Anti-cyclic citrullinated peptide antibodies, other common autoantibodies, and smoking as risk factors for lymphoma in patients with rheumatoid arthritis.

OBJECTIVES: Patients with rheumatoid arthritis (RA) are at increased risk of lymphoma. There is no biomarker to indicate future lymphoma risk in RA and it is not known whether factors associated with an increased risk of RA also confer an increased risk of lymphoma. We investigated whether anti-cyclic citrullinated peptide (CCP) antibodies, other autoantibodies, and smoking, are associated with lymphoma development in RA. METHOD: From two population-based case-control studies, the Scandinavian Lymphoma Etiology (SCALE) study and the Epidemiological Investigation of Rheumatoid Arthritis (EIRA) I study, we identified lymphoma cases with a validated RA diagnosis (n = 50), to whom we matched study participants with RA but no lymphoma (n = 261), lymphoma but no RA (n = 257), and neither RA nor lymphoma (n = 233). Lymphomas were classified according to the WHO classification. Blood samples were analysed for immunoglobulin G (IgG), IgM, and IgA isotypes and IgG1-4 subclasses of anti-CCP antibodies and for 15 antinuclear antibody (ANA)-associated specific autoantibodies. Relative risks were estimated as crude and adjusted odds ratios (adjOR) with 95% confidence intervals (CIs) using logistic regression. RESULTS: We found no association between anti-CCP IgG ≥ 25 units/mL (adjOR 1.4, 95% CI 0.7-2.7), anti-CCP IgG ≥ 500 units/mL (adjOR 1.4, 95% CI 0.7-3.0), anti-CCP Ig of other isotypes, other autoantibodies (adjOR any vs none 0.6, 95% CI 0.3-1.2), or cigarette smoking (adjOR ever vs never 1.1, 95% CI 0.5-2.2) and lymphoma risk among patients with RA. CONCLUSION: In this study, neither anti-CCP antibodies (IgG, IgG1-4, IgM, or IgA), nor other common autoantibodies, nor smoking predicted lymphoma risk in RA.

Oncolytic virus therapy of multiple tumors in the brain requires suppression of innate and elicited antiviral responses.

The occurrence of multiple tumors in an organ heralds a rapidly fatal course. Although intravascular administration may deliver oncolytic viruses/vectors to each of these tumors, its efficiency is impeded by an antiviral activity present in complement-depleted plasma of rodents and humans. Here, this activity was shown to interact with complement in a calcium-dependent fashion, and antibody neutralization studies indicated preimmune IgM has a contributing role. Short-term exposure to cyclophosphamide (CPA) partially suppressed this activity in rodents and humans. At longer time points, cyclophosphamide also abrogated neutralizing antibody responses. Cyclophosphamide treatment of rats with large single or multiple intracerebral tumors substantially increased viral survival and propagation, leading to neoplastic regression.

Aggregata bathytherma sp. nov. (Apicomplexa:Aggregatidae), a new coccidian parasite associated with a deep-sea hydrothermal vent octopus.

Aggregata bathytherma sp. nov. is described from the digestive tract of Vulcanoctopus hydrothermalis, a deep-sea octopus recently discovered associated with hydrothermal vents in the northeast Pacific Ocean. Oocysts typically are spherical in shape, sometimes irregular, 163 to 356 microm in length, and 219 to 313 microm in width. Each oocyst contains from 50 to over 200 sporocysts. Sporocysts measure 27 to 32 microm in longest diameter. The cyst wall is smooth and 1 microm thick. Each sporocyst typically contains 14 to 17 sporozoites, 49 microm in length. Histological lesions associated with the presence of A. bathytherma include rupture of the basal membrane and detachment of the epithelial cells. In heavily infected areas, most of the tissue of the host digestive tract is replaced by parasites. A. bathytherma is the first Aggregata species described from a host that lives in association with hydrothermal vents, and the third species of Aggregata from eastern North Pacific waters.

Intraneoplastic polymer-based delivery of cyclophosphamide for intratumoral bioconversion by a replicating oncolytic viral vector.

rRp450 is an oncolytic herpesvirus that expresses the CYP2B1 cDNA, responsible for bioconverting cyclophosphamide (CPA) into the active metabolites 4-hydroxyCPA/aldophosphamide (AP). However, formal proof of prodrug activation is lacking. We report that activation of CPA in cells infected with rRp450 generates a time-dependent increase of diffusible 4-hydroxyCPA/AP. For in vivo applications, a CPA-impregnated polymer was implanted into human tumor xenografts inoculated with rRp450. The area under the curve for 4-hydroxyCPA/AP was 806 microg/g of tumor tissue/h when CPA was administered via intraneoplastic polymer and 3 microg/g of tumor tissue/h when CPA was administered i.p. Therefore, (a) a lytic virus expressing a "suicide" gene can activate a prodrug; and (b) within rRp450-infected tumor, more prolonged and higher concentrations of activated metabolites are generated by intraneoplastic compared with systemic administration of prodrug.

