Molecular analysis of primary central nervous system and primary intraocular lymphomas

Primary central nervous system lymphoma (PCNSL) is usually a large B-cell, high grade non-Hodgkin's lymphoma (NHL) classified as a diffuse large cell lymphoma (DLCL). In rare cases, however, T cell lymphomas have been described. Although a relatively rare tumor, the incidence of PCNSL has increased dramatically over the past 15 years in both immuno-competent and immunocompromised patients. The disease is aggressive with a 5-year survival rate of less than 25 %. The cause of death is progressive and recurrent disease in the CNS, despite aggressive treatment. Approximately 20-25% of patients with PCNSL also have primary intra-ocular lymphoma (PIOL). PCNSL and PIOL are closely related and inter-connected pathologies involving two immune privileged sites. The study of PCNSL and PIOL has been limited due to the fact that viable malignant cells are rare and difficult to recognize. Moreover, the cells are difficult to culture and to date there is no good animal model for the disease. Here, we will present the current literature on the disease. In particular, we will present data suggesting that PCNSL in immuno-compromised and AIDS patients may correspond to two different pathologies. Furthermore, we will discuss how the study of these lymphomas can benefit from new advanced molecular biology techniques including single cell PCR and laser capture microdissection (LCM). PCNSL and PIOL are aggressive tumors, therefore, early diagnosis and prompt, aggressive treatment may improve prognosis. Advanced molecular biology will help delineate the oncogenesis of PCNSL and PIOL.     

Combined treatment of rituximab,idarubicin, dexamethasone,cytarabine, methotrexate with radiotherapy for primary central nervous system lymphoma

The overall response rates and long‐term survival of primary central nervous system lymphoma (PCNSL) are still significantly inferior to the results achieved in similar subtypes of extranodal non‐Hodgkin's lymphoma. It is clearly necessary to investigate new therapeutic methods on PCNSL. We encountered three patients histologically documented PCNSL as diffuse large B‐cell lymphoma (DLBCL). They were treated with R‐IDARAM which comprised rituximab, idarubicin, dexamethasone, cytarabine and methotrexate. Patient 1 received stereotactic brachytherapy (SBT) prior to chemotherapy performed with iodine‐125 seeds (cumulative therapeutic dose 50 Gy). After six cycles of R‐IDARAM at 3‐weekly intervals, radiotherapy was applied at a dosage of 2000–4000 cGy in conventional schedule (180 or 200 cGy/day) to whole brain or spinal cord in all patients. Complete remission (CR) was achieved after first two cycles of R‐IDARAM in all patients. All three patients remained in CR at the time of this report with a median duration of follow‐up of 23 months (ranging from 13 to 41 months). Three patients have been alive for 41, 13, 16 months respectively until now. The patient with the longest survival time was the one given SBT prior to chemotherapy. This study suggests that R‐IDARAM combining with radiotherapy maybe a high effective regimen in PCNSL patients especially those with primary central nervous system DLBCL. A comprehensive treatment combining internal radiotherapy by SBT, modified R‐IDARAM and followed reduced external radiotherapy may be a new treatment concept for PCNSL with higher efficiency and lower toxicity.     

High-dose sodium selenite can induce apoptosis of lymphoma cells in adult patients with non-Hodgkin's lymphoma

The present study was undertaken to explore the effect of administration of high doses of sodium selenite on the apoptosis of lymphoma cells in patients with non-Hodgkin’s lymphoma (NHL). Forty patients with newly diagnosed NHL were randomly divided into two groups. Group I received standard chemotherapy, whereas group II received adjuvant sodium selenite 0.2 mg kg⁻¹ day⁻¹ for 7 days in addition to chemotherapy. Flow cytometry was used for monitoring of lymphoma cells apoptosis at the time of diagnosis and after therapy in the two groups. Sodium selenite administration resulted in significant increase in percentage of apoptotic lymphoma cells after therapy in group II (78.9 ± 13.3% versus 58.9 ± 18.9%, p < 0.05). In addition, patients who received sodium selenite treatment demonstrated statistically significant increase in percentage of reduction of cervical and axillary lymphadenopathy, decrease in splenic size, and decreased percentage of bone marrow infiltration. Also, we found a statistically significant decrease in cardiac ejection fraction (CEF) in group I and no reduction in CEF in patients who received sodium selenite ‘group II’, denoting the cardioprotective effect of selenium. It is concluded that sodium selenite administration at the dosage and duration chosen has synergistic effect to chemotherapy in inducing apoptosis and, consequently, could improve clinical outcome.     

