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J J Body

Publications and source records attributed to J J Body.

At least 19 recordsLinked to original sources
PubMed1992

Nasal human calcitonin for tumor-induced hypercalcemia.

We treated four hypercalcemic cancer patients by nasal hCT, 3 x 2 mg daily, which has been reported to be active in Paget's disease at lower doses. Only one patient became normocalcemic and mean (+/- SEM) calcium levels fell from 11.6 +/- 0.2 mg/dl before therapy to 10.7 +/- 0.6 mg/dl 2-3 days after starting hCT. The tolerance was excellent but, because of insufficient efficacy, we do not recommend this form of therapy for cancer hypercalcemia.

Adenocarcinoma↗
PubMed1992

Metastatic bone disease: clinical and therapeutic aspects.

Breast and prostate carcinomas are the tumors most commonly associated with skeletal metastases, and the skeleton is the most common site of metastatic disease and of first distant relapse in breast cancer. Bone metastases are the source of considerable morbidity, including pain and functional disability, fractures, hypercalcemia, and epidural compression. The classical radionuclide bone scan remains the most effective tool for the screening of metastatic bone disease, but X-rays are more specific and remain the essential tool for the diagnosis and characterization of bone metastases. Computed tomography is much more useful to diagnose early metastatic involvement of bone, particularly of the spine. Patients with exclusive skeletal metastatic involvement are still frequently excluded from classical therapeutic trials because of the difficulties in the assessment of response. Recalcification of osteolytic lesions is indeed required when defining an objective response, but this criterion is insensitive and not quantitative. Moreover, the development of new osteoblastic lesions is often of difficult interpretation. A concomitant bone scan will help, but the absence of quantification of the changes and the "flare" phenomenon limit the usefulness of the technique. Pain and quality of life constitute simple, but frequently neglected, parameters of response to therapy. The clinical utility of tumor markers and of biochemical markers of bone turnover should also be more fully investigated. Neoplastic osteolysis is essentially mediated by the osteoclasts, which seem to be activated, maybe indirectly through the osteoblasts, by some tumor products. Various substances of tumoral origin have been proposed as mediators for this osteoclast activation, such as transforming growth factors, prostaglandins, and, more recently, products of the immune cells or parathyroid hormone-related peptide.(ABSTRACT TRUNCATED AT 250 WORDS)

Bone Neoplasms↗
PubMed1992

Bone metastases and tumor-induced hypercalcemia.

Tumor-induced hypercalcemia and tumor-induced osteolysis are essentially due to a marked increase in osteoclast-mediated bone resorption, although the kidneys play an important contributory role in the genesis of tumor-induced hypercalcemia. Parathyroid hormone-like protein plays an essential role in tumor-induced hypercalcemia, and maybe in tumor-induced osteolysis, but other factors could also be responsible for the osteoclast activation secondary to the neoplastic infiltration of the skeleton. Treatment of tumor-induced hypercalcemia essentially consists of volume repletion and administration of potent anti-osteolytic drugs. The bisphosphonate pamidronate is particularly useful for that matter and a dose of 1.0 to 1.5 mg/kg can normalize serum calcium in about 90% of hypercalcemic cancer patients. The apparently low response rate of bone metastases to systemic antineoplastic therapy seems to essentially reflect the relative insensitivity of our current methods for assessing response in tumor-induced osteolysis. Newly developed biochemical markers of bone turnover could be particularly useful for that matter. Bisphosphonates are the most potent of the available inhibitors of osteoclast activity. Prolonged administration of oral pamidronate could reduce by almost one half the complications of tumor-induced osteolysis, and repeated bisphosphonate infusions could induce a dramatic relief of bone pain in one third and a sclerosis of lytic lesions in one fourth of the cases. These data must, however, be confirmed in randomized, blinded trials and many questions remain unanswered concerning the optimal therapeutic schemes. Medical therapy of tumor-induced osteolysis by noncytotoxic means has nevertheless become a reality.

Antineoplastic Agents↗
PubMed1992

Urinary pyridinium cross-links as markers of bone resorption in tumor-associated hypercalcemia.

