Clara C Chen

National Institutes of Health, 베서스다, Maryland, United States

Are you Clara C Chen?

Claim your profile

Publications (71)504.64 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: To determine if sorafenib is associated with a 4-month probability of progression-free survival, which is consistent with 50%, as determined by clinical, radiographic, and prostate-specific antigen (PSA) criteria in patients with metastatic androgen-independent prostate cancer (AIPC). Patients with progressive metastatic AIPC were enrolled in an open-label, single-arm phase II study. Sorafenib was given continuously at a dose of 400 mg orally twice daily in 28-day cycles. Clinical assessment and PSA measurement were done every cycle whereas radiographic measurements were carried out every two cycles. Twenty-two patients were enrolled in the study to date, completing a planned first stage of the trial. Baseline patient characteristics included a median age of 63.9 years (range, 50-77 years), Gleason score of 9 (range, 4-9.5), and PSA concentration of 53.3 ng/mL (range, 2-1,905 ng/mL). Fifty-nine percent of patients had received one prior chemotherapy regimen. Of the 21 patients with progressive disease, 13 progressed only by PSA criteria in the absence of evidence of clinical and radiographic progression. Two patients were found to have dramatic reduction of bone metastatic lesions as shown by bone scan, although they met PSA progression criteria at the time when scans were obtained. Toxicities likely related to treatment included one grade 3 hypertension; one grade 3 hand-foot syndrome; and grade 1/2 toxicities: fatigue, anorexia, hypertension, skin rash, nausea, and diarrhea. Results from in vitro studies suggested that PSA is not a good marker of sorafenib activity. The geometric mean exposure (AUC(0-12)) and maximum concentration (C(max)) were 9.76 h mg/L and 1.28 mg/L, respectively. The time to maximum concentration (t(max)) and accumulation ratio (after second dose) ranged from 2 to 12 h and 0.68 to 6.43, respectively. Sorafenib is relatively well tolerated in AIPC with two patients showing evidence of improved bony metastatic lesions. Interpretation of this study is complicated by discordant radiographic and PSA responses. PSA may not be an adequate biomarker for monitoring sorafenib activity. Based on these observations, further investigation using only clinical and radiographic end points as progression criteria is warranted. Accrual to the second stage of trial is ongoing.
    Clinical Cancer Research 02/2008; 14(1):209-14. DOI:10.1158/1078-0432.CCR-07-1355 · 8.19 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 6-(18)F-Fluorodopamine ((18)F-FDA) PET is a highly sensitive tool for the localization of pheochromocytoma (PHEO). The aim of this study was to establish cutoff values for pathologic and physiologic adrenal gland tracer uptake. (18)F-FDA PET with CT coregistration was performed in 14 patients (10 men and 4 women; age [mean +/- SD], 42.9 +/- 13.3 y) with unilateral adrenal gland PHEO and in 13 control subjects (5 men and 8 women; age, 51.7 +/- 12.5 y) without PHEO. Standardized uptake values (SUVs) were compared between adrenal glands with PHEO and normal left adrenal glands in control subjects. (18)F-FDA accumulation was observed in all adrenal glands with PHEO and in 6 of 13 control adrenal glands (P = 0.02). The SUV was higher in adrenal glands with PHEO (mean +/- SD, 16.1 +/- 6.1) than in (18)F-FDA-positive control adrenal glands (7.7 +/- 1.4) (P = 0.005). SUV cutoffs for distinguishing between adrenal glands with PHEO and normal adrenal glands were 7.3 (100% sensitivity) and 10.1 (100% specificity). The SUVs of adrenal foci on (18)F-FDA PET facilitate the distinction between adrenal glands with PHEO and normal adrenal glands.
