Phase I Study of Lentiviral-Transduced Chimeric Antigen Receptor-Modified T Cells Recognizing Mesothelin in Advanced Solid Cancers.

This phase I study investigated the safety and activity of lentiviral-transduced chimeric antigen receptor (CAR)-modified autologous T cells redirected against mesothelin (CART-meso) in patients with malignant pleural mesothelioma, ovarian carcinoma, and pancreatic ductal adenocarcinoma. Fifteen patients with chemotherapy-refractory cancer (n = 5 per indication) were treated with a single CART-meso cell infusion. CART-meso cells were engineered by lentiviral transduction with a construct composed of the anti-mesothelin single-chain variable fragment derived from the mouse monoclonal antibody SS1 fused to intracellular signaling domains of 4-1BB and CD3zeta. Patients received 1-3 × 107 or 1-3 × 108 CART-meso cells/m2 with or without 1.5 g/m2 cyclophosphamide. Lentiviral-transduced CART-meso cells were well tolerated; one dose-limiting toxicity (grade 4, sepsis) occurred at 1-3 × 107/m2 CART-meso without cyclophosphamide. The best overall response was stable disease (11/15 patients). CART-meso cells expanded in the blood and reached peak levels by days 6-14 but persisted transiently. Cyclophosphamide pre-treatment enhanced CART-meso expansion but did not improve persistence beyond 28 days. CART-meso DNA was detected in 7/10 tumor biopsies. Human anti-chimeric antibodies (HACA) were detected in the blood of 8/14 patients. CART-meso cells were well tolerated and expanded in the blood of all patients but showed limited clinical activity. Studies evaluating a fully human anti-mesothelin CAR are ongoing.

Activity of Mesothelin-Specific Chimeric Antigen Receptor T Cells Against Pancreatic Carcinoma Metastases in a Phase 1 Trial.

Pancreatic ductal adenocarcinoma (PDAC) is resistant to T-cell-mediated immunotherapy. We engineered T cells to transiently express a messenger RNA encoding a chimeric antigen receptor (CAR) specific for mesothelin, a protein that is overexpressed by PDAC cells. We performed a phase I study to evaluate the safety and efficacy of adoptive cell therapy with autologous mesothelin-specific CAR T cells (CARTmeso cells) in 6 patients with chemotherapy-refractory metastatic PDAC. Patients were given intravenous CARTmeso cells 3 times weekly for 3 weeks. None of the patients developed cytokine release syndrome or neurologic symptoms and there were no dose-limiting toxicities. Disease stabilized in 2 patients, with progression-free survival times of 3.8 and 5.4 months. We used 18F-2-fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography/computed tomography imaging to monitor the metabolic active volume (MAV) of individual tumor lesions. The total MAV remained stable in 3 patients and decreased by 69.2% in 1 patient with biopsy-proven mesothelin expression; in this patient, all liver lesions had a complete reduction in FDG uptake at 1 month compared with baseline, although there was no effect on the primary PDAC. Transient CAR expression was detected in patients' blood after infusion and led to expansion of new immunoglobulin G proteins. Our results provide evidence for the potential antitumor activity of messenger RNA CARTmeso cells, as well as PDAC resistance to the immune response.

Photoinduced Terminal Hydride of [FeFe]-Hydrogenase Biomimetic Complexes.

The active site of the [FeFe]-hydrogenase ([FeFe]-H2ase) has a bridging carbonyl ligand and a terminal hydride in the key H-cluster intermediate Hhyd. However, nearly all of the synthetic mimics reported, so far, prefer a hydride bridging the two irons, and only few mimics with a terminal hydride were achieved by tuning the steric effects of bulky diphosphine ligands. Moreover, although intermediates with either a terminal hydride or a protonated bridging thiolate ligand were proposed to exist during protonation processes or hydrogen exchange in the [FeFe]-H2ase mimic, [Fe2(µ-pdt)(µ-H)(CO)4(PMe3)2]+ (1H+), only bridging hydrides were observed by time-resolved IR spectroscopy. In this report, FTIR spectroscopy of 1H+, under CO with longer irradiation time, revealed several new photoinduced species. In addition to the CO loss species, many of the photoinduced products can be assigned to 1H+ with a terminal hydride by comparison of their CO vibrational frequencies with density functional theory calculations.