Osteoclastic activity is increased in tumor-associated hypercalcemia, which, thus, constitutes an excellent opportunity to assess new markers of the bone resorption rate. We have measured the fasting urinary excretion of the pyridinium cross-links pyridinoline (Pyr) and deoxypyridinoline (D-Pyr) in 36 hypercalcemic cancer patients (mean +/- SD, 3.2 +/- 0.4 mmol/L for total serum Ca and 1.66 +/- 0.24 mmol/L for Ca2+). Thirty-two of them were reevaluated after treatment with iv bisphosphonates. Urinary Pyr and D-Pyr levels were higher than those in healthy controls (130 +/- 62 vs. 40 +/- 19 nmol/mmol creatinine for Pyr and 20 +/- 15 vs. 6 +/- 3 nmol/mmol creatinine for D-Pyr; P less than 0.001 for both). This represented a mean 3.3-fold increase over the normal mean compared to 5.8- and 3.4-fold increases for fasting urinary Ca and hydroxyproline, respectively. Individual values were elevated in 83% and 75% of the cases for Pyr and D-Pyr compared to 97% and 83% for urinary Ca and hydroxyproline, respectively. The levels of Pyr and D-Pyr tended to be higher in patients with head and neck tumors than in patients with breast cancer. Urinary Pyr and D-Pyr correlated with each other (r = 0.72; P less than 0.001) and were highly correlated with hydroxyproline (r = 0.68 and 0.83, respectively; P less than 0.001 for both), but poorly correlated with urinary Ca (r = 0.21; P = NS and r = 0.42; P = 0.01, respectively), suggesting that these markers reflect different events of bone resorption. Similarly, after bisphosphonate therapy, urinary Pyr and D-Pyr levels fell by 31% and 50%, respectively, compared to 38% for hydroxyproline and 76% for urinary Ca. There was a significant correlation between posttreatment D-Pyr and serum Ca levels (r = 0.43; P less than 0.05). In summary, we found that the urinary excretion of Pyr and D-Pyr was markedly increased in hypercalcemic cancer patients and was adequately lowered by bisphosphonate therapy. The urinary excretion of the pyridinium cross-links, especially D-Pyr, should be helpful to specifically quantitate bone matrix resorption and monitor the inhibition of bone resorption in cancer patients receiving antiosteolytic drugs.

Amino Acids↗
PubMed1992

Recovery of parathyroid hormone secretion during correction of tumor-associated hypercalcemia.

Spontaneous recovery of parathyroid secretion during correction of tumor-associated hypercalcemia by bisphosphonates provides a unique clinical opportunity to further unravel the complex relationship between Ca and PTH levels. We measured plasma ionised Ca (Ca2+) and serum intact PTH concentrations in 31 hypercalcemic cancer patients every 2 (range, 1-3) days over a period of 3-21 (median, 7) days after pamidronate therapy. The mean (+/- SD) initial Ca2+ concentration was 1.64 +/- 0.20 mmol/L (normal, 1.05-1.26 mmol/L), with a corresponding PTH level of 4.9 +/- 2.6 (median, 4.5; range, less than 2.0-14.7) ng/L. PTH levels were subnormal in 30 of 31 patients. During correction of hypercalcemia, the relationship between Ca2+ and PTH concentrations was best described by a polynomial regression (r = 0.89; P less than 0.001). The curve of the regression entered the normal range of PTH levels (10.5 ng/L) for a Ca2+ concentration of 1.21 mmol/L. Similarly, the mean Ca2+ level that caused a reproducible increase in PTH levels compared to baseline values was 1.21 +/- 0.12 (median, 1.17; range, 1.00-1.45) mmol/L. Comparable values were obtained when day to day variations in PTH levels were considered; the mean Ca2+ threshold level was 1.24 +/- 0.12 (median, 1.25; range, 1.00-1.43) mmol/L. This PTH secretory threshold was not significantly influenced by several factors, including the type of cancer hypercalcemia, the day to day variations in Ca2+ levels, various biochemical parameters of calcium metabolism, or the number of days to obtain a normal Ca2+ concentration. In summary, contrary to previous reports, our data show that the PTH secretory threshold during correction of tumor-associated hypercalcemia lies in the upper part of the normal range of Ca2+ concentrations and is not significantly influenced by the rate of change in Ca2+ levels.

