Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A variety of tumors and nontumorous lesions were used to illustrate some of the biologic, clinical, and pathologic aspects of inappropriate or ectopic endocrine and metabolic syndromes that have musculoskeletal repercussions. It is clear, both from the discussion and case material, that many mechanisms of ectopic endocrine syndromes have yet to be clarified. Elaborate techniques are available for hormonal estimations, but their routine use is prohibitively expensive and relatively unrewarding. Cells of a given lesion may be functionally heterogeneous or may fail to elaborate active products in substantial amounts. Different cells may produce similar peptides, while the same cells can produce more than one. Despite these difficulties, recognition of ectopic endocrine syndromes remains crucial to diagnosis and patient management, and thus corroboration or correlation must often rest on a cruder basis. In fact, the clinical significance of basic laboratory data, e.g., PTH elevation, may vary, as PTH may be immunoreactive but biologically inactive. As another example, hypercalcemia associated with myeloma may be variously related to coexistent hyperparathyroidism, renal disease, dehydration, or humoral osteolysis. Therefore, roentgenographic evidence of bone destruction or skeletal stigmata of hyperparathyroidism imbues laboratory data with greater significance. Paraneoplastic syndromes are of particular concern to the radiologist, as multiple systemic manifestations, occurring either synchronously or metachronously, may suggest the presence of an underlying or unifying lesion or even of a specific type of neoplasm. They may precede detection of neoplasms by months to years and can develop at any time during their course. Paraneoplastic syndromes may, furthermore, parallel the course of a lesion and be used as indicators of remission or recurrence. Conversely, those unassociated with overt symptoms possess endocrine markers that can reinforce sometimes silent skeletal stigmata. Familiarity with representative secretory products influencing the musculoskeletal system per se may often clarify seemingly innocuous and sometimes asymptomatic skeletal findings. Alert imagers may, therefore, detect, infer, or suspect particular syndromes when they present in a specific sequence or mosaic. Conversely, when apprised of their existence, imagers should know where their related effects may be sought or anticipated. Such relationships, sometimes serendipitously discovered, may be valuable assets in clinical diagnosis and patient management in both suspected and unsuspected cases.
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PMID:Skeletal manifestations of ectopic or inappropriate endocrine and metabolic syndromes. 198 23

The authors report on various diagnostic pitfalls on 102 patients having undergone exploratory cervicotomy for primary hyperparathyroidism. A false positive diagnostic error was made on 2% of the cases, bringing to 100 the number of patients with a confirmed diagnosis of primary hyperparathyroidism. False negative diagnosis was made on 4% of the patients: two late diagnoses leading to an acute toxic state and death postoperatively in both cases; two pure psychiatric variants leading to repetitive hospitalizations in psychiatry. Error in diagnosis because of a masking effect was made in 4% of the cases:--one association with a clear cell nephro--epithelioma--one association with a multiple myeloma--two associations with a benign monoclonal gammapathy. The absence of hypercalcemia, a diagnostic pitfall in the modern form of this disease was found in 7% of the cases. PTH hypersecretion which is virtually a constant finding in the normocalcemic form of the disease obviates in most cases the need of a bone biopsy and quantitative histomorphometric analysis. The association with another endocrinopathy was found in 12% of the cases (2 MEN I, 1 MEN II, 9 hyperthyroidism). Because of its high frequency in the aged (22% greater than 75 years) the diagnosis of this disease is difficult for its signs are mimicked as well by the aging process. The preoperative topographic diagnostic error is avoided since there doesn't seem to be any test which would preclude the normal surgical procedure of carefully exploring all 4 topographic sites of the parathyroid. Surgical errors can be numerous but minimized with the increasing experience of the operator. Histological errors are seen mainly in the normocalcemic variety where only electron microscopy can detect the typical signs of cellular hyperactivity.
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PMID:[Primary hyperparathyroidism. Apropos of 102 recent exploratory cervicotomies: diagnostic and clinical pitfalls]. 264 28

