Epstein-Barr virus-associated lymphoproliferative disorder after autologous bone marrow transplantation: report of two cases.

Epstein-Barr virus-associated lymphoproliferative disorders have been frequently reported as a complication of solid organ and allogeneic bone marrow transplantation. Their occurrence is rare after autologous bone marrow transplantation (BMT) with only five published reports in the literature. We report two cases of post-transplant lymphoproliferative disorder occurring after autologous BMT for Hodgkin's disease and non-Hodgkin's lymphoma. Post-transplant lymphoproliferative disorders can occur after autologous BMT and should be included in the differential diagnosis of patients with persistent fever, adenopathy or pulmonary infiltrates.

Neurotrophins and their receptors in nerve injury and repair.

Cytokines are a heterogenous group of polypeptide mediators that have been associated with activation of numerous functions, including the immune system and inflammatory responses. The cytokine families include, but are not limited to, interleukins (IL-I alpha, IL-I beta, ILIra and IL-2-IL-15), chemokines (IL-8/ NAP-I, NAP-2, MIP-I alpha and beta, MCAF/MCP-1, MGSA and RANTES), tumor necrosis factors (TNF-alpha and TNF-beta), interferons (INF-alpha, beta and gamma), colony stimulating factors (G-CSF, M-CSF, GM-CSF, IL-3 and some of the other ILs), growth factors (EGF, FGF, PDGF, TGF alpha, TGF beta and ECGF), neuropoietins (LIF, CNTF, OM and IL-6), and neurotrophins (BDNF, NGF, NT-3-NT-6 and GDNF). The neurotrophins represent a family of survival and differentiation factors that exert profound effects in the central and peripheral nervous system (PNS). The neurotrophins are currently under investigation as therapeutic agents for the treatment of neurodegenerative disorders and nerve injury either individually or in combination with other trophic factors such as ciliary neurotrophic factor (CNTF) or fibroblast growth factor (FGF). Responsiveness of neurons to a given neurotrophin is governed by the expression of two classes of cell surface receptor. For nerve growth factor (NGF), these are p75NTR (p75) and p140trk (referred to as trk or trkA), which binds both BDNF and neurotrophin (NT)-4/5, and trkC receptor, which binds only NT-3. After binding ligand, the neurotrophin-receptor complex is internalized and retrogradely transported in the axon to the soma. Both receptors undergo ligand-induced dimerization, which activates multiple signal transduction pathways. These include the ras-dependent pathway utilized by trk to mediate neurotrophin effects such as survival and differentiation. Indeed, cellular diversity in the nervous system evolves from the concerted processes of cell proliferation, differentiation, migration, survival, and synapse formation. Neural adhesion and extracellular matrix molecules have been shown to play crucial roles in axonal migration, guidance, and growth cone targeting. Proinflammatory cytokines, released by activated macrophages and monocytes during infection, can act on neural targets that control thermogenesis, behavior, and mood. In addition to induction of fever, cytokines induce other biological functions associated with the acute phase response, including hypophagia and sleep. Cytokine production has been detected within the central nervous system as a result of brain injury, following stab wound to the brain, during viral and bacterial infections (AIDS and meningitis), and in neurodegenerative processes (multiple sclerosis and Alzheimer's disease). Novel cytokine therapies, such as anticytokine antibodies or specific receptor antagonists acting on the cytokine network may provide an optimistic feature for treatment of multiple sclerosis and other diseases in which cytokines have been implicated.

Symptom-specific use of upper gastrointestinal endoscopy in human immunodeficiency virus-infected patients yields high dividends.