Seventy-one important questions for the conservation of marine biodiversity.

The ocean provides food, economic activity, and cultural value for a large proportion of humanity. Our knowledge of marine ecosystems lags behind that of terrestrial ecosystems, limiting effective protection of marine resources. We describe the outcome of 2 workshops in 2011 and 2012 to establish a list of important questions, which, if answered, would substantially improve our ability to conserve and manage the world's marine resources. Participants included individuals from academia, government, and nongovernment organizations with broad experience across disciplines, marine ecosystems, and countries that vary in levels of development. Contributors from the fields of science, conservation, industry, and government submitted questions to our workshops, which we distilled into a list of priority research questions. Through this process, we identified 71 key questions. We grouped these into 8 subject categories, each pertaining to a broad component of marine conservation: fisheries, climate change, other anthropogenic threats, ecosystems, marine citizenship, policy, societal and cultural considerations, and scientific enterprise. Our questions address many issues that are specific to marine conservation, and will serve as a road map to funders and researchers to develop programs that can greatly benefit marine conservation.

Anti-BCMA/CD19 CAR T Cells with Early Immunomodulatory Maintenance for Multiple Myeloma Responding to Initial or Later-Line Therapy.

We conducted a phase I clinical trial of anti-BCMA chimeric antigen receptor T cells (CART-BCMA) with or without anti-CD19 CAR T cells (huCART19) in multiple myeloma (MM) patients responding to third- or later-line therapy (phase A, N = 10) or high-risk patients responding to first-line therapy (phase B, N = 20), followed by early lenalidomide or pomalidomide maintenance. We observed no high-grade cytokine release syndrome (CRS) and only one instance of low-grade neurologic toxicity. Among 15 subjects with measurable disease, 10 exhibited partial response (PR) or better; among 26 subjects responding to prior therapy, 9 improved their response category and 4 converted to minimal residual disease (MRD)-negative complete response/stringent complete response. Early maintenance therapy was safe, feasible, and coincided in some patients with CAR T-cell reexpansion and late-onset, durable clinical response. Outcomes with CART-BCMA + huCART19 were similar to CART-BCMA alone. Collectively, our results demonstrate favorable safety, pharmacokinetics, and antimyeloma activity of dual-target CAR T-cell therapy in early lines of MM treatment. SIGNIFICANCE: CAR T cells in early lines of MM therapy could be safer and more effective than in the advanced setting, where prior studies have focused. We evaluated the safety, pharmacokinetics, and efficacy of CAR T cells in patients with low disease burden, responding to current therapy, combined with standard maintenance therapy. This article is highlighted in the In This Issue feature, p. 101.

Conceptual Framework for Cancer Care During a Pandemic Incorporating Evidence From the COVID-19 Pandemic.

PURPOSE: With successive infection waves and the spread of more infectious variants, the COVID-19 pandemic continues to have major impacts on health care. To achieve best outcomes for patients with cancer during a pandemic, efforts to minimize the increased risk of severe pandemic infection must be carefully balanced against unintended adverse impacts of the pandemic on cancer care, with consideration to available health system capacity. Cancer Australia's conceptual framework for cancer care during a pandemic provides a planning resource for health services and policy-makers that can be broadly applied globally and to similar pandemics. METHODS: Evidence on the impact of the COVID-19 pandemic on cancer care and health system capacity to June 2021 was reviewed, and the conceptual framework was developed and updated. RESULTS: Components of health system capacity vary during a pandemic, and capacity relative to pandemic numbers and severity affects resources available for cancer care delivery. The challenges of successive pandemic waves and high numbers of pandemic cases necessitate consideration of changing health system capacity in decision making about cancer care. Cancer Australia's conceptual framework provides guidance on continuation of care across the cancer pathway, in the face of challenges to health systems, while minimizing infection risk for patients with cancer and unintended consequences of delays in screening, diagnosis, and cancer treatment and backlogs because of service interruption. CONCLUSION: Evidence from the COVID-19 pandemic supports continuation of cancer care wherever possible during similar pandemics. Cancer Australia's conceptual framework, underpinned by principles for optimal cancer care, informs decision making across the cancer care continuum. It incorporates consideration of changes in health system capacity and capacity for cancer care, in relation to pandemic progression, enabling broad applicability to different global settings.