Autologous bone-marrow transplantation: host effects of high-dose BCNU.

Thirty-five patients with solid tumors received 44 courses of bis-chlorethylnitrosourea (BCNU) at doses ranging between 600 and 1,400 mg/m2 with cryopreserved or fresh autologous bone-marrow support. Eight patients treated at 600 mg/m2 received no bone-marrow support for their first course of BCNU. Maximum follow-up was 25 months (median, four months). Myelosuppression was severe and dose related but was less prolonged in the marrow-supported groups (p = 0.01) and was not dose limiting. Myelosuppression-related toxicity of infection and hemorrhage occurred in 21 (47%) of 44 courses of treatment. Pulmonary toxicity occurred in seven of 35 patients; abnormal liver function occurred in 18 of 30 patients greater than one month from treatment; and central nervous system symptoms that may have been drug related occurred in six of 35 patients. There was no renal or cardiac toxicity. Except for myelosuppression, toxicity was not dose related. Treatment-related deaths included four with pulmonary toxicity, two with liver toxicity, sepsis in four, and gastrointestinal tract toxicity in one patient. We conclude that the limiting side effect of high-dose BCNU (greater than or equal to 600 mg/m2) is visceral toxicity; the extent of myelosuppression is shortened by the infusion of bone marrow, whether cryopreserved or fresh; and marked tumor regression can be achieved with high-dose BCNU.

High-dose intravenous methotrexate for patients with nonleukemic leptomeningeal cancer: is intrathecal chemotherapy necessary?

PURPOSE: Standard treatments for neoplastic meningitis are only modestly effective and are associated with significant morbidity. Isolated reports suggest that concurrent systemic and intrathecal (i.t.) therapy may be more effective than i.t. therapy alone. We present our experience, which includes CSF and serum pharmacokinetic data, on the use of high-dose (HD) intravenous (i.v.) methotrexate (MTX) as the sole treatment for neoplastic meningitis. PATIENTS AND METHODS: Sixteen patients with solid-tumor neoplastic meningitis received one to four courses (mean, 2.3 courses) of HD (8 g/m2 over 4 hours) i.v. MTX and leucovorin rescue. Serum and CSF MTX concentrations were measured daily. Toxicity, response, and survival were retrospectively compared with a reference group of 15 patients treated with standard i.t. MTX during the same time interval. RESULTS: Peak methotrexate concentrations ranged from 3.7 to 55 micromol/L (mean, 17.1 micromol/L) in CSF and 178 to 1,700 micromol/L (mean, 779 micromol/L) in serum. Cytotoxic CSF and serum MTX concentrations were maintained much longer than with i.t. dosing. Toxicity was minimal. Cytologic clearing was seen in 81% of patients compared with 60% of patients treated intrathecally (P = .3). Median survival in the HD i.v. MTX group was 13.8 months versus 2.3 months in the i.t. MTX group (P = .003). CONCLUSION: HD i.v. MTX is easily administered and well tolerated. This regimen achieves prolonged cytotoxic serum MTX concentrations and CSF concentrations at least comparable to those achieved with standard i.t. therapy. Cytologic clearing and survival may be superior in patients treated with HD i.v. MTX. Prospective studies and a reconsideration of the use of i.t. chemotherapy for patients with neoplastic meningitis are warranted.

High microvascular blood volume is associated with high glucose uptake and tumor angiogenesis in human gliomas.

The purpose of this investigation was to elucidate the association between microvascular blood volume and glucose uptake and to link these measures with tumor angiogenesis. We demonstrate a regionally specific correlation between tumor relative microvascular blood volume (CBV), determined in vivo with functional magnetic resonance imaging techniques, and tumor glucose uptake determined with fluorodeoxyglucose positron emission tomography. Regions of maximum glucose uptake were well matched with maximum CBV across all patients (n = 21; r = 0.572; P = 0.023). High-grade gliomas showed significantly elevated CBV and glucose uptake compared with low-grade gliomas, (P = 0.009 and 0.008, respectively). Correlations between CBV and glucose uptake were then determined on a voxel-by-voxel basis within each patient's glioma. Correlation indices varied widely, but in 16 of 21 cases of human glioma, CBV and glucose uptake were correlated (r > 0.150). These measures were well correlated in all cases when comparing healthy brain tissue in these same patients. Tumor vascularity, as determined immunohistochemically and morphometrically on clinical samples, revealed statistically significant relationships with functional imaging characteristics in vivo. Regional heterogeneities in glucose uptake were well matched with functional magnetic resonance imaging CBV maps. Our findings support the concept that there is an association of microvascular density and tumor energy metabolism in most human gliomas. In addition, the findings are likely to have important clinical applications in the initial evaluation, treatment, and longitudinal monitoring of patients with malignant gliomas.

