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Jean-Jacques Body

Publications and source records attributed to Jean-Jacques Body.

At least 19 recordsLinked to original sources
PubMed2006

PTHrP, calcitonin and calcitriol in a case of severe, protracted and refractory hypercalcemia due to a pancreatic neuroendocrine tumor.

A patient with a primary neuroendocrine tumor of the pancreas, presented with severe hypercalcemia. This hypercalcemia of malignancy (HCM) failed to respond to intensive bisphosphonate treatment and needed continuous enhanced diuresis. Only after successful antitumor therapy did the hypercalcemia subside. Hypercalcemia was associated with increased concentrations of plasma PTHrP, calcitonin and 1,25-(OH)(2)D(3). Bone mineral density was markedly increased. We demonstrated the presence of both PTHrP and calcitonin in the tumor at the mRNA and protein level, using RT-PCR, immunohistochemistry and Western blotting. The high levels of plasma PTHrP and the demonstrated predominant renal mechanism in this case of HCM are suspected to be the cause for its refractoriness to bone resorption inhibitors. Our findings furthermore suggest that the tumoral production of calcitonin and PTHrP might have contributed to the increased bone mineral storage of calcium and thus probably attenuated the development of frank hypercalcemia.

Base Sequence↗
PubMed2006

Breast cancer: bisphosphonate therapy for metastatic bone disease.

The indications of bisphosphonate therapy in breast cancer patients go from the correction of hypercalcemia to the prevention of cancer treatment-induced bone loss. Bisphosphonates are part of our therapeutic armamentarium against metastatic bone pain, and at least 50% of the patients benefit from a clinically relevant analgesic effect. Placebo-controlled trials with oral or i.v. bisphosphonates have shown that prolonged administration can reduce the frequency of skeletal-related events by 30% to 40%. The superiority of zoledronic acid compared with pamidronate has been shown by a multiple-event analysis in a large randomized trial. The short infusion time of zoledronic acid also constitutes a convenient therapy. Where available, oral ibandronate offers an interesting alternative, especially for patients receiving hormone therapy. There are some toxicity concerns with the prolonged use of bisphosphonates. The occasional renal toxicity of zoledronic acid has led to the recommendation to monitor renal function before each infusion and to adjust the dose according to creatinine clearance. Osteonecrosis of the jaw could occur in up to 2.5% of breast cancer patients during long-term bisphosphonate therapy. It is often a significant complication that seems to be linked with the duration of therapy.

Bone Density Conservation Agents↗
PubMed2006

Advances in treating metastatic bone cancer: summary statement for the First Cambridge Conference.

The First Cambridge Conference on Advances in Treating Metastatic Bone Cancer, a symposium held in Cambridge, Massachusetts, October 28 to 29, 2005, was convened to discuss recent advances and research related to the natural history of bone metastases and skeletal complications, bone cancer biology, treatment of myeloma and other solid tumors, and treatment-induced bone loss. The conference format combined brief presentations with extended periods of discussion. The conclusions reached during the 2-day meeting are summarized in this article and presented in more detail in the individual articles and accompanying discussion sessions that comprise the conference proceedings.

Bone Neoplasms↗
PubMed2006

Sequence- and concentration-dependent effects of acute and long-term exposure to the bisphosphonate ibandronate in combination with single and multiple fractions of ionising radiation doses in human breast cancer cell lines.

Both bisphosphonates and radiotherapy are highly effective for the management of bone metastases. Our in vitro study examined the cytotoxic effects resulting from combinations of ibandronate and ionising radiations (RX) in various sequences on breast cancer cells. Single radiation doses were given before, at halftime of, or after acute ibandronate incubation (48 h). Single or fractionated radiation doses were applied at the end of chronic ibandronate incubation (5 weeks). Combination of acute ibandronate exposure and single radiation doses led to synergistic cytotoxic effects in MDA-MB-231 cell line, but only with low ibandronate concentrations in MCF-7 cell line. In both cell lines, synergy was more marked when ibandronate followed RX. After long-term ibandronate exposure, only high single radiation doses induced synergistic effects in MDA-MB-231 cell line. Synergy was only detected with low ibandronate concentrations in MCF-7 cell line. In both cell lines, fractionated radiation doses exerted similar effects. The combination of ibandronate with radiation can exert synergistic effects on the inhibition of breast cancer cells growth, depending on cell line, drug sequence and dosage. Our data might provide a rationale for associating bisphosphonates and radiotherapy for the treatment of bone metastases from breast cancer.