The effects of growth hormone on body composition and physical performance in recreational athletes: a randomized trial.

BACKGROUND: Growth hormone is widely abused by athletes, frequently with androgenic steroids. Its effects on performance are unclear. OBJECTIVE: To determine the effect of growth hormone alone or with testosterone on body composition and measures of performance. DESIGN: Randomized, placebo-controlled, blinded study of 8 weeks of treatment followed by a 6-week washout period. Randomization was computer-generated with concealed allocation. (Australian-New Zealand Clinical Trials Registry registration number: ACTRN012605000508673) SETTING: Clinical research facility in Sydney, Australia. PARTICIPANTS: 96 recreationally trained athletes (63 men and 33 women) with a mean age of 27.9 years (SD, 5.7). INTERVENTION: Men were randomly assigned to receive placebo, growth hormone (2 mg/d subcutaneously), testosterone (250 mg/wk intramuscularly), or combined treatments. Women were randomly assigned to receive either placebo or growth hormone (2 mg/d). MEASUREMENTS: Body composition variables (fat mass, lean body mass, extracellular water mass, and body cell mass) and physical performance variables (endurance [maximum oxygen consumption], strength [dead lift], power [jump height], and sprint capacity [Wingate value]). RESULTS: Body cell mass was correlated with all measures of performance at baseline. Growth hormone significantly reduced fat mass, increased lean body mass through an increase in extracellular water, and increased body cell mass in men when coadministered with testosterone. Growth hormone significantly increased sprint capacity, by 0.71 kJ (95% CI, 0.1 to 1.3 kJ; relative increase, 3.9% [CI, 0.0% to 7.7%]) in men and women combined and by 1.7 kJ (CI, 0.5 to 3.0 kJ; relative increase, 8.3% [CI, 3.0% to 13.6%]) when coadministered with testosterone to men; other performance measures did not significantly change. The increase in sprint capacity was not maintained 6 weeks after discontinuation of the drug. LIMITATIONS: Growth hormone dosage may have been lower than that used covertly by competitive athletes. The athletic significance of the observed improvements in sprint capacity is unclear, and the study was too small to draw conclusions about safety. CONCLUSION: Growth hormone supplementation influenced body composition and increased sprint capacity when administered alone and in combination with testosterone. PRIMARY FUNDING SOURCE: The World Anti-Doping Agency.

Australian women's awareness of breast cancer symptoms and responses to potential symptoms.

OBJECTIVES: Poor awareness of breast cancer symptoms has been associated with patient delay in seeking help; thus reduced survival, more aggressive treatment, and fewer treatment choices. The aim of this study was to develop a representative picture of Australian women's knowledge of symptoms, experienced potential symptoms, and behavioral responses. METHODS: A general population sample of approximately 3,000 women aged 30-69 completed a telephone survey; results were compared to previous surveys conducted in 1996 and 2003. RESULTS: The most commonly cited potential symptom of breast cancer was a lump in the breast, identified by 86% of respondents (an increase from 75% in 2003). Other commonly mentioned symptoms were discharge from the nipple, pain/soreness, skin puckering, or dimpling; and a change in breast shape. The proportion unable to name any potential symptoms of breast cancer decreased from one in ten in 2003 to approximately one in twenty in 2007. The primary reason for not seeking medical advice in response to a potential symptom was the belief that breast cancer was not present. CONCLUSIONS: Health promotion efforts need to continue to aim at increasing community understanding of potential breast cancer symptoms and encouraging women to act on potential symptoms by seeking medical advice.

Accuracy of combined protein gene product 9.5 and parafibromin markers for immunohistochemical diagnosis of parathyroid carcinoma.