Experimental tumor therapy in mice using the cyclophosphamide-activating cytochrome P450 2B1 gene.

Most malignant tumors of the central nervous system do not respond well to chemotherapy. The anticancer drug cyclophosphamide (CPA) is largely ineffective against these neoplasms as its conversion to DNA-alkylating, cytotoxic metabolites is restricted primarily to the liver and these metabolites do not readily cross the blood-brain barrier. Here, we show that brain tumor cells can be sensitized to the cytotoxic effects of CPA, both in culture and in vivo, by introduction of the hepatic enzyme responsible for the activation of CPA, cytochrome P450 2B1. Stable transfection of rat C6 glioma cells with the P450 2B1 gene rendered the cultured tumor cells sensitive to CPA. Further, C6 cells bearing this gene were more sensitive than parental cells to the cytotoxic action of CPA when grown subcutaneously in the flanks of athymic mice. Murine fibroblasts producing a retrovirus vector encoding P450 2B1 and expressing this enzyme were then prepared and grafted into the brains of athymic mice seeded with rat C6 gliomas. Intrathecal administration of CPA prevented the development of meningeal neoplasia and led to partial regression of the parenchymal tumor mass. By contrast, C6 glioma-bearing mice receiving fibroblasts expressing the Escherichia coli lacZ gene and CPA exhibited extensive meningeal tumors and parenchymal solid brain tumors. The in situ activation of CPA by cytochrome P450 2B1 provides a novel approach not only for brain tumor gene therapy, but also for negative, drug-conditional selection of other defined cell populations.

The theme of death in complex partial seizures.

The theme of death highlighted the depersonalization phenomena of four patients with complex partial seizures. These patients became preoccupied with death in association with psychomotor seizures, visual hallucinations, and altered perception of time and reality. The episodic sense of being dead or of having an appointment with death is a clue to the diagnosis of recurrent complex partial seizures even without overt motor stigmata of seizures. The syndrome differs from fear of death, steroid psychosis, the "near death syndrome," and Cotard's syndrome. Adjustment of antiseizure medication is an important therapeutic maneuver.

Magnetic resonance imaging in a family with hereditary cerebral arteriovenous malformations.

Because of a family history of neurologic problems and the documentation of three vascular lesions in one patient, we evaluated 18 members representing three family generations with magnetic resonance imaging. Of these, eight were normal, two had abnormalities probably not related to arteriovenous malformation, one scan was suboptimal, and the remaining eight had evidence of hemorrhagic lesions characteristic of arteriovenous malformation. Four of these patients had multiple lesions, and three patients with lesions had no neurologic symptoms. The findings suggest an autosomal dominant mode of inheritance in this unique case of familial cerebral arteriovenous malformation.

Lack of efficacy of 9-aminocamptothecin in adults with newly diagnosed glioblastoma multiforme and recurrent high-grade astrocytoma. NABTT CNS Consortium.

9-Aminocamptothecin (9-AC) was administered as a 72-h i.v. infusion every 2 weeks to a total of 99 adults with high-grade astrocytomas. Fifty-one patients with newly diagnosed glioblastoma multiforme received 9-AC treatment prior to radiation therapy and 48 patients with high-grade astrocytomas were treated at the time of tumor recurrence. Upon entrance into these research protocols, all patients had measurable disease that was evaluated on a monthly basis with volumetric CT or MRI scans. A partial response was defined by > or =50% reduction in the contrast enhancing volume on stable or decreasing doses of glucocorticoids. The study specified that all apparent responders would have central review of their radiologic studies and histopathology. The initial patients treated with 9-AC were also receiving anticonvulsants and were noted to have minimal myelosuppression with this chemotherapy. Thus, 9-AC doses were escalated from the previously reported maximum tolerated dose (MTD) of 850 microg/m2/24 h. We then established new MTDs for patients receiving enzyme-inducing anticonvulsants. We defined these MTDs to be 1,776 microg/m2/24 h for newly diagnosed, previously untreated patients and 1,611 microg/m2/24 h for patients with recurrent disease. Twenty-two patients with newly diagnosed glioblastoma multiforme received 9-AC at doses > or =1,776 microg/m2/24 h. Of these, 18 had evaluable disease on central review, and 0 of 18 (0%) demonstrated a partial or complete response. Twenty-one patients with recurrent high-grade astrocytomas were treated at 1,611 microg/m2/24 h; 20 had evaluable disease and 0 of 20 (0%) had a partial or complete response. Thus, the overall response rate in the 38 evaluable patients treated at the MTD was 0 of 38 (0%). Furthermore, of the 51 evaluable patients who were treated at doses less than the MTD, only one partial response was observed, yielding an overall response rate of 2%. Evidence of drug failure was rapid with tumor progression in one-half of patients after 2 drug cycles. 9-AC lacks evidence of substantial activity in patients with newly diagnosed or recurrent high-grade astrocytomas.