    Journal of Nuclear Medicine 01/2008; 48(12):1940-4. DOI:10.2967/jnumed.107.043281 · 5.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: 6-(18)F-fluoro-l-3,4-dihydroxyphenylalanine ((18)F-DOPA) PET is a useful tool for the detection of certain neuroendocrine tumors, especially with the preadministration of carbidopa, an inhibitor of DOPA decarboxylase. Whether carbidopa also improves (18)F-DOPA PET of adrenal pheochromocytomas and extraadrenal paragangliomas is unknown. The aim of this study was to investigate the sensitivity of (18)F-DOPA PET in the detection of paraganglioma and its metastatic lesions and to evaluate whether tracer uptake by the tumors is enhanced by carbidopa. Two patients with nonmetastatic adrenal pheochromocytoma, and 9 patients with extraadrenal abdominal paraganglioma (1 nonmetastatic, 8 metastatic), underwent whole-body CT, MRI, baseline (18)F-DOPA PET, and (18)F-DOPA PET with oral preadministration of 200 mg of carbidopa. The dynamics of tracer uptake by these lesions and the physiologic distribution of (18)F-DOPA in normal tissues were recorded. Seventy-eight lesions were detected by CT or MRI, 54 by baseline (18)F-DOPA PET (P = 0.0022 vs. CT/MRI), and 57 by (18)F-DOPA PET plus carbidopa (P = 0.0075 vs. CT/MRI, not statistically significant vs. baseline). In reference to findings on CT and MRI, the sensitivities of baseline (18)F-DOPA PET were 47.4% for lesions and 55.6% for positive body regions, versus 50.0% (lesions) and 66.7% (regions) for (18)F-DOPA PET plus carbidopa (neither is statistically significant vs. baseline). Compared with baseline, carbidopa detected additional lesions in 3 (27%) of 11 patients. Carbidopa increased the mean (+/-SD) peak standardized uptake value in index tumor lesions from 6.4 +/- 3.9 to 9.1 +/- 5.6 (P = 0.037). Pancreatic physiologic (18)F-DOPA uptake, which may mask adrenal pheochromocytoma, is blocked by carbidopa. Carbidopa enhances the sensitivity of (18)F-DOPA PET for adrenal pheochromocytomas and extraadrenal abdominal paragangliomas by increasing the tumor-to-background ratio of tracer uptake. The sensitivity of (18)F-DOPA PET for metastases of paraganglioma appears to be limited.
    Journal of Nuclear Medicine 11/2007; 48(10):1599-606. DOI:10.2967/jnumed.107.042721 · 5.56 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Most lesions in FD and their attendant functional disability occur within the first decade; 90% of lesions are present by 15 years, and the median age when assistive devices are needed is 7 years. These findings have implications for prognosis and determining the timing and type of therapy. Fibrous dysplasia of bone (FD) is an uncommon skeletal disorder in which normal bone is replaced by abnormal fibro-osseous tissue. Variable amounts of skeletal involvement and disability occur. The age at which lesions are established, the pace at which the disease progresses, if (or when) the disease plateaus, and how these parameters relate to the onset of disability are unknown. To answer these questions, we performed a retrospective analysis of a group of subjects with FD. One hundred nine subjects with a spectrum of FD were studied for up to 32 years. Disease progression was assessed in serial (99)Tc-MDP bone scans by determining the location and extent of FD lesions using a validated bone scan scoring tool. Physical function and the need for ambulatory aids were assessed. Ninety percent of the total body disease skeletal burden was established by age 15. Disease was established in a region-specific pattern; in the craniofacial region, 90% of the lesions were present by 3.4 yr, in the extremities, 90% were present by 13.7 yr, and in the axial skeleton, 90% were present by 15.5 yr. Twenty-five of 103 subjects eventually needed ambulatory aids. The median age at which assistance was needed was 7 yr (range, 1-43 yr). The median bone scan score for subjects needing assistance was 64.3 (range, 18.6-75) compared with 23.1 (range, 0.5-63.5) in the unassisted subjects (p < 0.0001). Among subjects needing assistance with ambulation, 92% showed this need by 17 yr. The majority of skeletal lesions and the associated functional disability occur within the first decade of life. The implication is that the window of time for preventative therapies is narrow. Likewise, therapeutic interventions must be tailored to where the patient is in the natural history of the disease (i.e., progressive disease [young] versus established disease [older subjects]). These findings have implications for prognosis, the timing and type of therapy, and the development of trials of new therapies and their interpretation.