CONTEXT: Parafibromin, encoded by HRPT2, is the first marker with significant benefit in the diagnosis of parathyroid carcinoma. However, because parafibromin is only involved in up to 70% of parathyroid carcinomas and loss of parafibromin immunoreactivity may not be observed in all cases of HRPT2 mutation, a complementary marker is needed. OBJECTIVE: We sought to determine the efficacy of increased expression of protein gene product 9.5 (PGP9.5), encoded by ubiquitin carboxyl-terminal esterase L1 (UCHL1) as an additional marker to loss of parafibromin immunoreactivity for the diagnosis of parathyroid carcinoma. DESIGN: In total, 146 parathyroid tumors and nine normal tissues were analyzed for the expression of parafibromin and PGP9.5 by immunohistochemistry and for UCHL1 by quantitative RT-PCR. These samples included six hyperparathyroidism-jaw tumor syndrome-related tumors and 24 sporadic carcinomas. RESULTS: In tumors with evidence of malignancy, strong staining for PGP9.5 had a sensitivity of 78% for the detection of parathyroid carcinoma and/or HRPT2 mutation and a specificity of 100%. Complete lack of nuclear parafibromin staining had a sensitivity of 67% and a specificity of 100%. PGP9.5 was positive in a tumor with the HRPT2 mutation L64P that expressed parafibromin. Furthermore, UCHL1 was highly expressed in the carcinoma/hyperparathyroidism-jaw tumor syndrome group compared to normal (P < 0.05) and benign specimens (P < 0.001). CONCLUSION: These results suggest that positive staining for PGP9.5 has utility as a marker for parathyroid malignancy, with a slightly superior sensitivity (P = 0.03) and similar high specificity to that of parafibromin.

Population screening and early detection of ovarian cancer in asymptomatic women.

The National Breast and Ovarian Cancer Centre position statement: 'Population screening and early detection of ovarian cancer in asymptomatic women', was developed and agreed following a Forum in February 2009 attended by key Australian stakeholders. The final position statement and supporting background information have been endorsed by key Australian colleges and agencies. Position statement on population screening and early detection of ovarian cancer in asymptomatic women: 1) There is currently no evidence that any test, including pelvic examination, CA125 or other biomarkers, ultrasound (including transvaginal ultrasound), or combination of tests, results in reduced mortality from ovarian cancer. 2) There is no evidence to support the use of any test, including pelvic examination, CA125 or other biomarkers, ultrasound (including transvaginal ultrasound), or combination of tests, for routine population-based screening for ovarian cancer. 3) Further validation in large clinical trials is required before current or new biomarkers could be recommended for routine use in a population screening setting.

Pharmacodynamics of growth hormone abuse biomarkers and the influence of gender and testosterone: a randomized double-blind placebo-controlled study in young recreational athletes.

CONTEXT: IGF axis proteins and collagen peptides are promising markers of GH abuse. OBJECTIVE: Our objective was to investigate whether responses of serum IGF axis and collagen markers to GH differ between men and women, and are influenced by testosterone (T). DESIGN: This was a randomized, double-blind, placebo-controlled study of 8-wk treatment followed by 6-wk washout. SETTING: The study was performed at a clinical research facility. PARTICIPANTS: A total of 96 recreationally trained healthy athletes (63 men, 33 women), aged 18-40 yr, were studied. INTERVENTION: All subjects received GH (2 mg/d sc) or placebo for 8 wk; men also received T (250 mg/wk im) or placebo for 5 wk. MAIN OUTCOME MEASURES: Serum IGF axis proteins (IGF-I, IGF binding protein-3, and acid labile subunit) and collagen peptides (N-terminal propeptide of type I procollagen, C-terminal telopeptide of type I collagen, and N-terminal propeptide of type III procollagen) were measured. RESULTS: GH induced significant increases in IGF axis and collagen markers that were greater in men than women (P < 0.001). Of the IGF axis markers, IGF-I showed the greatest increase. The relative incremental responses of the collagen markers in general were greater than the IGF markers, especially for PIIINP. The collagen markers increased and decreased more slowly with most remaining elevated (P < 0.01) after 6 wk, in comparison to IGF markers, which returned to baseline within 1 wk. Addition of T to GH amplified the response of PIIINP by more than 1.5-fold but did not affect any other marker. T alone did not affect IGF axis markers but modestly increased collagen markers. CONCLUSIONS: These markers of GH abuse are less responsive in women. The increases in collagen markers have a different time course to the IGF markers and extend the window of detection in both sexes. The response of PIIINP is increased by coadministration of T.