Comparative study on different therapies on patients with primary central nervous system lymphoma

Objective

To compare and analyze three therapies on patients with primary central nervous system lymphoma (PCNSL), aiming to provide evidences for future treatment and prognosis.

Advances and challenges in the treatment of primary central nervous system lymphoma

Primary central nervous system lymphoma (PCNSL), a rare variant of non-Hodgkin's lymphoma, is characterized by distinct biological characteristics and clinical behaviors, and patient prognosis is not satisfactory. The advent of high-dose (HD) methotrexate (HD-MTX) therapy has significantly improved PCNSL prognosis. Currently, HD-MTX-based chemotherapy regimens are recognized as first-line treatment. PCNSL is sensitive to radiotherapy, and whole-brain radiotherapy (WBRT) can consolidate response to chemotherapy; however, WBRT-associated delayed neurotoxicity leads to neurocognitive impairment, especially in elderly patients. Other effective approaches include rituximab, temozolomide, and autologous stem-cell transplantation (ASCT). In addition, new drugs against PCNSL such as those targeting the B-cell receptor signaling pathway, are undergoing clinical trials. However, optimal therapeutic approaches in PCNSL remain undefined. This review provides an overview of advances in surgical approaches, induction chemotherapy, radiotherapy, ASCT, salvage treatments, and novel therapeutic approaches in immunocompetent patients with PCNSL in the past 5 years. Additionally, therapeutic progress in elderly patients and in those with relapsed/refractory PCNSL is also summarized based on the outcomes of recent clinical studies.     

Response of antioxidant activity to excess copper in two cultivars of <Emphasis Type="Italic">Brassica campestris</Emphasis> ssp. <Emphasis Type="Italic">chinensis</Emphasis> Makino

Changes in ascorbic acid content and antioxidant enzyme activities were investigated in non-heading Chinese cabbage (Brassica campestris ssp. chinensis Makino) leaves of ‘Wutacai’ and ‘Erqing’ exposed to excess copper (Cu). Cu treatment reduced the fresh weight of shoot and root by 57% and 46% in ‘Wutacai’, and 60 and 54% in ‘Erqing’, respectively. The accumulation of copper in leaves was higher in ‘Wutacai’ than that in ‘Erqing’. Compared to the control, ascorbic acid (AsA) contents were significantly decreased after copper treatment in both cultivars, while they were higher in ‘Wutacai’ than in ‘Erqing’, which may explain the higher copper-tolerance of ‘Wutacai’ with higher copper accumulation. The higher AsA contents of ‘Wutacai’ resulted from their lower activities of degrading enzymes, such as ascorbate oxydase (AAO) and ascorbate peroxidase (APX), as well as the increasing activity of dehydroascorbate reductase (DHAR) after copper treatment compared with ‘Erqing’. Copper stimulated superoxide dismutase (SOD) activity in both cultivars, but for catalase (CAT), there was little difference between both cultivars. Peroxidases (POD) activity was decreased after copper treatment in ‘Erqing’, while in ‘Wutacai’, it was significantly increased at 14 days, and POD activity was higher in ‘Wutacai’ than that in ‘Erqing’ at 21 and 28 days. Therefore, the induced increasing activity of POD in ‘Wutacai’ also played an important role in its copper tolerance.     

Combination chemotherapy for acute lymphoblastic leukaemia in adults.