Neuropsychologic impairment in astrocytoma survivors.

Thirteen patients selected for long-term survival with primary astrocytic tumor (who failed to return to premorbid educational or vocational levels) were examined by neuropsychologic tests of specific and generalized higher cortical functions. In the absence of tumor regrowth or other neurologic disorders, each demonstrated difficulty in problem solving or coping with novel situations when previously acquired abilities, overlearned material, and psychometric intelligence appeared consistent with their premorbid level. The diffuse difficulties were unrelated to tumor type or location, and were not explicable by existing focal deficits, psychotic or depressive thought disorders, metabolic difficulties, or hydrocephalus. These examinations explained in part why these patients failed to resume active social lives or premorbid employment. The diffuse cortical dysfunction was most notable on the Category Test, Trails B, and Localization component of the Tactual Performance Test.

Assumptions in the radiotherapy of glioblastoma.

In the light of advances in computerized tomography (CT), we have retrospectively evaluated the assumptions that underlie the radiation therapy of glioblastoma: (1) No neuroradiologic technique provides an accurate delineation of tumor bulk and location, (2) glioblastoma is commonly multicentric, and (3) a major source of therapeutic failure is recurrence beyond radiotherapy fields. 1. CT scans, performed on glioblastoma patients within 2 months of postmortem examination, defined both gross and microscopic tumor extent (within a 2-cm margin) in all but 6 of 35 patients evaluated. The major source of error was subependymal spread (four patients). 2. Multicentricity occurred in only 4% of untreated and 6% of treated (radiotherapy with or without chemotherapy) patients. All multicentric lesions were identified on CT scans. 3. Serial CT scans on 42 patients revealed that glioblastoma recurred within a 2-cm margin of the primary site in 90%. Occurrences outside this margin were accurately delineated by CT in all instances. Because most patients show recurrence within or in close proximity to the original site, current radiation doses would appear to be inadequate for therapy of the primary tumor. CT scan accuracy may permit smaller-field and higher-dose irradiation therapy for glioblastoma.

Arteriographic correlates of handedness.

Bilateral intracranial arteriograms of 123 right-handed patients and 38 left-handed patients were evaluated for: (1) the angulation of the branches of the right and left middle cerebral arteries as they leave the Sylvian fissure, (2) the position of the posterior saggital sinus with respect to the anatomic saggital midline, and (3) the dominant right-sided and left-sided superficial cortical venous drainage (Labbé, Trolard, and Sylvian). Arteriographic evaluations of these points may prove useful in assessing cerebral dominance.

Head trauma and seizures as risk factors of glioblastoma.

This is a case-control study of 160 persons with glioblastoma and 128 of their "best friends" as controls. Subjects came mainly from greater Boston, and data were gathered by questionnaire and telephone interview. Among those who had had a "severe" head injury at age 15 or later, the age-adjusted rate ratio (RR) of glioblastoma was 10.6, p = 0.004. There were six cases and no controls who had seizures for 15 or more years. The related RR is inestimable, but has a p value of 0.03. We could not evaluate whether the latter association implies a direct relationship between the causes of seizures and the causes of glioblastoma, or if it reflects the effect of another factor, such as medications to control the seizures.

Expression of Epstein-Barr virus proteins in primary CNS lymphoma in AIDS patients.