    Journal of Bone and Mineral Research 09/2007; 22(9):1468-74. DOI:10.1359/jbmr.070511 · 6.59 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several radiopharmaceuticals such as (18)F-FDG, (123)I-metaiodobenzylguanidine (MIBG), and (99m)Tc-tetrofosmin have demonstrated uptake in brown adipose tissue (BAT). It is important to recognize these normal variants so that they are not misinterpreted as a significant pathologic state. In addition, these radiopharmaceuticals may shed light on BAT physiology. (18)F-6-fluorodopamine (F-DA) is being used as a PET radiopharmaceutical to image adrenergic innervation and suspected pheochromocytoma. Past reports have suggested that BAT is increased in pheochromocytoma patients. The images of 96 patients evaluated with (18)F-F-DA or (18)F-FDG PET/CT for known or suspected pheochromocytoma were reviewed retrospectively to determine whether localized uptake of a pattern typically associated with BAT was present. When available, contemporaneous images obtained using (123)I-MIBG were also reviewed for the presence of BAT. Of 67 patients imaged with (18)F-F-DA, BAT was found in 17.9%. Of 83 patients imaged with (18)F-FDG, 19.2% had BAT. Discordant findings related to uptake in BAT were often seen in patients studied with (18)F-FDG, (18)F-F-DA, or (123)I-MIBG. Overall, 26 (27.0%) of 96 patients showed BAT on at least 1 of the 3 imaging modalities. (18)F-F-DA can image BAT, most likely by localizing to sympathetic innervations in a manner similar to (123)I-MIBG. Patients with pheochromocytoma may have a greater BAT tissue mass or activation because of elevated levels of circulating catecholamines. Quantitative PET with (18)F-FDG and (18)F-F-DA may have a role in in vivo studies of BAT physiology in humans or animal models.
    Journal of Nuclear Medicine 08/2007; 48(7):1077-83. DOI:10.2967/jnumed.106.035915 · 5.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Germline mutations of the gene encoding subunit B of the mitochondrial enzyme succinate dehydrogenase (SDHB) predispose to malignant paraganglioma (PGL). Timely and accurate localization of these aggressive tumors is critical for guiding optimal treatment. Our aim is to evaluate the performance of functional imaging modalities in the detection of metastatic lesions of SDHB-associated PGL. Sensitivities for the detection of metastases were compared between [18F]fluorodopamine ([18F]FDA) and [18F]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET), iodine-123- (123I) and iodine-131 (131I) -metaiodobenzylguanidine (MIBG), 111In-pentetreotide, and Tc-99m-methylene diphosphonate bone scintigraphy in 30 patients with SDHB-associated PGL. Computed tomography (CT) and magnetic resonance imaging (MRI) served as standards of reference. Twenty-nine of 30 patients had metastatic lesions. In two patients, obvious metastatic lesions on functional imaging were missed by CT and MRI. Sensitivity according to patient/body region was 80%/65% for 123I-MIBG and 88%/70% for [18F]FDA-PET. False-negative results on 123I-MIBG scintigraphy and/or [18F]FDA-PET were not predicted by genotype or biochemical phenotype. [18F]FDG-PET yielded a by patient/by body region sensitivity of 100%/97%. At least 90% of regions that were false negative on 123I-MIBG scintigraphy or [18F]FDA-PET were detected by [18F]FDG-PET. In two patients, 111In-pentetreotide scintigraphy detected liver lesions that were negative on other functional imaging modalities. Sensitivities were similar before and after chemotherapy or 131I-MIBG treatment, except for a trend toward lower post- (60%/41%) versus pretreatment (80%/65%) sensitivity of 123I-MIBG scintigraphy. With a sensitivity approaching 100%, [18F]FDG-PET is the preferred functional imaging modality for staging and treatment monitoring of SDHB-related metastatic PGL.
    Journal of Clinical Oncology 07/2007; 25(16):2262-9. DOI:10.1200/JCO.2006.09.6297 · 17.88 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Although pulmonary hypertension (PH) is a common complication of sickle cell disease (SCD) associated with high mortality, there exist few data characterizing hemodynamics and cardiopulmonary function in this population. To characterize hemodynamics and cardiopulmonary function in patients with SCD with and without PH. Patients with SCD with PH (n = 26) were compared with control subjects with SCD but without PH (n = 17), matched for age, hemoglobin levels, and fetal hemoglobin levels. Upon catheterization, 54% of the patients with PH had pulmonary arterial hypertension, and 46% had pulmonary venous hypertension. When compared with control subjects, patients with PH exhibited lower six-minute-walk distance (435 +/- 31 vs. 320 +/- 20 m, p = 0.002) and oxygen consumption (50 +/- 3% vs. 41 +/- 2% of predicted, p = 0.02), and also had mild restrictive lung disease and more perfusion abnormalities on radionuclide lung scans. The six-minute-walk distance in this population inversely correlated with tricuspid regurgitant jet velocity (r = -0.55, p < 0.001), and mean pulmonary artery pressure (r = -0.57, p < 0.001), and directly correlated with maximal oxygen consumption (r = 0.49, p = 0.004), even after adjustment for hemoglobin, supporting an independent contribution of increasing pulmonary artery pressures to loss of exercise capacity. Patients with SCD-associated PH have both pulmonary arterial and venous PH associated with severe limitations in exercise capacity, likely compounded by interstitial lung fibrosis and severe anemia. These data support the use of the six-minute-walk distance as an index of PH and cardiopulmonary function in patients with SCD.