Within-subject variability and analytic imprecision of insulinlike growth factor axis and collagen markers: implications for clinical diagnosis and doping tests.

BACKGROUND: The utility of insulinlike growth factor (IGF) axis and collagen markers for a growth hormone (GH) doping test in sport depends on their stability and reproducibility. We sought to determine short-term within-subject variability of these markers in a large cohort of healthy individuals. METHODS: We measured IGF-I, IGF binding protein 3 (IGFBP-3), acid labile subunit (ALS), and the collagen markers N-terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (ICTP), and N-terminal propeptide of type III procollagen (PIIINP) in serum samples obtained on multiple occasions (median 3 per participant) over a 2- to 3-week period from 1103 elite athletes (699 men, 404 women) ages 22.2 (5.2) years [mean (SD)]. We estimated between-subject and within-subject variances by mixed-effects ANOVA. RESULTS: Within-subject variance accounted for 32% to 36% and 4% to 13% of the total variance in IGF markers and collagen markers, respectively. The within-subject CV ranged from 11% to 21% for the IGF axis markers and from 13% to 15% for the collagen markers. The index of individuality for the IGF axis markers was 0.66-0.76, and for the collagen markers, 0.26-0.45. For each marker, individuals with initial extreme measured values tended to regress toward the population mean in subsequent repeated measurements. We developed a Bayesian model to estimate the long-term probable value for each marker. CONCLUSIONS: These results indicate that in healthy individuals the within-subject variability was greater for IGF-I than for the collagen markers, and that where a single measurement is available, it is possible to estimate the long-term probable value of each of the markers by applying the Bayesian approach. Such an application can increase the reliability and decrease the cost of detecting GH doping.

A robust test for growth hormone doping--present status and future prospects.

Although doping with growth hormone (GH) is banned, there is anecdotal evidence that it is widely abused. GH is reportedly used often in combination with anabolic steroids at high doses for several months. Development of a robust test for GH has been challenging because recombinant human 22 kDa (22K) GH used in doping is indistinguishable analytically from endogenous GH and there are wide physiological fluctuations in circulating GH concentrations. One approach to GH testing is based on measurement of different circulating GH isoforms using immunoassays that differentiate between 22K and other GH isoforms. Administration of 22K GH results in a change in its abundance relative to other endogenous pituitary GH isoforms. The differential isoform method has been implemented; however, its utility is limited because of the short window of opportunity of detection. The second approach, which will extend the window of opportunity of detection, is based on the detection of increased levels of circulating GH-responsive proteins, such as insulin-like growth factor (IGF) axis and collagen peptides. Age and gender are the major determinants of variability for IGF-I and the collagen markers; therefore, a test based on these markers must take age into account for men and women. Extensive data is now available that validates the GH-responsive marker approach and implementation is now largely dependent on establishing an assured supply of standardized assays. Future directions will include more widespread implementation of both approaches by the World Anti-Doping Agency, possible use of other platforms for measurement and an athlete's passport to establish individual reference levels for biological parameters such as GH-responsive markers. Novel approaches include gene expression and proteomic profiling.

Integrin-linked kinase: a hypoxia-induced anti-apoptotic factor exploited by cancer cells.

Based on cDNA microarray results, integrin-linked kinase (ILK) emerged as an interesting candidate in hypoxia-mediated survival mechanisms employed by cancer cells. This notion was confirmed here by the following observations: the 5' promoter region of the ilk gene contains hypoxia responsive elements (HRE) that bind hypoxia-inducible factor (HIF) transcription factor complexes and drive HRE-luciferase gene expression in reporter assays; ILK protein and kinase activity are induced following hypoxia; downstream targets of ILK signaling are induced following hypoxia treatment; inhibition of ILK leads to increased apoptosis; and HIF and ILK are co-localized within human cancer tissues. The identification of ILK as a player in hypoxia survival signaling employed by cancer cells further validates ILK as a unique target for cancer therapy.