The yield of upper gastrointestinal endoscopy (esophago-gastroduodenoscopy; EGD) in human immunodeficiency virus (HIV)-infected patients based on presenting symptoms has not been well studied. We studied consecutive patients with documented HIV infection undergoing EGD at a large innercity hospital between August 1, 1990 and December 31, 1993; all had presenting symptoms and indications for EGD prospectively recorded at the time of EGD. All endoscopic abnormalities were routinely subjected to biopsy, and extensive histopathological evaluation was performed. EGD was considered helpful when the findings stimulated specific therapeutic intervention other than antifungal or antacid medications. The specific indications for EGD in 156 patients were as follows: esophageal symptoms, 102 patients (65%); abdominal pain, 18 (12%); upper gastrointestinal bleeding, 25 (16%); refractory nausea and vomiting, 11 (7%). Overall, pathologic findings were identified in 116 patients (74%): in refractory esophageal symptoms, 82%; upper gastrointestinal bleeding, 92%; abdominal pain, 39%; nausea and vomiting, 27%. EGD with biopsy identified a specifically treatable opportunistic disorder other than Candida in 80 patients (51%), including idiopathic esophageal ulcer (22%) or viral esophagitis and/or duodenitis (29%). EGD was not helpful in 22.3% of cases, those involving Candida (12.3%) and peptic ulcer disease (PUD)-related causes (10%). The mean CD4 count of patients with opportunistic pathologic findings (24/mm3, n = 79) was significantly lower than that of patients with PUD/gastroesophageal reflux disease (GERD) (167/mm3, n = 9) or negative EGDs (165/mm3, n = 35). Overall, the results of EGD influenced patient management in 78% of cases. We conclude that selective symptom-specific use of EGD, particularly in patients with esophageal symptoms refractory to antifungal therapy or gastrointestinal bleeding, usually identifies specifically treatable abnormalities, whereas EGD is less useful for the evaluation of abdominal pain or nausea and vomiting.

Rare causes of occult small intestinal bleeding, including aortoenteric fistulas, small bowel tumors, and small bowel ulcers.

The most common cause for gastrointestinal bleeding of small bowel origin is angiodysplasia, followed by tumors of the small intestine, and various other causes, including small bowel ulcers and aortienteric fistulas. With the advent of improved diagnostic tests, including push and sonde enteroscopy, timely endoscopic diagnosis of these rare small bowel lesions has become possible, enabling the clinician to make better therapeutic decisions. This article focuses on the rare small bowel sources of intermittent and chronic gastrointestinal blood loss.

Central nervous system Hodgkin's disease relapsing with eosinophilic pleocytosis.

Hodgkin's disease affecting the central nervous system is infrequent. Multiple lumbar punctures are sometimes required for cytological diagnosis. In this case fluoroscopy-guided cisternal puncture and routine lumbar punctures were used to obtain cerebrospinal fluid (CSF) samples for cytological analysis. Reed-Sternberg cells were observed on the CSF sample obtained through the cisternal puncture while none were seen in the samples obtained with routine lumbar punctures. Without cytology, the diagnosis of meningeal carcinomatosis remains elusive. In conclusion, cisternal punctures should be entertained early in the evaluation for meningeal carcinomatosis, particularly if lumbar punctures have been unsuccessful.

Hepatotoxicity of drugs used in the treatment of gastrointestinal disorders.

Hepatic injury from agents in this category is rare. For example, only a handful of cases of H2-receptor antagonist-related liver injury have been reported despite the hundreds of millions of doses prescribed since the introduction of these drugs more than 15 years ago. Hepatotoxicity from sulfasalazine is uncommon but may be fatal. Injury from other agents used to treat inflammatory bowel disease also may be seen, including veno-occlusive disease from azathioprine. Of increasing importance is the toxicity from alternative health supplements, such as herbal remedies, that may cause acute, sometimes fatal, hepatic necrosis.

Hepatobiliary toxicity of total parenteral nutrition in adults.

The enzymology and clinical manifestations of total parenteral nutrition (TPN)-induced liver abnormalities have been investigated extensively. The cause, pathogenesis, and treatment of TPN-related hepatic and biliary dysfunction in adults still are not well understood, however. The findings of experimental studies in animals has not necessarily correlated with the human data, and there have been few prospective, randomized controlled trials examining the mechanism, cause, or treatment of TPN-induced hepatobiliary toxicity in adults. This article examines the animal models of pathogenesis and treatment of TPN-induced intrahepatic and extrahepatic abnormalities, and provides a discussion of abnormalities seen in humans.

Inflammatory peripheral neuropathy following high dose chemotherapy and autologous bone marrow transplantation.