    American Journal of Respiratory and Critical Care Medicine 07/2007; 175(12):1272-9. DOI:10.1164/rccm.200610-1498OC · 11.99 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: [(123/131)I]metaiodobenzylguanidine (MIBG) scintigraphy is considered as the gold standard in the localization of pheochromocytoma. However, this method has less optimal sensitivity for the detection of pheochromocytoma associated with von Hippel-Lindau (VHL). Our preliminary results suggest that this is partially due to the low expression of cell membrane norepinephrine transporter system in VHL-related pheochromocytoma cells. Another probable cause may be the low affinity that [(123/131)I]MIBG has for these cells. Recently, 6-[(18)F]fluorodopamine ([(18)F]DA) positron emission tomography (PET) has been introduced as a novel functional imaging modality with high sensitivity for pheochromocytoma. Therefore, we investigated whether [(18)F]DA PET is more effective than [(123/131)I]MIBG scintigraphy in the diagnostic localization of VHL-related adrenal pheochromocytoma. In this study, we evaluated seven VHL patients in whom adrenal pheochromocytomas were confirmed by histopathology results. Adrenal pheochromocytomas were localized using computed tomography (CT), magnetic resonance imaging (MRI), [(123/131)I]MIBG scintigraphy and [(18)F]DA PET. [(18)F]DA PET localized pheochromocytoma in all the seven patients, as did in CT. In contrast, three out of the seven had negative results utilizing [(123/131)I]MIBG scintigraphy and one out of the six patients had negative MRI results. [(18)F]DA PET was found to show more promising results when compared with [(123/131)I]MIBG scintigraphy in the diagnostic localization of VHL-related adrenal pheochromocytoma, with a 100% rate of localization. Thus, [(18)F]DA PET in conjunction with CT/MRI should be considered as an effective method for the proper localization of VHL-related adrenal pheochromocytoma.
    European Journal of Endocrinology 05/2007; 156(4):483-7. DOI:10.1530/EJE-06-0712 · 3.69 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: To identify patients with androgen-independent prostate cancer (AIPC) with bone metastasis and no soft-tissue metastases at the time of protocol enrollment, and analyse their disease progression by computed tomography (CT), bone scan, and prostate-specific antigen (PSA) level to determine the utility of routine interval CT in such patients. Bone is the most common metastatic site in patients with AIPC and the only site of metastatic disease for many; because some with initial bone metastasis eventually develop soft-tissue disease, many clinical trials use routine CT to monitor for the latter as a sign of disease progression, but the actual incidence of new soft-tissue metastases is unknown and the role of routine interval CT in monitoring for disease progression, especially for asymptomatic patients, is unclear. Thus we reviewed 175 cases of metastatic AIPC from three randomized phase II clinical trials (docetaxel/thalidomide, docetaxel/vaccine, and ketoconazole/alendronate) at the National Cancer Institute between 1995 and 2004. The patients' PSA levels were assessed every 4 weeks, and CT and bone scans were done every 2-3 months. We retrospectively identified patients with bone metastasis only and examined subsequent CT for the occurrence of soft-tissue disease. For patients with progressive disease, we also examined bone scan and PSA progression. Of 175 patients with metastatic prostate cancer, 105 (60%) had bone metastasis only, 12 (6.9%) had soft-tissue metastases only, and 58 (33.1%) had both bone and soft-tissue metastases. The median (range) follow-up was 8 (1-44) months for the 105 patients with bone metastasis only. During that time, two patients (1.9%) developed new soft-tissue disease; one developed right iliac fossa lymphadenopathy after 8 months and the other developed a perirectal mass after 12 months. The patient with new lymphadenopathy also had multiple new bone lesions identified by bone scan and PSA progression. The patient with the perirectal mass had PSA progression and a palpable abnormality. This review of patients with AIPC and bone metastasis only, followed for a median of 8 months on clinical trials, shows that the incidence of asymptomatic new soft-tissue disease as the only sign of disease progression is quite low. Therefore, routine CT to exclude new soft-tissue disease in this population appears to be unwarranted. We recommend that for these patients CT is done only at the time of disease progression, as shown by bone scan, PSA level, or clinical presentation. We do not exclude the possibility that patients who remain on trial for significantly longer periods might benefit from routine interval CT.