Fifty-one adults with acute lymphoblastic leukaemia were entered into a trial of intense initial chemotherapy and early "prophylaxis" of the central nervous system (CNS). Initial treatment with OPAL (Oncovin (vincristine), prednisolone, adriamycin (doxorubicin), and L-asparaginase (colaspase)) followed by craniospinal or cranial irradiation and intrathecal methotrexate produced remission in 36 patients (71%). Seventeen of these patients relapsed three to 18 months after the start of remission; the remainder had been in remission for 12 to 52 months by the end of the study. The predicted median duration of complete remission was 18.5 months. None of the four patients who initially had clinical evidence of CNS disease, three of whom also had leukaemic cells identical to those found in Burkitt''s lymphoma, achieved remission. Those patients who initially had hepatomegaly or splenomegaly had a shorter remission than those without. The predicted median survival was 27 months in those who achieved complete remission, one month in those who did not, and 21 months overall. The addition of colaspase and doxorubicin to vincristine and prednisolone and the use of early CNS treatment clearly improved the remission rate among adults with acute lymphoblastic leukaemia, though the presence and length of remission was affected by the extent of disease at presentation. Burkitt-like leukaemia, which had a poor prognosis, is probably a separate disease and may benefit from a different therapeutic approach.     

Anthurium roots for micropropagation and Agrobacterium tumefaciens-mediated gene transfer

Growth of Blechnum spicant gametophytes was optimal in MS liquid medium, a 16-h photoperiod, and it was unaffected by variation of the pH between 4.7 and 8.7. Antheridia were observed during all developmental stages of the gametophyte: filamentous, spatulate or cordate and their formation was induced by compounds excreted into the culture medium by mature gametophytes. This antheridiogen activity was found in the fractions corresponding to free and apolar esters of gibberellins. IBA at 5 μM and 50 μM, and BA at 50 μM inhibited antheridiogen. Exogenous application of GA₃ allowed spore germination but strongly inhibited gametophyte development; the two dimensional state was not reached. This revised version was published online in June 2006 with corrections to the Cover Date.     

CNS lymphoma masquerading as stroke: Cases report and literature review

Central nervous system (CNS) involvement in Hodgkins lymphoma (HL) is extremely rare. There are only two reported case series of intracranial involvement of HL. CNS HL can be presented at any point in the course of HL, most mimicking with a prominent neurological symptom. This challenges the diagnosis of CNS involvement and stroke. Here, we report four cases of patients having refractory HL with CNS involvement to garner attention among neurologists for this rare disease presents with stroke symptoms and reviews its disease characteristics, prognosis, and treatment.     

原发性中枢神经系统淋巴瘤治疗方案的探讨

原发性中枢神经系统淋巴瘤(Primary central nervous system lymphoma,PCNSL)是仅累及中枢神经系统而全身其他部位未发现的结外非霍奇金淋巴瘤,发病率较低,进展快,死亡率高,其主要原因是中枢神经系统是淋巴瘤细胞抵抗化疗药物的一个避难所,血脑屏障通透性升高为淋巴瘤发生转移的重要机制之一[1],但其通透性升高机制尚不明确。其治疗和预后的观念不断发生变化,因此探讨最佳的治疗方案是本文的重点。     

Inflammation,Aging, and Cancer: Tumoricidal Versus Tumorigenesis of Immunity

Acute inflammation is a highly regulated defense mechanism of immune system possessing two well-balanced and biologically opposing arms termed apoptosis (‘Yin’) and wound healing (‘Yang’) processes. Unresolved or chronic inflammation (oxidative stress) is perhaps the loss of balance between ‘Yin’ and ‘Yang’ that would induce co-expression of exaggerated or ‘mismatched’ apoptotic and wound healing factors in the microenvironment of tissues (‘immune meltdown’). Unresolved inflammation could initiate the genesis of many age-associated chronic illnesses such as autoimmune and neurodegenerative diseases or tumors/cancers. In this perspective ‘birds’ eye’ view of major interrelated co-morbidity risk factors that participate in biological shifts of growth-arresting (‘tumoricidal’) or growth-promoting (‘tumorigenic’) properties of immune cells and the genesis of chronic inflammatory diseases and cancer will be discussed. Persistent inflammation is perhaps a common denominator in the genesis of nearly all age-associated health problems or cancer. Future challenging opportunities for diagnosis, prevention, and/or therapy of chronic illnesses will require an integrated understanding and identification of developmental phases of inflammation-induced immune dysfunction and age-associated hormonal and physiological readjustments of organ systems. Designing suitable cohort studies to establish the oxido-redox status of adults may prove to be an effective strategy in assessing individual’s health toward developing personal medicine for healthy aging.     