Antineoplastic Agents↗
PubMed2006

A study of the biological receptor activator of nuclear factor-kappaB ligand inhibitor, denosumab, in patients with multiple myeloma or bone metastases from breast cancer.

PURPOSE: Receptor activator of nuclear factor-kappaB ligand (RANKL) is essential for the differentiation, function, and survival of osteoclasts, which play a key role in establishment and propagation of skeletal disease in patients with multiple myeloma or bone metastases as well as many other skeletal diseases. Denosumab (AMG 162), a fully human monoclonal antibody to RANKL, was developed to treat patients with skeletal diseases. EXPERIMENTAL DESIGN: This was a randomized, double-blind, double-dummy, active-controlled, multicenter study to determine the safety and efficacy of denosumab in patients with breast cancer (n = 29) or multiple myeloma (n = 25) with radiologically confirmed bone lesions. Patients received a single dose of either denosumab (0.1, 0.3, 1.0, or 3.0 mg/kg s.c.) or pamidronate (90 mg i.v.). Bone antiresorptive effect was assessed by changes in urinary and serum N-telopeptide levels. Pharmacokinetics of denosumab also were assessed. RESULTS: Following a single s.c. dose of denosumab, levels of urinary and serum N-telopeptide decreased within 1 day, and this decrease lasted through 84 days at the higher denosumab doses. Pamidronate also decreased bone turnover, but the effect diminished progressively through follow-up. Denosumab injections were well tolerated. Mean half-lives of denosumab were 33.3 and 46.3 days for the two highest dosages. CONCLUSIONS: A single s.c. dose of denosumab given to patients with multiple myeloma or bone metastases from breast cancer was well tolerated and reduced bone resorption for at least 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with i.v. pamidronate.

Adult↗
PubMed2006

Bisphosphonates for malignancy-related bone disease: current status, future developments.

This review relates to the efficacy and safety of bisphosphonates in metastatic bone disease. It discusses practical recommendations and possible future indications for bisphosphonate therapy. The current aims of bisphosphonates for metastatic bone disease are to prevent skeletal-related events (SREs), reduce bone pain and improve quality of life. Phase III clinical trials of clodronate and pamidronate have established their efficacy against bone complications in patients with breast cancer and multiple myeloma, while randomized trials have shown SRE reductions with zoledronic acid in patients with breast cancer and multiple myeloma, prostate cancer, and lung and other solid tumors. These bisphosphonates also have some effect on metastatic bone pain. Ibandronate is a new aminobisphosphonate, available in more than 40 countries outside of the US as intravenous and oral formulations for the prevention of skeletal events in patients with breast cancer and bone metastases. Phase III studies have shown that both intravenously and orally administered ibandronate have efficacy for the prevention of skeletal events and for the reduction of metastatic bone pain. In addition to efficacy, the long-term tolerability of bisphosphonates in metastatic bone disease influences drug selection. Besides their use in patients with established bone metastases, recent and ongoing research suggests that bisphosphonates also have clinical benefit in the adjuvant setting, and for the treatment of cancer-treatment-induced bone loss. Such interesting new developments may underpin a new era of bisphosphonate use sometime in the near future.

Antineoplastic Agents↗
PubMed2006

Long-term safety of intravenous ibandronic acid for up to 4 years in metastatic breast cancer: an open-label trial.

BACKGROUND AND OBJECTIVE: Despite their widespread use in metastatic bone disease, some bisphosphonate drugs are associated with adverse events (AEs), particularly renal toxicity, adding to treatment burdens and increasing healthcare costs. Ibandronic acid is a single-nitrogen bisphosphonate with high efficacy against bone events and metastatic bone pain, and a renal safety profile compar- able to that of placebo. In this study, the safety of ibandronic acid was examined over a period of 4 years. PATIENTS AND METHODS: During an initial 96-week period, breast cancer patients with bone metastases were randomised in double-blind fashion to placebo or ibandronic acid 6mg administered by intravenous infusion over 1-2 hours every 3-4 weeks as part of a previously reported phase III trial (MF 4265 study). All patients completing the phase III trial were offered open-label active treatment for a further 96 weeks (extension phase). A total of 62 patients received ibandronic acid 6mg in this extension phase and were classified according to their initial treatment (placebo/ibandronic acid 6mg [placebo/6mg] and ibandronic acid 6mg/ibandronic acid 6mg [6mg/6mg] groups). Safety was assessed by AE reports and clinical laboratory evaluations. RESULTS: During the 4-year study, most patients experienced at least one AE, with malignancy progression being most commonly reported. However, fewer treatment-related AEs were reported in the extension phase (placebo/6mg: 6.3% [1/16]; 6mg/6mg: 13.0% [6/46]) than in the initial phase of the study (placebo: 56.3% [9/16]; 6mg: 67.4% [31/46]). Serious AEs were mainly due to malignancy progression. There were no clinically relevant renal AEs, and in both groups, serum creatinine levels were similar for up to 4 years. CONCLUSION: This 96-week open-label safety extension of a phase III, placebo-controlled trial demonstrates that long-term use of intravenous ibandronic acid is well tolerated.