1. This paper describes the production and characterization of monoclonal antibodies against bovine parathyroid hormone (bPTH)-(1-84). 2. Spleen cells from A/J mice successfully immunized with bPTH-(1-84) were fused with SP2/O myeloma cells using PEG 4000 as fusogen. The screening method employed microtiter plates coated with sheep antimouse IgG and the presence of specific monoclonal antibodies was demonstrated by the binding of 125I-bPTH-(1-84). 3. A detailed study of the specificity of the three viable monoclonals with highest affinity showed that two (6FH6 and 6CD4) were amino-terminal specific and the other (5BG9) carboxyl-terminal specific. The two amino-terminal monoclonal antibodies appear to recognize the same antigenic site. 4. The monoclonal antibodies produced are potentially useful reagents for the development of new methods for the measurement of PTH in biological fluids, studies on the interaction of PTH with its receptor, as well as localization of PTH producing cells.
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PMID:Monoclonal antibodies to bovine parathyroid hormone: production and characterization. 324 28

After confirming hypercalcemia by 3 successive measurements of the total plasma calcium corrected for a plasma protein concentration of 72 g/l, which excludes spurious hypercalcemia due to dehydration, the physician orientates the aetiological diagnosis bearing in mind that primary hyperparathyroidism PHPT is the cause of 85 p. 100 of all asymptomatic forms of hypercalcaemia whilst overt or occult malignancy is the main cause (60 p. 100) of symptomatic forms of hypercalcaemia with PHPT responsible for 20 p. 100 of cases. Other causes, including drug toxicity with Vit D, calcium, Vit A, lithium, thiazide and aluminium hydroxide, sarcoidosis, hyperthyroidism, Addison's disease, pheochromocytoma and familial endocrine disorders are much rarer. Nevertheless, these rarer causes must be excluded on the clinical history and examination followed by radiological (chest X ray, plain abdomen X ray, bone X rays) and simple biological tests. The latter and/or scans tests should also help in a rapid diagnosis of metastatic carcinoma and multiple myeloma, so that the major diagnostic problem is to distinguish primary HPT from occult malignancy. This problem is greatly facilitated by reliable assays of C terminal or medium PTH rather than renal CAMP which is increased in 80 p. 100 of occult malignancies. When PTH assays is unavailable or unreliable Dent's hydrocortisone suppression test may be useful as a fall in'serum calcium is associated with occult malignancy in 70 p. 100 of cases and non-suppression is associated with PHPT in 91 p. 100 of cases. Discriminant analysis of the usual biochemical parameters may be helpful in this differential diagnosis and is accurate in about 90 p. 100 of cases. However, the association of PHPT and malignancy is also possible and not fortuitous.
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PMID:[Stages of the etiological diagnosis of hypercalcemia]. 389 Jun 61

Quantitative bone histology was studied in 23 patients with malignant hypercalcemia (MH) due to carcinoma (16) or immunoproliferative disease (7). Plasma calcium was 3.37 +/- 0.47 (mean +/- SD) mmol/liter. Bone resorbing surface (RS) was measured using a sensitive histochemical stain to identify osteoclasts. In the MH patients with carcinoma, the RS was 3.1 +/- 2.6% compared to 1.0 +/- 0.3% in controls (P less than 0.02). In the myeloma patients it was 2.3 +/- 1.7%, and in normocalcemic patients with malignant disease 0.8 +/- 1.1%. RS did not correlate with serum PTH, and several high RS values were associated with undetectable PTH. RS correlated with forming surface (FS) in MH patients (r = 0.44, P less than 0.05) and controls (r = 0.68, P less than 0.005), but there was a greater RS relative to FS in MH patients than in controls (P less than 0.005). "Excess" RS in the MH patients was calculated by subtracting the RS accounted for by the measured FS, using the relationship defined by the controls. Bone loss, as reflected in urinary calcium excretion, correlated weakly with excess RS (r = 0.44, P less than 0.05) but was high even when excess RS was zero. Thus, the histological findings do not account for the bone loss, and additional resorption around bone metastases is likely; the results of this study are consistent with a humoral substance produced by the malignant tissue causing generalized bone resorption in addition to bone dissolution around metastases.
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PMID:Quantitative bone histology in the hypercalcemia of malignant disease. 713 Mar 37