    BJU International 04/2007; 99(3):525-8. DOI:10.1111/j.1464-410X.2006.06654.x · 3.13 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer. T cells with reactivity against the ovarian cancer-associated antigen alpha-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor gamma chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells. Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells. Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.
    Clinical Cancer Research 11/2006; 12(20 Pt 1):6106-15. DOI:10.1158/1078-0432.CCR-06-1183 · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Although the majority of pheochromocytomas (PHEO) are benign, a subset is malignant. Computed tomography (CT) and magnetic resonance imaging (MRI) localize PHEO with high sensitivity but, because of limited specificity, [(131)I]- or [(123)I]-metaiodobenzylguanidine ([(131)I]- or [(123)I]-MIBG) is often used as a complementary agent. 6-[18F]-fluorodopamine ([18F]-DA) has been developed as a radiopharmaceutical for the targeting of noradrenergic pathways, and has been shown to result in a better detection rate of PHEO sites than MIBG; however, [18F]-DA has shown a lack of accumulation in some patients with metastatic PHEO. Five patients with widespread metastatic PHEO who had CT and MRI evidence of metastatic disease (one man and four women; age range, 25-64 years), and who underwent imaging with [(123)I]-MIBG, [18F]-DA and 2-[18F]-fluoro-2-deoxy-D-glucose ([18F]-FDG), were evaluated retrospectively. Tomographic imaging was performed and positron emission tomography (PET) images were inspected visually and quantitatively. All five patients had [(123)I]-MIBG scans that grossly underestimated the extent of disease when compared with conventional CT and MRI. All lesions seen on [(123)I]-MIBG scans were detected on [18F]-DA scans, which also detected additional lesions. Nonetheless, [18F]-DA also failed to detect numerous lesions seen on CT and MRI. In all of these cases, [18F]-FDG PET showed lesions that were not detected on either [(123)I]-MIBG or [18F]-DA scans. When [(123)I]-MIBG or [18F]-DA fails to localize lesions seen on conventional imaging studies, [18F]-FDG may be recommended as an ancillary test for the diagnosis and localization of metastatic PHEO. This is particularly important in patients with aggressive PHEO.
    Nuclear Medicine Communications 02/2006; 27(1):31-6. DOI:10.1097/01.mnm.0000189780.54658.e8 · 1.37 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Autoimmune lymphoproliferative syndrome (ALPS) is associated with mutations that impair the activity of lymphocyte apoptosis proteins, leading to chronic lymphadenopathy, hepatosplenomegaly, autoimmunity, and an increased risk of lymphoma. We investigated the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in discriminating benign from malignant lymphadenopathy in ALPS. We report that FDG avidity of benign lymph nodes in ALPS can be high and, hence, by itself does not imply presence of lymphoma; but FDG-PET can help guide the decision for selecting which of many enlarged nodes in ALPS patients to biopsy when lymphoma is suspected.