Adult↗
PubMed2005

Additive growth inhibitory effects of ibandronate and antiestrogens in estrogen receptor-positive breast cancer cell lines.

INTRODUCTION: Bisphosphonates are inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and they have become standard therapy for the management of bone metastases from breast cancer. These drugs can also directly induce growth inhibition and apoptosis of osteotropic cancer cells, including estrogen receptor-positive (ER+) breast cancer cells. METHODS: We examined the anti-proliferative properties of ibandronate on two ER+ breast cancer cell lines (MCF-7 and IBEP-2), and on one ER negative (ER-) cell line (MDA-MB-231). Experiments were performed in steroid-free medium to assess ER regulation and the effect of ibandronate in combination with estrogen or antiestrogens. RESULTS: Ibandronate inhibited cancer cell growth in a dose- and time-dependent manner (approximate IC50: 10(-4) M for MCF-7 and IBEP-2 cells; 3 x 10(-4) M for MDA-MB-231 cells), partly through apoptosis induction. It completely abolished the mitogenic effect induced by 17beta-estradiol in ER+ breast cancer cells, but affected neither ER regulation nor estrogen-induced progesterone receptor expression, as documented in MCF-7 cells. Moreover, ibandronate enhanced the growth inhibitory action of partial (4-hydroxytamoxifen) and pure (ICI 182,780, now called fluvestrant or Faslodex) antiestrogens in estrogen-sensitive breast cancer cells. Combination analysis identified additive interactions between ibandronate and ER antagonists. CONCLUSION: These data constitute the first in vitro evidence for additive effects between ibandronate and antiestrogens, supporting their combined use for the treatment of bone metastases from breast cancer.

Apoptosis↗
PubMed2005

Evidence-based guidelines for the prevention and treatment of glucocorticoid-induced osteoporosis: a consensus document of the Belgian Bone Club.

Glucocorticoids (GCs) are frequently prescribed for various inflammatory and/or life-threatening conditions concerning many systems in the body. However, they can provoke many aftereffects, of which osteoporosis (OP) is one of the most crippling complications, with its host of fractures. The dramatic increase in bone fragility is mainly attributable to the GC-induced rapid bone loss in all skeletal compartments. We have reviewed the meta-analyses and randomized controlled studies reporting medical therapeutic interventions currently registered in Belgium for the management of GC-OP comparatively with a placebo. Based on this research, an expert meeting developed a consensus on the prevention and therapy of GC-OP. The pathophysiology of GC-OP is complex. Several factors, acting separately or synergistically, have been described. Their great number could help to understand the rapidity of bone loss and of bone fragility occurrence, indicating that a rapid therapeutic intervention should be implemented to avoid complications. All patients on GCs are threatened with OP, so the prevention and/or therapy of GC-OP should be considered not only for postmenopausal females, but also for osteopenic premenopausal females and for males put on a daily dose of at least 7.5 mg equivalent prednisolone that is expected to last at least 3 months. Non-pharmacological interventions, such as exercise and avoidance of tobacco and alcohol, should be recommended, even if their role is not definitely settled in GC-OP prevention. Supplemental calcium and vitamin D should be considered as the first-line therapy because of the decrease in intestinal calcium absorption provoked by GCs. They also could be considered either as isolated therapy in patients taking less than 7.5 mg prednisolone daily and/or for a predicted period shorter than 3 months or as adjuvant therapy to other more potent drugs. Hormone replacement therapy could be considered in young postmenopausal females on GC, such as in postmenopausal OP, or in men with low androgen levels. Calcitonin appears to have a protective effect on trabecular bone in GC-OP, just as in postmenopausal OP. There is an increasing body of evidence supporting the antifracture efficacy of bisphosphonates, notably alendronate and risedronate. Preventative and curative therapy of GC-OP should be maintained as long as the patient is on GC treatment and could be stopped after weaning from GC, because there is more than circumstantial evidence of some recovery of BMD when GCs are stopped. There is no indication in GC-OP for any combination of two antiresorptive agents (except for calcium and vitamin D) or for an antiresorptive and an anabolic agent. There is indeed no proof that the increased costs of combined treatments will translate into increased therapeutic efficacy.

