Frontiers in the treatment of glioblastoma: Past, present and emerging.

This systematic review collated evidence on the burden of XLH in adults. Data captured highlight the substantial ongoing burden of XLH in adulthood and identified unmet needs. Greater awareness and understanding of the impact of XLH in adulthood are needed to improve care and outcomes in adults with XLH. X-linked hypophosphataemia (XLH) is a rare metabolic bone disease characterized by renal phosphate wasting and musculoskeletal manifestations. Whilst the disease’s impact in children is well documented, information on the effects of this progressive, debilitating condition on adults is lacking. This systematic review aimed to collate existing evidence on the burden of XLH in adulthood to identify unmet needs. MEDLINE, Embase and Cochrane Library databases and recent congress reports were searched on 19 February 2019 for English-language publications describing the medical, humanistic and socio-economic impact of XLH in adults (≥ 18 years old). In addition, a structured Internet search was conducted. Of the 2351 articles identified, 91 met the selection criteria along with 44 congress abstracts. Data show that adults with XLH experience a range of clinical manifestations, particularly skeletal deformities and (pseudo)fractures, along with pain, dental abnormalities and impaired physical function and mobility. XLH in adulthood impacts on quality of life and places limitations on daily activities. The level of healthcare resource utilization among adults with XLH is indicative of substantial socio-economic burden; further research is needed to quantitate the economic impact on the healthcare system, society and patients. Adults with XLH may not receive appropriate care and treatment; a possible explanation for this is a lack of awareness among healthcare professionals. XLH in adults is associated with considerable disease burden and unmet needs. Forthcoming studies and increased awareness of the impact of XLH in adulthood should help to improve management of XLH in adulthood and patient outcomes.

/pdf/burden-of-disease-associated-with-x-linked-hypophosphataemia-17nuoowc9b.pdf

Burden of disease associated with X-linked hypophosphataemia in adults: a systematic literature review

Crossfibrillar mineral tessellation in normal and Hyp mouse bone as revealed by 3D FIB-SEM microscopy.

X-linked hypophosphatemia (XLH) is characterized by increased activity of circulating FGF23 resulting in renal phosphate wasting and abnormal bone mineralization. Hyperparathyroidism may develop in XLH patients; however, its prevalence, pathogenesis, and clinical presentation are not documented. This observational study (CNIL 171036 v 0) recruited XLH adult patients in a single tertiary referral center. Each patient was explored in standardized conditions and compared with two healthy volunteers, matched for sex, age, and 25-OH vitamin D concentrations. The primary endpoint was the proportion of patients with hyperparathyroidism. The secondary endpoints were the factors influencing serum parathyroid hormone (PTH) concentrations and the prevalence of hypercalcemic hyperparathyroidism. Sixty-eight patients (51 women, 17 men) were enrolled and matched with 136 healthy volunteers. Patients had higher PTH concentrations compared with healthy controls (53.5 ng/L, interquartile range [IQR] 36.7-72.7 versus 36.0 ng/L, IQR 27.7-44.0, p < .0001). Hyperparathyroidism was observed in 17 patients of 68 (25%). In patients, a positive relationship between PTH and calcium concentrations and a negative relationship between PTH and phosphate concentrations were observed. Seven (10%) patients (3 premenopausal women, 1 postmenopausal woman, and 3 men) were diagnosed with hypercalcemic hyperparathyroidism. All underwent parathyroid surgery, with consecutive normalization of calcium and PTH concentrations. Hyperparathyroidism is a frequent complication in XLH adult patients. Disruption of the physiological regulation of PTH secretion contributes to parathyroid disease. Early-onset hypercalcemic hyperparathyroidism can be effectively and safely cured by surgical resection. © 2020 American Society for Bone and Mineral Research.

https://asbmr.onlinelibrary.wiley.com/doi/pdf/10.1002/jbmr.3992

Hyperparathyroidism in Patients With X-Linked Hypophosphatemia

X-linked hypophosphatemia (XLH) is the most common genetic form of hypophosphatemic rickets and osteomalacia. In this disease, mutations in the PHEX gene lead to elevated levels of the hormone fibroblast growth factor 23 (FGF23), resulting in renal phosphate wasting and impaired skeletal and dental mineralization. Recently, international guidelines for the diagnosis and treatment of this condition have been published. However, more specific recommendations are needed to provide guidance at the national level, considering resource availability and health economic aspects. A national multidisciplinary group of Belgian experts convened to discuss translation of international best available evidence into locally feasible consensus recommendations. Patients with XLH may present to a wide array of primary, secondary and tertiary care physicians, among whom awareness of the disease should be raised. XLH has a very broad differential-diagnosis for which clinical features, biochemical and genetic testing in centers of expertise are recommended. Optimal care requires a multidisciplinary approach, guided by an expert in metabolic bone diseases and involving (according to the individual patient’s needs) pediatric and adult medical specialties and paramedical caregivers, including but not limited to general practitioners, dentists, radiologists and orthopedic surgeons. In children with severe or refractory symptoms, FGF23 inhibition using burosumab may provide superior outcomes compared to conventional medical therapy with phosphate supplements and active vitamin D analogues. Burosumab has also demonstrated promising results in adults on certain clinical outcomes such as pseudofractures. In summary, this work outlines recommendations for clinicians and policymakers, with a vision for improving the diagnostic and therapeutic landscape for XLH patients in Belgium.

