immune system though modulation of T cells and IFN-γ pathway. Support: NIH grants: R01 CA188743, R01 CA206220, R01 CA209921 Citation Format: Tao Sun, Ekaterina Shatalova, Oliver Braubach, Dmytro Klymyshyn, Eggehard Holler, Jiawei Wang, Lian Li, Jiyuan Yang, Jindrich Kopecek, Julia Y. Ljubimova. Nano-immuno combination therapy to treat brain primary central nervous system lymphoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2869.

Primary central nervous system lymphoma (PCNSL) is an uncommon extranodal form of non-Hodgkin lymphoma affecting the brain, leptomeninges, eyes, or the spinal cord, in the absence of systemic involvement. The predominant risk factor for disease development is immunodeficiency. PCNSL is an acquired immune deficiency syndrome (AIDS) defining malignancy; however, the incidence in this patient population is decreasing due to advancements in antiretroviral treatment. On the other hand, among immunocompetent individuals, the incidence of PCNSL has increased over the past few decades, representing 3–4 % of all primary brain tumors (Eby et al. Cancer 62(11):2461–2465, 1988). The explanation for the growing incidence is not clear. PCNSL has a predilection for the elderly population with a median age of diagnosis of 55 years and peak incidence in the sixth and seventh decades of life (Hochberg and Miller, J Neurosurg 68(6):835–853, 1988; Fine and Mayer, Ann Intern Med 119(11):1093–1104, 1993).

Primary central nervous system lymphoma (PCNSL) is a rare type of malignant lymphoma which originates in the central nervous system without spreading to other systems. It is more predisposable to immunodeficient individuals. However, an increase in the incidence of PCNSL has been also observed in the healthy population in recent years. PCNSL has short phase of clincal release, and easy to relapse with poor prognosis. Some studies have shown that relative prognostic factors were associated with age, performance status, the radiotherapy and chemotherapy modalities, the response to early adminstration of the glucocorticoid,tissue pathologic type and the molecular biologic marks. Key words: Central nervous system; Lymphoma; Prognosis

Primary Central Nervous System Lymphoma in Children: A Report of 12 Cases.

436P - Population-Based Incidence and Outcome of Primary Central Nervous System Lymphoma – a Study By the Austrian Brain Tumor Registry, 2005–2010

Multiomic dissection of immune-privileged DLBCL reveals divergent immune subtypes in testicular and primary central nervous system lymphoma

Primary central nervous system (CNS) lymphoma is a rare disease, usually resistant to therapy. In the case presented, a 51-year-old woman with documented primary cerebellar CNS lymphoma, lymphoplasmacytoid type, underwent surgical resection and whole brain irradiation and then recurred within the CNS. Treatment with 17 courses of high-dose methotrexate resulted in complete disappearance of the tumor and clearing of all neurologic signs and symptoms. She is now free of disease 12 months after beginning chemotherapy. The potential usefulness of systemic anti-metabolites for treatment of CNS lymphoma, primary or disseminated, is discussed.

Overexpression of BCL-2, BCL-X, and BAX in Primary Central Nervous System Lymphomas that Occur in Immunosuppressed Patients

Primary Central Nervous System Lymphoma (PCNSL) is most often non-Hodgkin lymphoma diffuse large B cell lymphoma (NHL-DLBCL) confined exclusively to the central nervous system. Its pathogenesis remains unknown in immunocompromised patients. Recent studies pointed out that systemic NHL, especially B cell NHL, might be associated with Hepatitis B virus (HBV) [1, 2]. We thus reported the prevalence of HBV in immunocompetent patients with PCNSL and search for a possible association. We included 109 patients treated for PCNSL in our department in Paris, France, from 2002 to 2012. The inclusion criteria were: (i) aged C18 years, (ii) pathologically documented diagnosis of ocular or cerebral DLBC-PCNSL, (iii) HIV seronegative and (iv) available HBV serology. The control population included 319 patients treated in the same Department, from 1993 to 2011, for other primary brain tumors (PBT) and with available HBV serology. We compared prevalence of HBsAg, anti-HBc and anti-HBs between these populations using a Fischer’s test (STATA 8.0, Woolf test). We also compared prevalence of HBsAg and anti-HBc in the PCNSL group to the French and greater Paris’ area (GPA) populations using an exact test based on binomial probability function [3]. The characteristics of the PCNSL and the PBT populations are reported in Table 1. Prevalence of HBsAg was greater among the PCNSL patients than within the French population (p = 0.01) and the GPA population (p = 0.02). In addition, prevalence of anti-HBc in the PCNSL patients was higher than within the French population (p = 0.01). Although no statistically significant difference was found between PCNSL and PBT patients (p = 0.49 regarding HBsAg, p = 0.10 regarding anti-HBc and p = 0.23 regarding anti-HBs), a trend for a positive association between HBV and PCNSL was highlighted. Regarding active (p = 0.49) and past infections (p = 0.10) and Electronic supplementary material The online version of this article (doi:10.1007/s11060-015-1879-x) contains supplementary material, which is available to authorized users.

Primary central nervous system lymphomas (PCNSLs) and high-grade gliomas (HGGs) arising in the cerebellum is extremely low, making the differential diagnosis difficult or even impossible. The purpose of this study was to define the MR features of cerebellar PCNSL in immunocompetent patients, and to determine whether a combination of conventional MR and DW imaging can assist in the differentiation of PCNSLs and HGGs. Twelve PCNSLs and 15 HGGs confirmed by pathological analysis were retrospectively identified. The apparent diffusion coefficient (ADC) and conventional MRI parameters were compared for differences between PCNSL and HGG groups using the independent sample t test or chi-square test. Both ADCmin and ADCtotal values were lower in the PCNSL group than those in the HGG group (ADCmin: 0.53 × 10−3 vs. 0.83 × 10−3 mm2/sec, P < 0.001; ADCtotal: 0.66 × 10−3 vs. 0.98 × 10−3 mm2/sec, P = 0.001). As for conventional MR features, there were significant difference in the tumor size, enhancement patterns, the presence of cystic changes, edema degree and streak-like edema (all P < 0.01); but there were no significant difference in lesion type, the presence of bleeding, and involvement of brain surface between two groups (P = 0.554, 0.657 and 0.157, respectively). The results revealed that several conventional MR features, including enhancement patterns, branch-like enhancement and streak-like edema may be useful for the differentiation of PCNSL and HGG in cerebellum and, when combined with ADC values, further improve the discriminating ability.

Keywords: Primary CNS lymphoma; Relapse; follow-up; magnetic resonance imaging; surveillance imaging