Calcium↗
PubMed1992

Monoclonal immunoradiometric assay and polyclonal radioimmunoassay compared for measuring neuron-specific enolase in patients with lung cancer.

Neuron-specific enolase (NSE) is the most sensitive and specific tumor marker for small-cell lung cancer (SCLC). We evaluated a new monoclonal IRMA (Sangtec) for NSE and compared it with a polyclonal RIA (Pharmacia) in patients with SCLC or other lung cancers (NSCLC). We measured NSE concentrations in 100 healthy subjects (NI group), 100 patients with benign pulmonary diseases (BPD group), and 194 patients with advanced lung cancer (97 SCLC and 97 NSCLC). Intra- and interassay CVs were less than 7% for both assays, and dose-dilution curves paralleled their respective standard curves. Values measured by both assays were highly correlated in all groups. NSE concentrations were significantly (P less than 0.001) lower by IRMA than by RIA in NI and BPD groups. The upper 95th percentile values for NSE in the NI group were 11.7 micrograms/L in the RIA and 9.2 micrograms/L in the IRMA. In NSCLC, the values were significantly (P less than 0.05) lower by IRMA but the percentage of subjects with increased values was higher (vs the NI group, 31% for RIA and 44% for IRMA, P less than 0.005). Diagnostic sensitivity for SCLC was improved with IRMA: 83% of values with RIA and 93% with IRMA were increased above the NI group values (P less than 0.005); the corresponding values for SCLC vs BPD were 81% and 89% (P less than 0.05). NSE values measured in 39 patients with SCLC after chemotherapy were more often increased and were significantly higher with the IRMA than with the RIA (P less than 0.005).

Adolescent↗
PubMed1992

Hypertrophic osteoarthropathy and thyroid cancer.

We describe a case of aggressive undifferentiated thyroid cancer associated with rapidly evolving hypertrophic osteoarthropathy (HOA) that developed at the time of pulmonary dissemination of the thyroid neoplasm. The syndrome appeared to be paraneoplastic, possibly due to a substance normally cleared by the lungs.

Bone and Bones↗
PubMed1991

Calcitonin secretion in idiopathic renal stone formers.

Several studies demonstrated a reduction in bone mineral content (BMC) in idiopathic renal stone formers (RSF). We found this reduction in association with a chronic low-calcium diet. Low calcium intake could theoretically result in calcitonin deficiency, responsible for increased bone resorption. This hypothesis was tested in 22 male RSF eating a low-calcium diet (350 +/- 72 SD mg/day) for 2 years or more, who showed a significant reduction in their BMC. When compared to 15 normal male subjects eating a free diet, RSF showed increases in serum alkaline phosphatase activity and fasting urinary excretion of hydroxyproline and calcium, suggesting increased bone turnover. Plasma calcitonin levels were measured by radioimmunoassay following an extraction-concentration technique (exCT). Basal plasma exCT levels were higher (P less than 0.005) in RSF (4.1 +/- 0.8 SEM pg/ml) than in normal subjects (2.8 +/- 0.4). Following a 5 minute infusion of 2 mg elemental calcium per kg, levels of plasma exCT tended to increase more, although not significantly, in RSF (51.3 +/- 9.4 pg/ml) than in normal subjects (36.6 +/- 9.7). The CT secretory response, taking into account changes in serum calcium concentration (delta exCT/delta Ca), was higher (P less than 0.05) in RSF (50.0 +/- 10.0) than in normal subjects (25.6 +/- 6.6). Our study thus demonstrates that RSF chronically fed a low-calcium diet have increased basal plasma CT levels and increased CT cells responsiveness. CT deficiency cannot therefore be considered a cause for the low BMC associated with a chronic low-calcium diet in RSF.

Adult↗
PubMed1991

Stimulation of calcitonin secretion by an oral calcium load test in normal subjects and in idiopathic renal stone formers.