A 40-year-old man with non-Hodgkin's lymphoma developed severe ascending sensorimotor neuropathy 10 days after treatment with high dose chemotherapy and autologous bone marrow rescue. The neuropathy had axonal plus demyelinating features on electrophysiological studies. Sural nerve biopsy showed heavy infiltration of the epineurium and endoneurium with mononuclear cells. The patient had no other evidence of graft-versus-host disease. He failed to respond to plasmapheresis but responded to high dose steroids.

Leptomeningeal carcinomatosis: a report of 3 cases and review of the literature.

Once thought to be rare, leptomeningeal carcinomatosis from systemic cancer is becoming more common as cancer patients are living longer. Lung, breast and malignant melanoma comprise the majority of solid tumor cases with this condition. The hallmark of the disease and the differential diagnosis are discussed. Only the identification of malignant cells in the cerebrospinal fluid provides as clear-cut diagnosis. Biochemical markers, thus far, cannot substitute for a positive cytology, but may aid in the diagnosis. We report and discuss 3 cases of complete biochemical and radiological assessment and variable degree of aggressiveness of treatment. Better control of the systemic cancer may result in prolongation of life.

Central nervous system involvement in patients with diffuse aggressive non-Hodgkin's lymphoma.

Central nervous system (CNS) involvement was evaluated in 277 consecutive patients with aggressive non-Hodgkin's lymphoma treated by the Nebraska Lymphoma Study Group. Three patients (1.1%) developed CNS involvement at presentation and 11 (4.0%) at relapse. The involvement was meningeal in 8 patients and documented by CSF cytology; it was parenchymal in 2 patients and proven by biopsy; and it was in the cauda equina in 1 patient at autopsy. Factors significantly associated with a greater likelihood of CNS relapse were age less than 60 years and epidural disease. Other factors, including tumor histology, extranodal disease at presentation, response to therapy, sex, and symptom type, were not significantly associated with a higher risk of CNS relapse. Survival of the patients presenting with CNS disease (6, 26, and 27+ months) was longer than patients whose CNS disease relapsed (median 2 months).

Detection of primary Epstein-Barr virus infection in a patient with X-linked lymphoproliferative disease receiving immunoglobulin prophylaxis.

Serologic diagnosis for Epstein-Barr virus (EBV) infection is problematic when patients receive exogenous immunoglobulin. We recently diagnosed primary EBV infection by detecting EBV-determined nuclear antigen (EBNA) and EBV-DNA in peripheral blood mononuclear cells (PBMC) using immunofluorescence, in situ hybridization and polymerase chain reaction (PCR) techniques in a patient with X-linked lymphoproliferative disease (XLP) who received prophylactic immunoglobulins for EBV infection. These combined techniques may be helpful for early and accurate diagnosis of EBV infection in highly vulnerable patients.

Variable expression of Epstein-Barr virus genome as demonstrated by in situ hybridization in central nervous system lymphomas in immunocompromised patients.

In situ hybridization, using a biotinylated sequence from the internal repeat (IR1) region of Epstein-Barr virus (EBV), was performed on two well characterized EBV-infected cell lines, B95-8 (productively infected) and Namalwa (latently infected), and on eighteen formalin-fixed paraffin-embedded primary central nervous system (CNS) lymphomas. Ten of the lymphomas were from immunocompetent patients, and eight were from immunocompromised patients (five had acquired immunodeficiency syndrome (AIDS), two had renal allografts, and one had X-linked immunoproliferative (XLP) disease). Both fresh and paraffin-embedded B95-8 cells showed detectable hybridization signal in 5 to 10% of cells, with other cells showing lower signal. Fresh Namalwa cells showed signal in every cell and in 40% of paraffin-embedded cells. Evidence of EBV genome was seen in seven of eight lymphomas from immunocompromised patients and in none of the lymphomas from immunocompetent ones. In the EBV-positive lymphomas, three patterns of hybridization were recognized: +3, more than 60% of tumor cells positive, +2, 20 to 60% of tumor cells positive, and +1, less than 20% of tumor cells positive. There was no definite relationship between survival after diagnosis and hybridization pattern type. While the signal in Namalwa cells was uniform, a wide variation in the degree and intensity of signal was noted among the seven positive tumors and even in different areas of the same tumor. This heterogeneity raises the possibility of lytic or secondary infection in a small number of the latently infected tumor cells.

