Cystic lesions accompanying extra-axial tumours.

We examined the mechanism of cyst formation in extra-axial tumours in the central nervous system (CNS). Cyst fluid, cerebrospinal fluid (CSF) and blood plasma were analysed in eight patients with nine peritumoral cysts: four with meningiomas, two with intracranial and two spinal intradural schwannomas. Measuring concentrations of various proteins [albumin, immunoglobulin G (IgG), IgA, alpha 2-macroglobulin and IgM] in cyst fluid, CSF and blood plasma provides insight into the state of the semipermeability of the blood-brain barrier (BBB) and blood-cerebrospinal fluid barrier. Peritumoral cysts accompanying intra-axial brain tumours are the end result of disruption of the BBB and oedema formation. Unlike intra-axial tumours which lie embedded within nervous tissue, extra-axial tumours tend to be separated from nervous tissue by arachnoid and pia mater. High concentrations of proteins were measured in the cyst fluid, approaching blood plasma levels, suggesting a local barrier disruption, and passage across the arachnoid, pia mater and cortical/medullary layer into the CNS parenchyma, leaving the protein concentrations of CSF practically unchanged. We confirmed that very high concentrations of protein are to be found in tumour cysts, plasma proteins forming almost 90% of the total protein in the cyst. We review current hypotheses on the pathogenesis of cysts accompanying neoplasms, particularly meningiomas and schwannomas, and conclude that the majority of proteins in cyst fluid in extra-axial, intradural meningiomas and schwannomas are plasma proteins. This provides a strong argument for pathogenesis of extra-axial intradural tumour cysts in favour of leakage of plasma proteins out of the tumour vessels into the nervous tissue.

Analysis of fluid in cysts accompanying various primary and metastatic brain tumours: proteins, lactate and pH.

There is a growing interest in cystic lesions of the brain. By examining the cyst content of brain tumours more insight into the pathogenesis of cyst formation has been found. In this study, 39 samples of cyst fluid of 34 patients with a cyst accompanying a brain tumour were collected and studied biochemically regarding their protein content, lactate and pH. In this study we investigated the relation between the grade of malignancy and the lactate-concentration and the discrepancy between the high levels of lactate in cysts and their alkaline environment. The results of the measurements of the concentrations of albumin, immunoglobulines (IgG, IgA, IgM) and alpha 2-macroglobulin in cysts compared to those in sera suggest that cyst formation associated with tumour is based upon a disruption of the blood-brain barrier with exudation of plasma proteins into the brain parenchyma resulting in accumulation of fluid (oedema) and eventually in formation of a cyst. There appears to be a positive relation between the grade of malignancy and the concentration of lactate in the cysts with a significant 2-fold increase in lactate concentration in malignant tumour cysts compared to the more benign tumour cysts (p < 0.001) probably on account of aerobic glycolysis with production of lactate by the tumour. The measured pH values in the cysts were above normal, resulting in a discrepancy of the high levels of lactate in the cyst with the alkaline environment and this suggests efflux of H(+)-ions by a Na/H exchange mechanism to compensate for the change of pH.

The pathogenesis of cysts accompanying intra-axial primary and metastatic tumors of the central nervous system.

Recent reports have suggested that cyst formation accompanying astrocytomas in the central nervous system (CNS) is due to an edematous process caused by blood-brain barrier (BBB) disruption and not a result of necrosis. This study is performed to investigate whether the hypothesis of cyst formation based on BBB disruption also applies to various pathologically different intra-axial gliomatous tumors and metastases. By chemical analysis, using immunokinetic nephelometry, isoelectric focussing, cellulose acetate electrophoresis and a biuretic method, the concentrations of albumin, immunoglobulin G (IgG), IgA, alpha2-macroglobulin, IgM and total protein were measured and proportions of concentrations of these proteins were compared in cyst fluid, blood plasma and cerebrospinal fluid (CSF). Our data, based on the chemical analysis of cyst fluid and blood plasma of 37 patients, including 2 ependymomas (one cerebral; one thoracic), 3 oligodendrogliomas, 4 hemangioblastomas, 5 cerebellar astrocytomas and 1 cervical, 1 giant astrocytoma grade one, 1 gangliocytoma, 1 neuroblastoma and 19 metastases (five lung-; two renal-; three breast-; one melanoma-; one thyroid metastasis and seven metastases of unknown origin) present high protein concentrations in the cysts with a highly similar spectrum of proteins in the tumor cyst fluid and blood plasma, suggesting a BBB disruption followed by exudation of plasma proteins into the brain parenchyma with formation of edema and transition of edematous tissue into a cyst accompanying the tumor. Although histopathologically different types of tumor tissue are involved, data suggests that the pathogenesis of cysts accompanying gliomatous tumors and metastases in the CNS is based on BBB disruption and consequent edema, as is the case in the formation of cysts in anaplastic astrocytomas.