Kaposi's sarcoma associated herpesvirus G-protein coupled receptor activation of cyclooxygenase-2 in vascular endothelial cells.

BACKGROUND: Kaposi's sarcoma associated herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), a highly vascularized neoplasm characterized by endothelial-derived spindle-shaped tumor cells. KSHV-infected microvascular endothelial cells demonstrate increased cyclooxygenase-2 (COX-2) expression and KS lesions have high levels of prostaglandin E2 (PGE2), a short-lived eicosanoid dependent on cyclooxygenase activity that has been linked to pathogenesis of other neoplasias. To determine whether increased COX-2 expression and PGE2 production is mediated by the angiogenic and tumorigenic KSHV-encoded G-protein coupled receptor (vGPCR), we developed a recombinant retrovirus to express vGPCR in Human Umbilical Vascular Endothelial Cells (HUVEC). RESULTS: In the present study, we show that vGPCR-expressing HUVEC exhibit a spindle-like morphology that is characteristic of KS endothelial cells and demonstrate selective induction of PGE2 and COX-2. By treating vGPCR-expressing HUVEC with selective and non-selective COX inhibitors, we show that vGPCR-induced PGE2 production is dependent on the expression of COX-2 but not COX-1. CONCLUSION: Taken together, these results demonstrate that vGPCR induces expression of COX-2 and PGE2 that may mediate the paracrine effects of this key viral protein in KS pathogenesis.

Gene expression of parathyroid tumors: molecular subclassification and identification of the potential malignant phenotype.

Parathyroid tumors are heterogeneous, and diagnosis is often difficult using histologic and clinical features. We have undertaken expression profiling of 53 hereditary and sporadic parathyroid tumors to better define the molecular genetics of parathyroid tumors. A class discovery approach identified three distinct groups: (1) predominantly hyperplasia cluster, (2) HRPT2/carcinoma cluster consisting of sporadic carcinomas and benign and malignant tumors from Hyperparathyroidism-Jaw Tumor Syndrome patients, and (3) adenoma cluster consisting mainly of primary adenoma and MEN 1 tumors. Gene sets able to distinguish between the groups were identified and may serve as diagnostic biomarkers. We demonstrated, by both gene and protein expression, that Histone 1 Family 2, amyloid beta precursor protein, and E-cadherin are useful markers for parathyroid carcinoma and suggest that the presence of a HRPT2 mutation, whether germ-line or somatic, strongly influences the expression pattern of these 3 genes. Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors. Furthermore, our findings likely preclude an adenoma to carcinoma progression model for parathyroid tumorigenesis outside of the presence of either a germ-line or somatic HRPT2 mutation. These findings provide insights into the molecular pathways involved in parathyroid tumorigenesis and will contribute to a better understanding, diagnosis, and treatment of parathyroid tumors.

Gamma-herpesvirus neoplasia: a growing role for COX-2.

Both human gamma-herpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) induce neoplasia. Burkitt's and Hodgkin's lymphomas harbor EBV sequences, while KSHV has been associated with Kaposi's sarcoma (KS), primary effusion lymphoma (PEL), and multicentric castleman's disease (MCD). Each of these gamma-herpesvirus-associated malignancies displays typical characteristics of neoplasia, such as angiogenesis and cell survival. One enzyme commonly overexpressed in breast, prostate, and colon cancers is cyclooxygenase-2 (COX-2). Recently, COX-2 overexpression has been reported in herpesvirus infections in vitro. This review will outline potential mechanisms by which COX-2 may participate in herpesvirus-induced neoplasia.

A critical evaluation of bioimpedance spectroscopy analysis in estimating body composition during GH treatment: comparison with bromide dilution and dual X-ray absorptiometry.