Bone Density↗
PubMed2005

Ibandronate in metastatic bone disease: a review of preclinical data.

Bisphosphonates are widely used to prevent and treat skeletal complications of metastatic bone disease. There is increasing evidence that, besides inhibiting osteoclast activity and reducing bone resorption, bisphosphonates also have an anti-tumor effect. This paper reviews the preclinical data for ibandronate. Ibandronate increased the proportion of apoptotic tumor cells in vitro and in vivo, possibly following activation of caspase-like proteases. In vitro, ibandronate also prevented adhesion and spreading of tumor cells to bone, and tumor cell invasion. These inhibitory effects were additive when ibandronate was given with paclitaxel or docetaxel. In animal models of tumor-induced osteolysis, ibandronate significantly reduced the development of osteolytic lesions. Efficacy for the prevention and reduction of bone metastases was related to the timing of treatment; ibandronate treatment initiated prior to or shortly after tumor cell inoculation inhibited the growth of bone metastases and preserved skeletal integrity most effectively. As with other bisphosphonates, the influence of ibandronate on soft tissue metastases has been inconsistent. Overall, preclinical evidence supports the rationale for adjuvant treatment with ibandronate for patients at risk of metastatic bone disease. The renal safety profile of ibandronate supports its suitability for long-term adjuvant use, even with intermittent high dosing. Adjuvant clinical trials have been initiated. The ability of bisphosphonates to preserve skeletal integrity is also of benefit in other clinical settings. Recent studies in rat models demonstrate improved osseointegration of joint implants following ibandronate therapy, with potential application in patients with conditions such as degenerative arthritis or osteoporosis.

Animals↗
PubMed2005

Preclinical perspectives on bisphosphonate renal safety.

Renal insufficiency is not rare in cancer patients who may receive nephrotoxic medications as antineo-plastic agents or for comorbid conditions. Thus, the choice of a particular bisphosphonate for patients with metastatic bone disease should be based not only on efficacy but also on the risk for renal deterioration. Some i.v. bisphosphonates have been associated with occasional renal toxicity in the clinical setting. Preclinical studies have also shown that there may be considerable differences among bisphosphonate renal safety profiles. Comparative studies show variations in the risk for histopathologic damage and the ability to cause cumulative toxicity during intermittent dosing. Reasons for the differences among bisphosphonates are not fully understood; however, research shows that they may be influenced by pharmacokinetic properties such as renal tissue half-life or protein binding and intracellular potency. Further preclinical analyses are needed to confirm and evaluate differences among bisphosphonates.

Animals↗
PubMed2005

Longterm reduction of back pain risk in women with osteoporosis treated with teriparatide compared with alendronate.

OBJECTIVE: To compare the effects on back pain of teriparatide versus alendronate, we analyzed the reporting of back pain in a head to head comparator trial and a followup study. METHODS: In the comparator trial, women were randomized to receive either daily self-injected teriparatide 40 microg plus an oral placebo (n = 73), or daily oral alendronate 10 mg plus self-injected placebo (n = 73). Treatment was for a median 14 months. After completion of the comparator trial, 72% of these patients enrolled in a nontreatment followup study. Adverse events were recorded at each comparator trial visit and followup study visit, and the incidence of new or worsening back pain in each group was compared. RESULTS: During the comparator trial, compared with women randomized to alendronate 10 mg, women randomized to teriparatide 40 microg had reduced risk for any back pain (relative risk 0.27, 95% CI 0.09-0.82) and moderate or severe back pain (relative risk 0.19, 95% CI 0.04-0.86). The differences in the reporting of back pain between the teriparatide treated women and the alendronate treated women were sustained during an interval including the comparator trial plus 18 additional months. During an interval including the comparator trial plus 30 additional months, teriparatide treated patients had numerically fewer occurrences of back pain and moderate or severe back pain. CONCLUSION: Compared with women randomized to alendronate 10 mg, women randomized to teriparatide 40 microg had reduced risk of back pain during the trial and 2.5 years of followup.