    American Journal of Hematology 02/2006; 81(2):81-5. DOI:10.1002/ajh.20523 · 3.48 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Alendronate (AL), a potent oral bisphosphonate, blocks the secretion of matrix metalloproteinase-2 and the establishment of bone metastases in animal models. Ketoconazole (KT) has demonstrated activity in androgen independent prostate cancer (AIPC). In this study we determined whether KT plus AL produced acceptable disease responses compared with KT alone. As the experimental design, 72 patients with progressive AIPC metastatic to bone were randomized to receive KT (1,200 mg daily) plus hydrocortisone (H) (30 mg daily) with or without AL (40 mg daily). Prostate specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decrease, time to progression and response duration. The pharmacokinetics of KT and AL were characterized and changes in circulating angiogenic factors were assessed. At a median potential followup of 23.9 months the proportion of patients with a greater than 50% decrease in PSA was similar in the KT/H/AL and KT/H, groups (50% and 47%, respectively). The median duration of response was 8.9 and 6.3 months in the KT/H/AL and KT/H groups, respectively (p = 0.125). Median progression-free survival was not significantly prolonged in the KT/H/AL group (4.6 vs 3.8 months, p = 0.27). There was no significant difference in overall survival between the 2 treatment arms but there was a trend toward improved survival in the KT/H arm (p = 0.074). Toxicity in the 2 groups was mild and there were no clear associations between changes in circulating angiogenic factor levels and clinical outcomes in either treatment arm. There were no statistically significant differences in response rate, progression-free survival or overall survival between KT/H alone and KT/H plus AL treatment in patients with AIPC. The addition of AL to KT/H may increase the response duration with an acceptable safety profile compared with treatment with KT/H alone. However, the addition of AL offers no survival benefit in patients with AIPC.
    The Journal of Urology 04/2005; 173(3):790-6. DOI:10.1097/01.ju.0000147013.09157.8e · 3.75 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: An instrument to measure skeletal burden in fibrous dysplasia was developed. Biological and clinical relevance was shown by correlating skeletal burden scores with bone markers, quality of life, and ambulatory status. Childhood scores predict adult ambulatory status, and scores were unaffected when bone markers decreased with bisphosphonate treatment or aging. Fibrous dysplasia (FD) is a skeletal disease with a broad clinical expression. There is no objective method to assess the extent of skeletal involvement or predict outcome. We developed an instrument to measure skeletal burden that correlates with physical function, health-related quality of life (HRQL), and ambulatory status. Seventy-nine patients with FD underwent bone scintigraphy. The skeletal burden score was derived from a weighted score based on the regional measurement using bone scintigraphy to estimate the amount of FD in anatomical segments. Six readers scored 20 scans twice to determine the inter- and intrareader agreement. To assess biological significance, scores were correlated with bone markers. To assess functional outcome, scores on the SF-36 (adults) or CHQ-PF50 (children) were correlated with skeletal burden scores. In a group of patients who had bone scans as children and adults (n = 6), the ability to predict ambulatory status was tested. Skeletal burden scores were assessed in patients before and after treatment with pamidronate (n = 5). The inter- and intrareader agreement of burden scores were r = 0.96, and 0.98, respectively (p < 0.001 for both). The scores correlated with markers of bone metabolism and HRQL (Spearman rho, 0.54-0.67 p < 0.001 and -0.43, p = 0.001, respectively). The mean score of patients who ambulated unassisted was significantly lower than those requiring assistance (p < 0.001 unassisted versus crutch and/or wheelchair). In unassisted ambulators, younger patients had higher scores, suggesting high childhood scores may predict adulthood impairment. In six patients with childhood and adulthood scans, childhood scores >30 predicted assisted ambulation in adulthood. There was a negative correlation between bone markers and age (Spearman rho, -0.42 to -0.70; p < 0.001), but not age and skeletal burden score. Pamidronate treatment decreased serum alkaline phosphatase but had no effect on the skeletal burden score. This is a validated and reliable instrument for the measurement of skeletal burden of FD and is able to predict functional outcome.
    Journal of Bone and Mineral Research 02/2005; 20(2):219-26. DOI:10.1359/JBMR.041111 · 6.59 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Both docetaxel and thalidomide have demonstrated activity in androgen-independent prostate cancer (AIPC). We compared the efficacy of docetaxel to docetaxel plus thalidomide in patients with AIPC. Seventy-five patients with chemotherapy-naïve metastatic AIPC were randomly assigned to receive either docetaxel 30 mg/m(2) intravenously every week for 3 consecutive weeks, followed by a 1-week rest period (n = 25); or docetaxel at the same dose and schedule, plus thalidomide 200 mg orally each day (n = 50). Prostate-specific antigen (PSA) consensus criteria and radiographic scans were used to determine the proportion of patients with a PSA decline, and time to progression. After a median potential follow-up time of 26.4 months, the proportion of patients with a greater than 50% decline in PSA was higher in the docetaxel/thalidomide group (53% in the combined group, 37% in docetaxel-alone arm). The median progression-free survival in the docetaxel group was 3.7 months and 5.9 months in the combined group (P =.32). At 18 months, overall survival in the docetaxel group was 42.9% and 68.2% in the combined group. Toxicities in both groups were manageable after administration of prophylactic low-molecular-weight heparin in the combination group. In this randomized phase II trial, the addition of thalidomide to docetaxel resulted in an encouraging PSA decline rate and overall median survival rate in patients with metastatic AIPC. After the prophylactic low-molecular-weight heparin was instituted to prevent venous thromboses, the combination regimen was well tolerated. Larger randomized trials are warranted to assess the impact of this combination.