We examined the expression of the Epstein-Barr virus (EBV)-induced proteins (LMP [latent membrane protein], EBNA-2, and CD23) and a lytic protein, viral capsid antigen (VCA), in five acquired immune deficiency syndrome (AIDS)-related primary CNS lymphomas (PCNSLs). We compared that expression with the expression of the same proteins in PCNSL from six immunocompetent patients and severe combined immune deficiency (SCID) mouse brains injected with EBV-infected lymphoblastoid cell lines (LCLs). Brain biopsy tissue from an AIDS patient with progressive multifocal leukoencephalopathy (PML) and a normal brain was also studied. Three of the AIDS PCNSLs expressed both human immunoglobulin kappa and lambda light chains and two expressed lambda light chain only. All non-AIDS-related PCNSLs expressed a single light-chain isotype. All five AIDS-related PCNSLs expressed LMP-1 (> 40%), EBNA-2 (> 60%), and VCA (1 to 5%) of tumor cells. These proteins were similarly expressed in the SCID/human chimeras. None of the PCNSLs from immunocompetent subjects, the normal brain, or the brain of the patient with PML expressed these proteins. PCNSL in AIDS patients bears greater similarity to EBV-infected LCLs than to PCNSL from immunocompetent patients.

T-cell infiltration of primary CNS lymphoma.

We stained 13 primary CNS lymphomas (PCNSLs) (six from patients with AIDS, seven from immunocompetent patients) with a panel of antibodies to T cells (pan T cell [CD3], T helper cell [CD4], T suppressor cell [CD8], delta/delta cell [CD4-8-]), B cells (CD20), hematopoietic cells (T200), and NK cell (CD56). We estimated the percentage of tumor cells staining with each antibody. All tumors were B-cell lymphomas. The non-AIDS tumors showed a significant infiltration with CD3+ cells (mean of 10.82% of total cells). The AIDS patients' tumors showed a smaller percentage of CD3+ infiltrating cells (mean, 4.88% of total cells) (p<0.01). CD4+ cells were 9.11% of the total hematopoietic cells in the non-AIDS patients and 3.13% in AIDS patients (p<0.01). AIDS patients showed some CD8+ cells (0.3%), which was significantly higher than in immunocompetent patients (0%) (p<0.05). Very few tumor cells stained with the NK cell and delta/delta cell markers. Both immunocompetent and AIDS patients with PCNSL exhibit significant CD3+ and CD4+ cell infiltration of their tumors; this infiltration is significantly lower in AIDS patients. AIDS patients show a minor CD8+ cell infiltration of their tumors. These results on PCNSL are different from systemic lymphomas, which show a higher CD4 and CD8 cell infiltration, and may offer insights into the more aggressive nature of AIDS-related PCNSL.

Therapy of primary CNS lymphoma with methotrexate-based chemotherapy and deferred radiotherapy: preliminary results.

Disease-free survival in primary CNS lymphoma has improved with the advent of methotrexate-based pre-irradiation chemotherapy. Prolonged response durations have been noted in six of eight patients refusing radiation therapy in two of our prior series. We have treated an additional 11 patients with methotrexate-based chemotherapy without subsequent planned irradiation. Some received maintenance chemotherapy. Most have had durable responses with little or no toxicity. Prolonged responses can be maintained without radiation therapy, thus avoiding potential long-term radiation toxicity.

Herpes simplex infection and experimental allergic encephalomyelitis. An experimental model system for reactivation of EAE.

The effects of herpes simplex virus type 1 (HSV-1) infection on the course of experimental allergic encephalomyelitis (EAE) were studied in rats. Fifty percent of animals given two intracerebral injections of HSV-1, one before and one after induction of EAE, showed clinical and pathologic evidence of recently exacerbated EAE 16 days after the second HSV-1 injection. When HSV-1 injections were administered subcutaneously before and after induction of EAE, 45% of survivors showed pathologic changes of recent EAE. A single injection intracerebally or subcutaneously of HSV-1 given before the development of EAE did not change the clinical severity or time course of EAE. A single injection intracerebrally or subcutaneously of HSV-1 given after the development of EAE did not cause clinical recrudescence of the EAE. Pathologic but not clinical evidence of EAE recurrence was found in three of nine animals given one injection of HSV-1 intracerebrally before and one of control material intracerebrally after induction of EAE. Pathologic evidence of EAE recurrence was found in six of 14 rats given one injection of control material intracerebrally before and one of HSV-1 intracebrally after induction of EAE. Cell suspensions, free of HSV-1, given prior and subsequent to the development of EAE did not cause a change in the EAE severity or a recrudescence of the EAE.

Stroke in a 15-year-old girl secondary to terminal carotid dissection.

A 15-year-old girl died 14 days after hemiplegia suddenly developed. On arteriography, intimal separation of the middle cerebral arteries showed as a long attenuated column of dye--the "string" sign. Pathologic examination showed intimal separation starting at the distal bifurcation of the right internal carotid artery and extending into the middle and anterior cerebral arteries. The arteriographic string sign as evidence of dissection may aid diagnosis of this cause of childhood hemiplegia.