Circulating concentrations of calcitonin (CT) have been found high in idiopathic renal calcium stone formers (RSF). It has been postulated that this could result from increased serum calcium concentrations following calcium-containing meals. To verify this hypothesis, 15 male idiopathic RSF and 15 male normal subjects underwent plasma CT measurements, following an extraction-concentration technique (exCT), in basal state and during an oral calcium load test. Most RSF exhibited increased excretion of calcium following oral calcium loading, suggesting overabsorption of calcium, but serum calcium did not increase more in RSF than in normal subjects. Basal plasma exCT concentrations were normal in RSF. ExCT plasma concentrations following calcium loading, and the area under the curve of exCT levels, tended to be higher in RSF than in normal subjects, but not significantly. Our results thus do not support the hypothesis that increased plasma CT levels in RSF result from increased serum calcium concentrations following calcium-containing meals.

Administration, Oral↗
PubMed1991

Efficacy and safety of the bisphosphonate tiludronate for the treatment of tumor-associated hypercalcemia.

Tiludronate is a new bisphosphonate whose efficacy has already been reported for the prevention of postmenopausal bone loss. We have evaluated its efficacy and tolerance by a dose-finding study in 19 hypercalcemic cancer patients after adequate intravenous (iv) rehydration. Treatment consisted of 3 days of iv tiludronate given at doses of 3.0 mg/kg/day (n = 3), 4.5 mg/kg/day (n = 3), or 6.0 mg/kg/day (n = 13); this iv therapy was followed by 17 days of oral tiludronate, 400 mg (n = 13) or 800 mg (n = 6) daily. Treatment had to be discontinued in 9 patients, including 3 because of evident treatment failure and 1 because of severe toxicity. After iv tiludronate, 13/18 patients had a normal Ca level, including 10/12 who had received 6.0 mg/kg/day, but Ca2+ levels were fully normalized in only 4/18 and 3/12 patients, respectively. After 6.0 mg/kg/day, Ca levels had fallen from 12.1 +/- 0.3 to 10.0 +/- 0.4 mg/dl (P less than 0.0005), whereas fasting urinary calcium excretion went from 0.639 +/- 0.099 to 0.272 +/- 0.054 mg Ca/mg creatinine on d4 (P less than 0.001). On the other hand, oral tiludronate was unable to normalize Ca in patients who were still hypercalcemic after the iv course, although the daily administration of 800 mg appeared to be more efficient than the 400 mg daily dosage. The administration of tiludronate caused an increase in serum phosphate levels, from 2.9 +/- 0.2 to 3.7 +/- 0.2 mg/dl after the iv course, probably through an increase in the TmP/GFR index, which went from 2.3 +/- 0.2 to 3.6 +/- 0.4 mg/dl (P less than 0.05). Three patients had an increase in serum creatinine levels after the iv course, one obese patient developing an acute renal insufficiency; during oral tiludronate therapy, 5 other patients also presented an increase in serum creatinine levels. Oral tiludronate administration was also associated with occasional nausea and vomiting. In summary, compared with aminobisphosphonates, tiludronate is not indicated for the treatment of tumor-associated hypercalcemia because of the need for high iv doses which are potentially nephrotoxic.

Bone Resorption↗
PubMed1991

Effects of Carbetimer, a new antineoplastic drug, on bone metabolism.

Carbetimer is a new antineoplastic agent whose main side effects consist of neurotoxicity and long-term dose-dependent hypercalcemia. We previously showed that Carbetimer is a potent calcium chelator responsible for an acute decrease in ionized Ca levels observed in vivo. However, the mechanism of the progressive increase in serum Ca remains unknown. We have evaluated the bone-resorbing effects of Carbetimer on 45Ca-prelabelled neonatal mouse calvariae. Carbetimer induced a dose-dependent increase in 45Ca release which started at a concentration of 1 mg/ml and reached a mean of 3.3 times the control values at 10 mg/ml. This marked increase in 45Ca release was similar on previously killed bones and could not be inhibited by calcitonin. Such concentrations are probably therapeutically relevant given the known affinity of Carbetimer for bone and the large daily doses administered to cancer patients (10-15 g). Since Carbetimer could exert its antineoplastic action through immunomodulation, we also studied its effects on the production of TNF-alpha and IFN-gamma which are also known to affect bone metabolism. Carbetimer did not stimulate TNF-alpha release from isolated normal human monocytes or lymphocytes, but it markedly inhibited T-lymphocyte production of IFN-gamma, which became undetectable at a concentration of 1 mg of Carbetimer/ml. In summary, Carbetimer-induced hypercalcemia appears to be due to a direct stimulation of osteolysis, but possibly also to an inhibition of IFN-gamma production.