Developing a population-based registry for patients with paraproteinemias or multiple myeloma.

The development of a population-based registry on paraproteinemia and multiple myeloma is described. A unique feature of this registry is the multidisciplinary approach to obtain and collect new cases. Clinical chemists, internists, hematologists, and pathologists could all enter patients. All patients newly diagnosed in the mid-western part of The Netherlands (1.7 million inhabitants in 1992) with a paraproteinemia or multiple myeloma in 1991, 1992, and 1993 were included. The project was composed of a registry of clinical and laboratory data extracted from the patient's records, storage of 1 ml serum at diagnosis, and a yearly follow-up. A total of 1832 entries was received, of which 83% met the inclusion criteria. Comparison of this database with the Regional Cancer Registry showed that the paraprotein registry was successful as far as registration of myeloma patients was concerned. We conclude that the multidisciplinary approach used in this paraprotein registry is feasible and has resulted in a unique collection of patients for studying potential pre-malignant conditions such as paraproteinemia.

Development of a "Myeloma Risk Score" using a population-based registry on paraproteinemia and myeloma.

Diagnostic systems for monoclonal gammopathies use bone marrow and X-ray examinations to exclude multiple myeloma (MM). Data from a population-based registry of unselected patients with paraproteinemia indicate that these tests are often done only when MM is suspected. We used 441 randomly selected patients to develop a simple four point "Myeloma Risk Score" based on two readily available laboratory tests. One point was given for paraprotein concentration > or = 10 g/l, one point for IgG and IgA, and two points for IgD and light chains only. A score of 0 or 1 indicated a low risk for MM, with scores of 2 and 3 signifying high risks. Sensitivity, specificity, positive and negative predictive value (PV) for the Myeloma Risk Score in the training sample were 92%, 88%, 79%, and 96% respectively. Extrapolating these results to a larger cohort showed that 90% of patients with a monoclonal gammopathy could be classified correctly as having MM or a non-myeloma condition. The Myeloma Risk Score can identify patients with a paraproteinemia at risk for MM, and who are therefore candidates for bone marrow and X-ray examination.

A population-based registry on paraproteinaemia in The Netherlands. Comprehensive Cancer Centre West, Leiden, The Netherlands.

Patients with monoclonal gammopathies comprise a heterogenous group. The few studies on incidence and follow-up are single-centre-based and may reflect referral bias. To avoid this, all patients (n=1275) in midwestern Netherlands with a newly discovered paraproteinaemia in 1991, 1992 and 1993 were included in a population-based registry and divided into four major diagnostic groups: multiple myeloma and plasmacytoma (n=230, 18%), other haematological diseases (n=141, 11%), paraprotein-related internal diseases (n=191, 15%) and monoclonal gammopathy of undetermined significance (MGUS, n=713, 56%). To avoid a possibly erroneous diagnosis, patients who were classified as having MGUS but who did not undergo confirmatory bone marrow examination were included in a separate group 'provisional MGUS' (n=524, 41%), whereas patients who did were classified as having 'definite MGUS' (n=189, 15%). The 'provisional MGUS' patients were relatively older and had more often a poor performance status, but differences between this and the 'definite MGUS' group were otherwise small. Patients complaining of general malaise more often had a full work-up of their paraproteinaemia. Bone pain, hypercalcaemia, high total protein, and high ESR occurred predominantly in the myeloma group, whereas fever or infection was less often seen in these patients. This registry of patients with paraproteinaemias provided valuable data related to all different diseases associated with paraproteinaemia.

Serum neural cell adhesion molecule differentiates multiple myeloma from paraproteinemias due to other causes.