Milk-alkali syndrome can be caused by ingesting large amounts of calcium carbonate. Coincident with the promotion of calcium carbonate as treatment for both dyspepsia and osteoporosis, milk-alkali syndrome is now a common cause of hypercalcemia severe enough to require admission to the hospital. The syndrome accounted for less than 2% of such admissions before 1990, but from 1990 through 1993, it was the cause of hypercalcemia for over 12% of these patients. Only primary hyperparathyroidism and hypercalcemia of malignancy (excluding multiple myeloma) are more common. The diagnosis of milk-alkali syndrome is made almost entirely based on the patient's history; careful attention to dietary practices and over-the-counter drug use is required, as numerous over-the-counter medications contain calcium carbonate. Modern assays for PTH demonstrate the expected suppression of PTH by hypercalcemia. Nonetheless, measurement of PTH must be performed in a timely manner as treatment with intravenous saline may result in hypocalcemia and elevated PTH soon after admission. Given the pathophysiology of milk-alkali syndrome compared to other causes of hypercalcemia, hypocalcemia with rebound hyperparathyroidism is probably unique to milk-alkali syndrome.
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PMID:Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia. 789 47

Recent studies have shown that treatment with bisphosphonates could be effective against the myelomatous skeletal deterioration. However, the mechanisms of action of these drugs in multiple myeloma (MM) have been poorly studied. In the present study, 11 patients with MM and bone lesions were treated orally with 30 mg/day of risedronate for 6 months, and monitored for 6 additional months. Mean serum calcium decreased from day 4, with a concomitant increase in circulating levels of PTH (1-84) and 1,25-(OH)2D. These parameters reached their nadir on day 7 and returned to baseline value during the treatment period. Markers of bone resorption, pyridinoline and deoxypyridinoline decreased from day 7; they were at 50% and 78% of their basal value at the end of treatment and follow-up periods, respectively. A significant reduction of estimates of bone formation (serum alkaline phosphatase and osteoclacin) appeared at month 3 and persisted for the remainder of the 9-month period. Histomorphometric analysis showed a significant reduction of activation frequency, number of osteoclasts and erosion depth. Bone turnover was high at baseline, and normal after treatment, without mineralisation defects. Mean wall thickness was not different before and after treatment. Spinal bone mineral density measured by dual energy X-ray absorptiometry increased (5.3%) at the end of treatment. We conclude that oral risedronate in multiple myeloma induces a noticeable and rapid inhibition of bone resorption.
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PMID:Biologic, histologic and densitometric effects of oral risedronate on bone in patients with multiple myeloma. 802 50

Interleukin-6 (IL-6) is known to enhance osteoclast recruitment, and thereby bone resorption. Thus, IL-6 has been proposed to mediate hypercalcemia in multiple myeloma and the enhanced osteoclastic activity seen in postmenopausal osteoporosis. We recently reported that the calcium concentration in plasma affects IL-6 secretion from mononuclear blood cells. To investigate the underlying mechanism, we have studied the effect of calcium on IL-6 formation in mononuclear blood cells ex vivo and in vitro. Thirteen healthy volunteers were given 1 g of calcium orally after overnight fasting. Plasma levels of ionized calcium (pCa2+) and serum levels of parathyroid hormone (sPTH) were measured after 2 and 4 h, with all subjects still fasting. After 2 h, pCa2+ was increased and sPTH decreased in all 13 persons. IL-6 secretion ex vivo from mononuclear blood cells drawn 4 h after calcium intake was increased 185% as compared with IL-6 secretion from cells drawn just before calcium intake. In control experiments without calcium intake, there was no alteration in pCa2+ and no effect on IL-6 secretion from mononuclear blood cells. In vitro studies revealed that stimulation of isolated mononuclear blood cells with physiological concentrations of calcium dose-dependently increased IL-6 secretion with an estimated EC50 at 1.2 mM Ca2+. No effect on the IL-6 secretion was seen following treatment of the isolated mononuclear blood cells with PTH or calcitonin. These observations demonstrate that the plasma calcium concentration affects IL-6 secretion from mononuclear blood cells. The in vitro data indicate the involvement of a direct calcium sensing mechanism. These findings might have implications in hypercalcemia and should also be borne in mind when considering the role of cytokines in osteoporosis.
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PMID:Regulation of interleukin-6 secretion from mononuclear blood cells by extracellular calcium. 904 Oct 54