    Journal of Clinical Oncology 08/2004; 22(13):2532-9. DOI:10.1200/JCO.2004.05.074 · 17.88 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: P-glycoprotein (Pgp) inhibitors have been under clinical evaluation for drug resistance reversal for over a decade. Valspodar (PSC 833) inhibits Pgp-mediated efflux but delays drug clearance, requiring reduction of anticancer drug dosage. We designed an infusional schedule for valspodar and vinblastine to mimic infusional vinblastine alone. The study was designed to determine the maximally tolerated dose of vinblastine, while attempting to understand the pharmacokinetic interactions between vinblastine and valspodar and to determine the response rate in patients with metastatic renal cell cancer. Patients and Methods: Thirty-nine patients received continuous infusion valspodar and vinblastine. Vinblastine was administered for 3 days to compensate for the expected delay in clearance and the required dose reduction. Valspodar was administered initially at a dose of 10 mg/kg/d; the dose of vinblastine varied. The maximum-tolerated dose of vinblastine was 1.3 mg/m(2)/d. As suggested previously, serum valspodar concentrations exceeded those needed for Pgp inhibition. Consequently, the dose of valspodar was reduced to 5 mg/kg, allowing a vinblastine dose of 2.1 mg/m(2)/d to be administered. Pharmacodynamic studies demonstrated continued inhibition of Pgp at lower valspodar doses by functional assay in Pgp-expressing CD56+ cells and by (99m)Tc-sestamibi imaging. A 15-fold range in cytochrome p450 activity was observed, as measured by midazolam clearance. No major responses were observed. These results suggest that the pharmacokinetic impact of cytochrome P450 inhibition by valspodar can be reduced although not eliminated, while preserving Pgp inhibition, thus separating the pharmacokinetic and pharmacodynamic activities of valspodar.
    Clinical Cancer Research 08/2004; 10(14):4724-33. DOI:10.1158/1078-0432.CCR-0829-03 · 8.19 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Conventional imaging modalities cannot localize the source of ACTH in 30-50% of patients with Cushing's syndrome (CS) caused by ectopic ACTH secretion (EAS). We prospectively evaluated whether [(18)F]fluorodeoxyglucose (FDG) positron emission tomography (PET) or [(111)In]-diethylenetriaminepentaacetate-D-Phe-pentetreotide (OCT) at higher than standard doses of radionuclide (18 mCi; H-OCT), can detect these tumors. Seventeen patients with presumed EAS based on inferior petrosal sinus sampling results underwent routine anatomical imaging studies [computed tomography (CT) and magnetic resonance imaging (MRI)] and OCT scintigraphy with 6 mCi (L-OCT). Research studies included FDG-PET in all patients and H-OCT if L-OCT was negative. ACTH-secreting tumors were localized in 13 patients and were occult in four. Nine of 17 CT, six of 16 MRI, six of 17 FDG-PET, eight of 17 L-OCT, and one of nine H-OCT studies were true positives. The sensitivity of CT and combined H- and L-OCT scintigraphy was higher (both 53%; 95% confidence interval, 29-76%) than that of MRI (37%; 95% confidence interval, 16-64%) or FDG-PET (35%; 95% confidence interval, 15-61%). FDG-PET did not detect tumors that were occult on CT/MRI. L-OCT was a useful complementary modality to CT and MRI. As H-OCT identified a tumor in one patient with otherwise negative imaging, it should be considered only when other imaging modalities fail to localize the ACTH-secreting tumor in patients with EAS.