Detection of Epstein-Barr virus in CNS lymphomas by in-situ hybridization.

We used an optimized in-situ hybridization technique employing a biotinylated Epstein-Barr (EB) virus sequence, BamH1V (3.1 kb), to detect this sequence in 2 EB virus-infected cell lines (B95-8 and Namalwa) and 8 CNS lymphomas. We obtained a good hybridization signal from cytospins of B95-8 (EB virus productively infected) and Namalwa (EB virus latently infected, 1 copy per cell) cell lines. We were able to detect signal from both cell lines after overnight fixation in 10% formalin and paraffin embedding, but development time in the detection chromogen required longer incubation and the signal intensity was lower than in cytospin cells. We then used the technique to examine formalin-fixed, paraffin-embedded primary CNS lymphoma tissue from 4 patients who were immunocompromised (1 renal transplant, 3 acquired immune deficiency syndrome) and 4 patients who were not. All 4 CNS lymphomas from immunocompromised patients hybridized well with BamH1V, exhibiting a pattern of staining similar to Namalwa cells and nonlytically infected B95-8 cells. There was no relationship between the intensity and degree of reaction and the patients' survival. None of the 4 CNS lymphomas in immunocompetent patients or uninvolved brain showed any reactivity with BamH1V. We suggest that low-abundance targets are detectable in paraffin-embedded tissue by in-situ hybridization using biotinylated probes. Detection of EB viral sequences in CNS lymphomas in immunocompromised patients suggests a role for the virus in the pathogenesis of this tumor.

Species cross-reactivities of antisera reacting with myelin basic peptide 43-88. Applications for the detection of peptide in rabbit plasma.

Previous investigations have demonstrated that the detection and measurement of peptides of myelin basic protein (BP) by immunochemical procedures are heavily dependent on the conformation of BP peptides and the specificities of antisera to these peptides. In the present study a double antibody-radioimmunoassay was used to assess the species specificity of antisera from 4 rabbits and 2 sheep against myelin basic protein (BP) peptide 43-88. Although some antisera showed broad reactivity, others were selective for species of BP used in the immunogen. By optimizing the reaction of one of the sheep anti-human peptide 43-88 for detection of rabbit BP peptide 43-88, it was possible to detect immunoreactive BP peptide 43-88 in the plasma of rabbits previously injected with bovine BP peptide 43-88 and complete Freund's adjuvant (CFA). Peptide could be detected in plasma for 1-2 days immediately after subcutaneous injection and again between days 20 and 50. Plasma antibody to rabbit BP peptide 43-88 also appeared 15-20 days after immunization and persisted often in an oscillatory pattern reciprocal for the peptide level. Neither peptide nor antibody was detected in the plasma of normal rabbits or of rabbits injected with bovine spinal cord homogenate-CFA, bovine renal homogenate-CFA or CFA alone. There was no relationship of the level of immunoreactive BP peptide 43-88, antibody to this peptide or their patterns to clinical or neuropathological changes in the animals. Quantitation and analysis of BP peptides in body fluids of animals with diseases affecting central nervous system myelin may provide information relevant to human demyelinating diseases.

Metabolism of a peptide of human myelin basic protein in the rabbit.

Material cross-reactive with myelin basic protein (BP) peptide 43-88 has been identified as a major BP-like antigen appearing in human cerebrospinal fluid during acute myelin injury. In an effort to develop a means for detecting this material in the more accessible body fluids of blood and urine, as well as to determine its metabolic fate, the manner in which rabbits handle human BP peptide 43-88 was investigated. Unlabeled peptide was administered intravenously, and its concentration in plasma was monitored by radioimmunoassay. In studies of 10 rabbits, the peptide disappeared from blood in two phases, the first showing a half-life of 6.0 +/- 1.2 minutes and the second a half-life of 51.6 +/- 5.4 minutes. Organ-exclusion experiments indicated a rapid clearance, predominantly by the kidney, for the peptide, with tubular reabsorption and cleavage into smaller peptide fragments a probable catabolic mechanism.