Animals↗
PubMed1991

Intravenous administration of amphotericin B entrapped in liposomes: induction of high serum levels of TNF alpha.

The rate of objective response to second-line chemotherapy with cyclophosphamide, adriamycin and vincristine increased from 13% to 55% in two consecutive series of patients with small-cell lung cancer when the therapy was potentiated by amphotericin B (2 mg/kg i.v.) entrapped in liposomes (= ampholiposomes). Patients who received ampholiposomes had a rapid and significant (p less than 0.01) increase of serum TNF alpha concentrations (median value: from less than 10 to 261 pg/mL) followed by a rise in serum neopterin and CRP. No major side effects were observed. Administration of ampholiposomes appeared to be a safe method for obtaining relatively high serum levels of TNF alpha that could potentiate anticancer chemotherapy.

Adult↗
PubMed1991

Estrogen-like activity of a subpopulation of natural antiestrogen receptor autoantibodies in man.

We recently reported that a subpopulation of immunoglobulin G (IgG) in man interacts with the hormone-binding site of estrogen receptors (ER), competes with [3H]estradiol (E2) uptake, and decreases effective ER concentrations in cell cultures. The present work further characterizes the immunological properties of these antibodies and defines their biological activity. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting techniques, enriched preparations of the natural anti-ER IgG subpopulation (IgGs) were found to specifically immunoprecipitate ER extracted from MCF-7 mammary carcinoma cells and to compete with [3H]tamoxifen-aziridine for ER binding. During 18-h incubations IgGs decreased [3H]E2 binding capacity of MCF-7 cells in a dose-dependent manner similar to E2. Like E2 but unlike antiestrogens, this biological effect corresponded to down-regulation of the receptor protein and depended on a mechanism specifically inhibited by actinomycin D. Moreover, IgGs antagonized the decrease of [3H]E2 binding capacity produced by the strong antiestrogen methyl-hydroxytamoxifen; this antagonism was additive to that of E2. On the other hand, IgGs like estrogens increased progesterone receptor concentrations and cathepsin D secretion. The biological activity of IgGs was neutralized by anti-IgG antibodies and by ICI 164,384, a "pure" steroid antagonist of E2, confirming that immunoglobulins G were responsible for this activity and acted at the E2-binding site. These observations indicate that some natural antibodies in man can function like potent estrogens on ER and mammary cells.

Autoantibodies↗
PubMed1991

Parathyroid hormone-related protein: elevated levels in both humoral hypercalcemia of malignancy and hypercalcemia complicating metastatic breast cancer.

A RIA for PTH-related protein (PTHrP) is described, using a polyclonal goat antiserum against synthetic PTHrP-(1-40) and recombinant PTHrP-(1-84) as standard. The detection limit is 2 pmol/L, and intra- and interassay coefficients of variation are 4.8% and 13.6%, respectively. This assay does not detect PTH even at concentrations of up to 2000 pmol/L. Cross-reactivity studies using various synthetic PTHrP peptides localize the antibody-binding epitope between residues 20 and 29. Hypercalcemic patients with a range of solid tumors and no evidence of bone metastases on radionuclide scanning (n = 27) all had detectable PTHrP levels (range, 2.8-51.2 pmol/L). Of 17 patients with solid tumors (other than breast) and bone metastases, 11 (64%) also had detectable PTHrP levels (range, 4.9-47.5 pmol/L). Twenty samples from breast cancer patients with hypercalcemia, 19 with evidence of bone metastases, and 1 with a negative bone scan were assayed, and detectable PTHrP levels were found in 13 (65%; range, 3.8-61.6 pmol/L). Patients with squamous cell carcinomata and normal serum calcium levels (n = 11) had no detectable PTHrP or levels close to the detection limit of the assay (range, less than 2 to 3.7 pmol/L). Plasma levels in normal volunteers were below the detection limit of the assay in all but 1 of 38 normal subjects. Patients with chronic renal failure on hemodialysis (n = 18) and patients with primary hyperparathyroidism (n = 14) all had undetectable PTHrP in this assay. This assay allows positive identification of patients with PTHrP-mediated hypercalcemia and, therefore, should be useful in the clinical investigation of the hypercalcemic patient. Furthermore, it has allowed detection of circulating PTHrP in hypercalcemic breast cancer patients with bone metastases, indicating a significant role for PTHrP in this disease.