Aged↗
PubMed2004

Ligand-independent and agonist-mediated degradation of estrogen receptor-alpha in breast carcinoma cells: evidence for distinct degradative pathways.

Molecular chaperones and co-chaperones, such as heat-shock proteins (Hsp's), play a pivotal role in the adequate folding and the stability of steroid hormone receptors. As shown by immunofluorescence staining and immunoblot analysis, the Hsp90 inhibitor radicicol induced a rapid (within hours) depletion of estrogen receptor-alpha (ER) in MCF-7 and IBEP-2 breast carcinoma cells. Inhibition of proteasomes (MG-132, LLnL) or of protein synthesis (cycloheximide), which both suppressed E(2)-induced downregulation of ER, failed to modify ER degradation caused by radicicol. On the other hand, partial antiestrogens, such as hydroxytamoxifen (a triphenylethylene) and LY 117,018 (a benzothiophene) stabilized ER, making it immune to radicicol-induced degradation. Furthermore, radicicol did not interfere with ER upregulation induced by hydroxytamoxifen. Thus, the current study points to possible variation in the mechanism/pathway of ER breakdown. Besides, the protective effect of partial antiestrogens suggests that ER stability is only compromized by Hsp90 disruption when the receptor is in its native, unliganded form.

Breast Neoplasms↗
PubMed2004

Successful use of ketamine for intractable cancer pain.

UNLABELLED: GOALS AND WORK: Despite medical awareness, intractable pain is a serious problem in cancer and occurs in up to 2% of advanced cancer patients. However, few data are available concerning the optimal treatment of such patients. The emergence of intractable pain may notably be due to the activation of N-methyl-D-aspartate (NMDA) receptors located in the central nervous system. NMDA antagonists might thus be an interesting approach in such pain syndromes. PATIENTS AND METHODS: Twelve patients with intractable cancer pain received a test dose of 5-10 mg of ketamine, a strong NMDA antagonist, in order to determine their response and tolerance to the drug. Continuous intravenous infusions of ketamine associated with morphine were then administered. MAIN RESULTS: The acute test dose was successful in all cases (VAS <3/10 after 5 min). The prolonged use of ketamine allowed us to reduce the total daily dose of morphine required (range: 200-1,200 mg) by 50% and allowed eight patients to go home with a portable pump with morphine and ketamine during a relatively long period of time (range: 7-350 days, median: 58 days). Side effects were moderate (dizziness) and they were limited to the test phase. CONCLUSION: Our data suggest the importance of NMDA receptors in the genesis of chronic cancer pain and indicate that NMDA antagonists should be further studied for the management of cancer pain and, in particular, intractable pain.

Adult↗
PubMed2004

Efficacy and safety of ibandronate in the treatment of opioid-resistant bone pain associated with metastatic bone disease: a pilot study.

PURPOSE: Bone metastases are associated with severe and sometimes intractable pain, compromising patient quality of life (QOL). This open-label pilot study investigated the effects of short-term intensive treatment with intravenous (i.v.) ibandronate on opioid-resistant bone pain in patients with skeletal metastases. PATIENTS AND METHODS: Eighteen patients with advanced tumors and metastatic bone disease received nonstandard treatment with 4 mg of ibandronate administered i.v. (2-hour infusion) for 4 consecutive days (16-mg total dose). Baseline opioid analgesic use was equivalent to 400 mg/d of morphine. Patients were assessed for 6 weeks or until death. Changes from baseline were determined for bone pain, opioid consumption, patient functioning, QOL, performance status, and biochemical markers of calcium metabolism and bone turnover. Renal function was assessed by serum urea and creatinine measurement. RESULTS: Short-term, intensive ibandronate treatment significantly reduced bone pain scores within 7 days (P <.001). Pain reductions were sustained over the study period. Ibandronate significantly improved QOL, patient functioning, and performance status (P <.05). Mean values of the urinary cross-links pyridinoline and deoxypyridinoline tended to increase after day 21, returning close to baseline values by day 42. There was no correlation between the change in crosslinks values and the change in pain scores after ibandronate treatment. Ibandronate was well tolerated, with no evidence of renal toxicity. CONCLUSION: Nonstandard, intensive treatment with i.v. ibandronate seems to have a marked analgesic effect in patients with opioid-resistant bone pain from metastatic bone disease. Further investigation is warranted.

Adult↗