Extranodal marginal zone lymphoma of the dura mater with IgH/MALT1 translocation and review of literature

Primary central nervous system lymphoma (PCNSL) is an extranodal non-Hodgkin lymphoma involving brain, intraocular structures and spinal cord, without evidence of systemic disease. The majority of PCNSLs are diffuse large B-cell type. We encountered a rare case of primary dural marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) with extension into the brain in a 59-year-old man. A magnetic resonance imaging scan showed a 22-mm tumor located in the left posterior temporal lobe extending from the dura. Histopathology revealed a lymphoplasmacytic infiltration of the dura and the brain parenchyma in a perivascular pattern. Immunohistochemical and in situ hybridization studies showed a B-cell phenotype with kappa light chain restriction. Fluorescent in situ hybridization study showed a t(14;18)(q32;q21) with immunoglobulin heavy-chain/MALT1 fusion. The molecular study for immunoglobulin heavy-chain gene rearrangement by polymerase chain reaction showed a clonal gene rearrangement.     

Toxic epidermal necrolysis associated with radiotherapy and phenytoin in a patient with non-Hodking's lymphoma: A case report

Toxic epidermal necrolysis (TEN) is a disease which is characterized by fever and desquamation of the skin and mucosal membranes. It is usually related with drugs, especially aromatic anticonvulsants which are recognized as the most common cause of this disorder. Cranial irradiation may act as a precipitating factor along with anticonvulsants for the development of TEN. We report a 28-year-old patient with central nervous system (CNS) relapsed non-Hodgkin lymphoma (NHL) who developed TEN after cranial radiotherapy and concurrent phenytoin treatment.     

Rapidly progressive and fatal EBV-related encephalitis in a patient with advanced HIV-1 infection at presentation: a case report and review of the literature

Epstein-Barr virus (EBV) has been associated with primary central nervous system lymphoma and other EBV-related malignancies in HIV infected patients, and detection of EBV DNA in cerebrospinal fluid (CSF) by polymerase chain reaction (PCR) has been demonstrated to be a good marker of PCNSL. Conversely, EBV has been rarely associated with encephalitis in HIV patients. Here we describe for the first time the case of an HIV-infected, late presenter Caucasian man, diagnosed with a rapidly progressive diffuse encephalitis at presentation. A very high viral load for EBV was detected in CSF by PCR. The patient died 12 days after the onset of encephalitis in spite of supportive, antiviral and antiretroviral therapy. Our experience would suggest that in profoundly immunosuppressed HIV patients EBV may cause severe encephalitis in the absence of lymphoproliferative disorders.     

Plant regeneration and transient GUS expression in a range of lavandin (Lavandula × intermedia Emeric ex Loiseleur) cultivars

Five cultivars of lavandin were compared for their ability to regenerate plantlets in vitro and for their susceptibility to genetic transformation. Both processes were shown to be strongly cultivar-dependent. For regeneration, best results were obtained with cultivar ‘37–70’ which gave an average of 7 shoots from one initial explant after 4 months culture in vitro. The other cultivars produced between 0.5 and 3.5 shoots per explant. These differences were mostly due to the variable efficiency of the shoot elongation and rooting steps. An Agrobacterium-mediated transformation system using the β-glucuronidase and neomycin phosphotransferase II genes was established. The β-glucuronidase expression was analysed for both leaf explants six days after inoculation and kanamycin-resistant calluses obtained after a six-week culture on a selective medium. For each cultivar, kanamycin-resistant calluses showing a β-glucuronidase activity were obtained. The transformation efficiency ranged from 3% for cultivar ‘Certitude’ to 89% for cv. ‘41–70’ and ‘B–110’. Some kanamycin-resistant calluses were organogenic. This revised version was published online in June 2006 with corrections to the Cover Date.     