    Journal of Clinical Endocrinology &amp Metabolism 06/2004; 89(5):2214-21. DOI:10.1210/jc.2003-031812 · 6.31 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: In patients with polyostotic fibrous dysplasia of bone, the peak incidence of fractures is during the first decade of life, followed by a decrease thereafter. Phosphaturia is associated with an earlier incidence and increased frequency of fractures. Fibrous dysplasia (FD) is a disorder involving either one (monostotic) or several bones (polyostotic FD [PFD] and sometimes is associated with cafe-au-lait hyperpigmentation of the skin and one or more hyperfunctioning endocrinopathies (McCune-Albright syndrome [MAS]). Both PFD and MAS are often associated with phosphaturia. Although fractures occur frequently in PFD/MAS, fracture incidence and the effect of age and co-existing metabolic abnormalities (endocrinopathy and/or phosphaturia) on fractures are ill defined. We reviewed the medical records and examined the endocrine and phosphorus metabolism of 35 patients with PFD/MAS. We report on the age at which extremity fractures occurred and their location and treatment. The results of endocrine and phosphorus metabolism testing and associations between age of first fractures, number of fractures, fracture rate, and metabolic abnormalities were noted. The average follow-up was 14.2 years (range, 2-39 years), during which 172 fractures occurred. The number and sites of fractures were 103 femoral, 25 tibial, 33 humeral, and 11 forearm. Twenty-seven patients had PFD with one or more endocrinopathies and/or phosphaturia, and eight had PFD alone. The endocrinopathies included precocious puberty (n = 19), hyperthyroidism (n = 9), growth hormone excess (n = 6), and one patient each with Cushing syndrome and primary hyperparathyroidism. Twelve patients had phosphaturia. The peak rate of fractures occurred between 6 and 10 years of age and decreased thereafter. Patients with metabolic abnormalities sustained their first fracture at an earlier age (6.9 versus 16.6 years, p < 0.005) and had a higher lifetime rate of fractures (0.29 versus 0.08 fractures/year), relative to patients with PFD alone. Phosphaturia was the single metabolic dysfunction associated with both an earlier age of first fracture (5.1 versus 16.6 years, p < 0.05) and a greater lifetime fracture rate (0.35 versus 0.08 fractures/year, p < 0.05). The occurrence of extremity fractures in FD peaks between 6 and 10 years of age and declines thereafter. Fractures occur earlier and more frequently in the presence of phosphaturia. These data have implications for long-term prognosis, clinical management, and interpretation of therapeutic interventions.
    Journal of Bone and Mineral Research 04/2004; 19(4):571-7. DOI:10.1359/JBMR.0301262 · 6.59 Impact Factor
  • Clinical Nuclear Medicine 02/2004; 29(1):35-6. DOI:10.1097/01.rlu.0000102762.66515.67 · 2.86 Impact Factor
  • Clinical Nuclear Medicine 01/2004; 28(12):979-80. DOI:10.1097/01.rlu.0000099808.30653.06 · 2.86 Impact Factor

Publication Stats

3k Citations
504.64 Total Impact Points

Institutions

  • 2001–2015
    • National Institutes of Health
      • • Center for Clinical Research
      • • Department of Laboratory Medicine
      • • Radiology and Imaging Sciences Department
      • • Program in Reproductive and Adult Endocrinology
      • • Branch of Craniofacial and Skeletal Diseases
      베서스다, Maryland, United States
  • 2014
    • CRC Press Online
      Boca Raton, Florida, United States
  • 2008–2013
    • NCI-Frederick
      Фредерик, Maryland, United States
  • 2007–2012
    • Radboud University Medical Centre (Radboudumc)
      Nymegen, Gelderland, Netherlands
  • 2011
    • Eunice Kennedy Shriver National Institute of Child Health and Human Development
      • Program in Developmental Endocrinology and Genetics (PDEGEN)
      Роквилл, Maryland, United States
  • 2008–2009
    • Department of Nuclear Medicine
      Nyitra, Nitriansky, Slovakia
  • 2006
    • National Institute of Allergy and Infectious Diseases
      • Laboratory of Immunoregulation
      베서스다, Maryland, United States
  • 2005
    • Leiden University
      Leyden, South Holland, Netherlands
  • 2003
    • National Cancer Institute (USA)
      • Center for Cancer Research
      Bethesda, MD, United States