Serum neural cell adhesion molecule (NCAM) has been described as a prognostic marker in multiple myeloma (MM). Both C-reactive protein (CRP) and beta 2-microglobulin (beta 2M) are established prognostic markers in MM. We tested the diagnostic value of these markers in 212 serum samples of patients with paraproteinemia registered prospectively in a population-based registry. Sixty patients had MM and 152 had other monoclonal gammopathies (hematologic diseases [48], paraneoplastic disease [35], autoimmune disease [15], and monoclonal gammopathy of undetermined significance [56]). CRP and beta 2M had wide and overlapping ranges in all diagnostic categories. However, serum neural cell adhesion molecule (NCAM) was low (< 20 U/mL) in all but 4 of 152 nonmyeloma cases and high (> or = 20 U/mL) in 31 (52%) of the 60 MM cases. Two patients with non-Hodgkin's lymphoma, 1 with chronic lymphatic leukemia, and 1 with autoimmune disease had serum NCAM values between 20 and 30 U/mL. In a discriminant analysis in which serum NCAM, CRP, beta 2M, paraprotein type and concentration, hemoglobin, leukocyte and thrombocyte counts, creatinine, corrected calcium, lactate dehydrogenase, and alkaline phosphatase were included, paraprotein type and concentration and serum NCAM turned out to be the best combination of parameters predicting whether a patient had MM, with 89% of cases being correctly classified. Even without bone marrow and x-ray examinations, serum NCAM, in combination with paraprotein type and concentration, can differentiate between MM and nonmyeloma patients.

Severe thrombotic complications in a postpartum patient with active Crohn's disease resulting in ischemic spinal cord injury.

This report describes a 33-year-old female patient who presented with severe neurological symptoms and signs during postpartum relapse of Crohn's ileocolitis. The cause of the neurological deficit was extensive major vessel thrombosis resulting in spinal cord ischemia. Etiologic factors involved in this exceptional thrombotic state are discussed with emphasis on the relationship between low levels of folic acid, homocysteine metabolism, and coagulation.

The pathogenesis of syringomyelia in spinal cord ependymoma.

A spinal cord ependymoma with syringomyelia is presented. The pathogenesis of syrinx formation, associated with intramedullary tumors is not fully understood. In order to examine the mechanism of formation of the tumor-associated syrinx, syrinx fluid was obtained during surgery and concentrations of proteins were measured in the syrinx fluid, the cerebrospinal fluid (CSF) and blood serum. Protein analysis of fluid specimens showed the fluid in tumor-associated syrinx to be an exudate. This strongly indicates that, in this case, intramedullary tumor-associated syringomyelia is based on disruption of the blood-brain barrier.

Effect of deproteinization and reagent buffer on the enzymatic assay of L-carnitine in serum.

Tris and HEPES were systematically compared as buffers for the enzymatic assay of L-carnitine. The deproteinization methods preceding the assay were also compared. The following conclusions were drawn. 1. Both Tris and HEPES act on the catalytic site of the enzyme, acetylCoA: carnitine O-acetyltransferase (EC 2.3.1.7), which is used for the conversion of L-carnitine to acetylcarnitine. HEPES is a competitive inhibitor, and no acetylated product of HEPES is formed. In the presence of Tris a limited amount of acetylTris is formed, and an appropriate blank corrects for this effect. 2. The incubation time of the assay is strongly influenced by the preceding deproteinization method. The enzyme is influenced by inorganic salt, which acts as a competitive inhibitor. 3. If Tris is used in place of HEPES in end-point assays, optimal conditions and shorter assay times are achieved with less enzyme and less acetylCoA, provided more elaborate deproteinization methods are used. 4. The HEPES system is more costly, but preferable for the determination of both total and free L-carnitine in combination with a matched deproteinization method.

Pheochromocytoma-induced hypertensive encephalopathy revealing MEN-IIa syndrome in a 13-year old boy. Implications for screening procedures and surgery.

In the multiple endocrine neoplasia (MEN) type II syndrome, pheochromocytomas become manifest at a later age than medullary thyroid carcinomas (MTC) do. The present report concerns a 13-year-old boy, belonging to a MEN-IIA kindred, who was admitted because of convulsive seizures related to hypertensive encephalopathy. A pheochromocytoma was suspected immediately and appropriate medical therapy was initiated. A right adrenal pheochromocytoma was removed, as well as a pheochromocytoma of an accessory right adrenal gland. Today, three years later our patient is still asymptomatic and the results of the thyroid C-cell provocative tests remain normal. This case clearly justifies the conclusion that periodic investigation of MEN-II family members to detect both medullary thyroid carcinoma and pheochromocytoma should begin early in life, as the latter may be the initial life-threatening expression of the disease. Long-term follow-up of patients treated with unilateral adrenalectomy will permit better definition of the risk of contralateral recurrence in such cases.