OBJECTIVE: To compare estimates by bioimpedance spectroscopy analysis (BIS) of extracellular water (ECW), fat mass (FM), and fat-free mass (FFM) against standard techniques of bromide dilution and dual energy X-ray absorptiometry (DXA) during intervention that causes significant changes in water compartments and body composition. METHODS: Body composition analysis using BIS, bromide dilution, and DXA was performed in 71 healthy recreational athletes (43 men, 28 women; aged 18-40 years; BMI 24 ± 0.4 kg/m(2)) who participated in a double-blinded, randomized, placebo-controlled study of GH and testosterone treatment. The comparison of BIS with bromide dilution and DXA was analyzed using linear regression and the Bland-Altman method. RESULTS: At baseline, there was a significant correlation between BIS and bromide dilution-derived estimates for ECW, and DXA for FM and FFM (P<0.001). ECW by BIS was 3.5 ± 8.1% lower compared with bromide dilution, while FM was 22.4 ± 26.8% lower and FFM 13.7 ± 7.5% higher compared with DXA (P<0.01). During treatment, the change in ECW was similar between BIS and bromide dilution, whereas BIS gave a significantly greater reduction in FM (19.4 ± 44.8%) and a greater increase in FFM (5.6 ± 3.0%) compared with DXA (P<0.01). Significant differences in body composition estimates between the BIS and DXA were observed only in men, particularly during the treatment that caused greatest change in water compartments and body composition. CONCLUSION: In healthy adults, bioimpedance spectroscopy is an acceptable tool for measuring ECW; however, BIS overestimates FFM and substantially underestimates FM compared with DXA.

Clinical case seminar: Fibroblast growth factor 23: a new clinical marker for oncogenic osteomalacia.

The phosphate-wasting condition, oncogenic osteomalacia, is problematic to diagnose and manage clinically due to difficulty in locating the causative tumor. Fibroblast growth factor 23 (FGF23) has recently been implicated in the pathogenesis of oncogenic osteomalacia. In this case the patient presented with clinical features typical of oncogenic osteomalacia. Removal of an angiolipoma from the thigh did not correct the clinical or biochemical abnormalities. Subsequent identification and removal of a benign giant cell tumor in the pubic ramus, however, did result in normalization of his symptoms and signs. Positive staining for FGF23 protein by immunohistochemistry was demonstrated in the giant cell tumor, but not in the angiolipoma. The serum concentration of FGF23 was elevated in preoperative serum, then normalized after removal of the giant cell tumor. Expression of both FGF23 mRNA and protein was demonstrated in the giant cell tumor tissue, and FGF23 mRNA expression and renal phosphate uptake inhibitory activity were also detected in cultured giant cell tumor cells. This case provides further evidence for the involvement of FGF23 in the pathogenesis of oncogenic osteomalacia and for the utility of serum FGF23 measurement and immunohistochemical detection of FGF23 in the diagnosis and clinical management of this condition.

Bone as a source of FGF23: regulation by phosphate?

The identification of FGF23 as a factor involved in several disorders of phosphate regulation and of PHEX as the gene mutated in X-linked Hypophosphatemic Rickets indicates that both these genes may be involved in phosphate homeostasis, although their physiological roles are unclear. In this study, FGF23 mRNA expression was analyzed by real-time RT-PCR and found to be higher in normal human bone than in kidney, liver, thyroid, or parathyroid tissue, while expression in oncogenic osteomalacia tumor tissue was several hundred-fold higher than in bone. Expression of FGF23 mRNA in human osteoblast-like bone cells, quantitated by real-time RT-PCR, increased with increasing extracellular phosphate and was 2-fold higher in cells treated with 2 mM extracellular phosphate compared to 0 mM phosphate treatment. PHEX mRNA expression increased 1.3-fold after treatment with 2 mM phosphate. FGF23 expression in the bone cells increased with increased mineralization over a 20-day treatment period under mineralizing conditions with beta-glycerophosphate, while PHEX expression decreased. The results indicate that FGF23 mRNA expression in bone cells is regulated by extracellular phosphate and by mineralization. These results support proposals that bone may be a source of circulating FGF23 and suggest that FGF23 expression by bone is regulated.