In order to clarify the pathogenesis of hypercalcemia in multiple myeloma, we measured plasma levels of parathyroid hormone related peptide (PTHrP), tumor necrosis factor alpha (TNF-alpha), tumor necrosis factor beta (TNF-beta), intact PTH and, serum 1,25-dihydroxyvitamin D in fifteen patients of multiple myeloma. We also measured serum levels of inorganic phosphorus (iP) and alkalinephosphatase activity (ALP). No significant differences in iP (3.2 +/- 0.4 vs. 4.0 +/- 2.2 mg/dl), ALP (150 +/- 28 vs. 335 +/- 305 IU/l) 1,25(OH)2 D (31.5 +/- 17.0 vs. 23.3 +/- 11.2 pg/ml) or TNF-alpha (7.8 +/- 2.1 vs. 8.0 +/- 2.0 pg/ml) were observed between normocalcemic and hypercalcemic patients. Plasma iPTH levels in hypercalcemic patients were significantly lower than those in normocalcemic patients (28.5 +/- 9.4 vs. 16.3 +/- 5.6 pg/ml, p = 0.01). Plasma levels of TNF-beta were less than 15.6 pg/ml in all subjects. On the other hand, the frequency of patients with abnormally high plasma levels of PTHrP was significantly greater (2/9 for normocalcemia vs 5/6 for hypercalcemia, chi 2 = 5.20, p = 0.02) in patients with hypercalcemia than in normocalcemic patients. Furthermore, a significant positive relationship between plasma PTHrP levels and corrected serum calcium levels (cCa) was observed using Spearman's correlation analysis by rank in fifteen myeloma cases (rs = 0.66, p = 0.013). These results suggest that PTHrP might be involved in the elevation of serum calcium levels in hypercalcemic myeloma patients. However, a few cases exhibit normocalcemia despite elevated plasma PTHrP levels or hypercalcemia without high plasma PTHrP levels. Therefore, further studies are necessary to elucidate the pathogenesis of hypercalcemia in multiple myeloma.
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PMID:Raised plasma concentrations of parathyroid hormone related peptide in hypercalcemic multiple myeloma. 937 Jan 19

MECHANISM OF BONE DESTRUCTION IN MALIGNANT OSTEOLYSIS: Many mechanisms have been described to explain the excessive osteoclastic activity: local stimulation factors (cytokines, lymphokines) are mainly found in breast cancer of myeloma; a general stimulation factor (PTH rP) is found predominantly in lung cancer, head and neck cancer and in cancer of the kidney or ovary. CONTRIBUTION OF BISPHOSPHONATES: The use of bisphosphonates is warranted to counteract the overactivity of the osteoclasts in humans, especially since these drugs could have a direct effect on cancer cells and also have their own therapeutic effect. There are four objectives for using bisphosphonates in cancer patients: lowering serum calcium levels, pain relief, treatment and prevention of bone metastasis. Four bisphosphonates have marketing approval in France for this indication. PROVEN AND TO BE PROVEN EFFECTS: The serum calcium lowering effect and the curative effect for the treatment of bone metastasis are well documented for all four formulations which all meet the clinical requirements for marketing approval. The preventive effect on the development of secondary bone localizations of primary cancers remains to be demonstrated and will require extensive testing in humans. There is however room for hope of substantial progress in cancerology.
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PMID:[Action of bisphosphonates on malignant osteolysis]. 1052 64


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