Review Article – A System for Analysing Features in Studies Integrating Ecology, Development, and Evolution

Ecology is being introduced to Evolutionary Developmental Biology to enhance organism-, population-, species-, and higher-taxon-level studies. This exciting, bourgeoning troika will revolutionise how investigators consider relationships among environment, ontogeny, and phylogeny. Features are studied (and even defined) differently in ecology, development, and evolution. Form is central to development and evolution but peripheral to ecology. Congruence (i.e., homology) is applied at different hierarchical levels in the three disciplines. Function is central to ecology but peripheral to development. Herein, the supercategories form (‘isomorphic’ or ‘allomorphic’), congruence (‘homologous’ or ‘homoplastic’), and function (‘adaptive’ or ‘nonadaptive’) are combined with two developmental mode (i.e., growth) categories (‘conformational’ or ‘nonconformational’) to provide a 16-class system for analysing features in studies in which ecology, development, and evolution are integrated.     

Changes of CSF-Cu and -Zn in children with acute lymphoblastic leukemia

In 20 Dutch children with acute lymphoblastic leukemia (ALL), Cu and Zn levels in cerebrospinal fluid (CSF) were studied during standard treatment (Protocol ALL-BFM-86/SNWLK-ALL-VII). CSF-Cu in 10 controls was 0.04±0.02 μmol/L, lower compared to values in adults. At the moment of diagnosis, CSF-Cu values were higher, 0.06±0.03 μmol/L, and during maintenance therapy lower, 0.01±0.01 μmol/L. Children with central nervous system (CNS) involvement ALL as judged by CAT Scan and EEG—in addition to cytology—showed lower CSF-Cu values compared to children without. CSF-Zn values were also measured. CSF-Zn was 0.05 μmol/L and did not vary. Cu/Zn molar ratios were increased at the onset of treatment, and decreased during maintenance therapy. The changes in CSF-Cu may follow the natural course of the disease or may relate to the success of treatment, reflecting a decrease of leukemia activity. Another explanation concerns a risk to CNS damage by low CSF-Cu causing neuron dysfunction. Conditions necessary for the interpretation of these results into a clinical strategy for followup study are outlined.     

A Sublethal Dose of TNFα Potentiates Kainate-Induced Excitotoxicity in Optic Nerve Oligodendrocytes

Glutamate receptor-induced cell death, known as excitotoxicity in both neurons and oligodendrocytes, has been implicated as a common pathway of cell death in numerous central nervous system (CNS) diseases and trauma. Research in both neuronal and oligodendrocyte excitotoxicity has examined glutamate’s receptor-mediated effects on CNS cells, and explored strategies to protect cells exposed to the elevated glutamate levels that occur in CNS trauma and disease. Proinflammatory cytokines are also elevated in the injured CNS, and have also been implicated in CNS cell death. Recently, several laboratories have examined cytokines’ effects on neuronal and glial excitotoxicity. Here, we review literature concerning the dynamic susceptibility of both neurons and oligodendrocytes to excitotoxicity, and present new data from our laboratory showing that the susceptibility of oligodendrocytes to excitotoxicity is acutely potentiated by the proinflammatory cytokine TNFα.     

Solitary primary CNS lymphoma: long term survival following total resection

Primary non-Hodgkin's CNS lymphoma is rare, constituting 0.3–1.5% of all intracranial neoplasms in patients without AIDS. In the past 10 years the incidence has tripled in this population. The role of surgery is commonly limited to obtaining adequate tissue for diagnosis. This has precluded the evaluation of total surgical resection for a surgically accessible solitary lesion. We have encountered a 36-year-old healthy white male with primary CNS lymphoma who is HIV-negative and who has survived over five years disease free after total surgical resection of his lymphoma.