Adult↗
PubMed1990

Evaluation of squamous cell carcinoma antigen as a new marker for lung cancer.

Carcinoembryonic antigen (CEA) is the only tumor marker of proven, although limited, value for the management of patients with non-small cell lung cancer (NSCLC). The authors have prospectively assessed the potential value of a new tumor marker, squamous cell carcinoma antigen (SCC Ag), in a large series of patients with advanced lung cancer (LC). Squamous cell carcinoma antigen and CEA levels were measured in 382 healthy persons (N1 group), 90 patients with benign pulmonary diseases, and 291 patients with LC (129 with SCLC and 162 with NSCLC, including 96 with squamous LC). Carcinoembryonic antigen levels were higher in smokers than in nonsmokers, but smoking habits did not influence the serum concentrations of SCC Ag. Elevated values (above the 95th percentiles of N1, i.e., 7.5 ng/ml for CEA and 3.0 ng/ml for SCC Ag) were observed in 11.1% of patients with benign pulmonary diseases for both markers. Carcinoembryonic antigen was more sensitive than SCC Ag, even for squamous LC (56% versus 35% of elevated values, P less than 0.01). The specificity toward squamous LC was better, however, for SCC Ag, for which levels were elevated in only 8.5% of SCLC and in 18% of other forms of NSCLC, compared with 49% and 55%, respectively, for CEA. Moreover, measurement of SCC Ag and CEA levels did not give redundant information: thus, in squamous LC and SCC Ag level was elevated in 32% of the patients with a normal CEA level, increasing from 57% to 71% the proportion of patients with at least one elevated marker. Lastly, elevation of CEA or SCC Ag levels was an adverse prognostic factor in squamous LC (P = 0.05 for CEA; P = 0.07 for SCC Ag). In conclusion, SCC Ag appears to be worthwhile of further investigation in squamous LC. The authors found that this new marker provided additional information on CEA and that it was more specific for squamous LC than CEA.

Adolescent↗
PubMed1990

Calcitonin and bone mass status in congenital hypothyroidism.

Calcitonin (CT) deficiency and its possible repercussions on bone mass were studied in a group of 9 adult patients (7 females, 2 males) with congenital hypothyroidism of dysgenetic origin. Using a new extraction method (exCT) which considerably improves the sensitivity and the specificity of the assay for CT-monomer, we measured CT levels before and after a short calcium (Ca) stimulation test (2 mg Ca/kg over 5 minutes) to evaluate C-cell secretory reserve. Mean basal plasma CT concentrations were lower in the hypothyroid women (mean +/- SEM: 0.6 +/- 0.1 pg/ml) than in 30 normal female controls (1.7 +/- 0.2 pg/ml, P less than 0.001). Serum calcium increased similarly in the two groups, but postinfusion CT levels were lower in the hypothyroid women, (1.7 +/- 0.2 pg/ml) than in normal women (16.8 +/- 2.9 pg/ml), P less than 0.001. Hypothyroid women showed a 10% reduction in bone mineral content at the diaphyseal site in the radius, 0.840 +/- 0.037 g/cm, compared with normal age-matched controls, 0.930 +/- 0.020 g/cm, (P less than 0.05). Our study demonstrates the existence of a profound CT-monomer deficiency in adult patients with thyroid agenesis or dysgenesis. Both calcitonin deficiency and thyroid hormone treatment could play a role in the observed bone loss. Attention should therefore be paid to bone metabolism during treatment of congenital hypothyroidism to avoid further bone loss.

Adolescent↗