/pdf/consensus-recommendations-for-the-diagnosis-and-management-5gm06rum26.pdf

Consensus Recommendations for the Diagnosis and Management of X-Linked Hypophosphatemia in Belgium

Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia

Entotherapy an image-guided drug-eluting microcylinder platform, has the potential to bypass the limitations of systemic chemotherapy use in the treatment of canine brain tumours. Gliomas, which are common in dogs and also represent the majority of fatal brain tumours in humans, can be amenable to chemotherapy with temozolomide. Biopolymer microcylinders conjugated with temozolomide and gadolinium were implanted into partially resected tumours of four client-owned dogs with gliomas. All four dogs presented with generalized seizures and had mild to no neurologic deficits at the time of craniotomy. All dogs underwent craniotomy for implantation of the microcylinders into partially resected gliomas (glioblastoma multiforme {n = 1} or oligodendroglioma {n = 3}). All dogs recovered well from the craniotomy and implantation procedure. This novel procedure appears to be feasible and tolerated in tumour-bearing dogs. A future controlled clinical study can now aim to evaluate the microcylinder implantation for long-term efficacy.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/vms3.124

Intratumoral temozolomide in spontaneous canine gliomas: feasibility of a novel therapy using implanted microcylinders.

The receptor for Colony Stimulating Factor 1 (CSF1), c-fms, is highly expressed on mature osteoclasts suggesting a role for this cytokine in regulating the function of these cells. Consistent with this idea, in vitro studies have documented a variety of effects of CSF1 in mature osteoclasts. To better define the role of CSF1 in these cells, we conditionally deleted c-fms in osteoclasts (c-fms-OC-/-) by crossing c-fmsflox/flox mice with mice expressing Cre under the control of the cathepsin K promoter. The c-fms-OC-/- mice were of normal weight and had normal tooth eruption. However, when quantified by DXA, bone mass was significantly higher in the spine and femur of female knock out mice and in the femurs of male knock out mice. MicroCT analyses of femurs showed that female c-fms-OC-/- mice had significantly increased trabecular bone mass with a similar trend in males and both sexes demonstrated significantly increased trabecular number and reduced trabecular spacing. Histomorphometric analysis of the femoral trabecular bone compartment demonstrated a trend towards increased numbers of osteoclasts, +26% in Noc/BPm and +22% in OcS/BS in the k/o animals but this change was not significant. However, when the cellular volume of osteoclasts was quantified, the c-fms-OC-/- cells were found to be significantly smaller than controls. Mature osteoclasts show a marked spreading response when exposed to CSF1 in a non-gradient fashion. However, osteoclasts freshly isolated from c-fms-OC-/- mice had a near complete abrogation of this response. C-fms-OC-/- mice treated with (1-34)hPTH 80 ng/kg/d in single daily subcutaneous doses for 29 days showed an attenuated anabolic response in trabecular bone compared to wild-type animals. Taken together, these data indicate an important non-redundant role for c-fms in regulating mature osteoclast function in vivo.

/pdf/selective-deletion-of-the-receptor-for-csf1-c-fms-in-3gxk2419ae.pdf

Selective deletion of the receptor for CSF1, c-fms, in osteoclasts results in a high bone mass phenotype, smaller osteoclasts in vivo and an impaired response to an anabolic PTH regimen

Abstract Context X-linked hypophosphatemia (XLH) is a genetic disease, causing life-long hypophosphatemia due to overproduction of fibroblast growth factor 23 (FGF23). XLH is associated with Chiari malformations, cranial synostosis, and syringomyelia. FGF23 signals through FGFR1c and requires a coreceptor, α-Klotho, which is expressed in the renal distal convoluted tubules and the choroid plexus (ChP). In the ChP, α-Klotho participates in regulating cerebrospinal fluid (CSF) production by shuttling the sodium/potassium adenosine triphosphatase (Na+/K+-ATPase) to the luminal membrane. The sodium/potassium/chloride cotransporter 1 (NKCC1) also makes a substantial contribution to CSF production. Objective Since CSF production has not been studied in XLH, we sought to determine if there are changes in the expression of these molecules in the ChP of Hyp mice, the murine model of XLH, as a first step toward testing the hypothesis that altered CSF production contributes to the cranial and spinal malformations seen this disease. Methods Semi-quantitative real-time PCR was used to analyze the level of expression of transcripts for Fgfr1c, and thee key regulators of CSF production, Klotho, Atp1a1 and Slc12a2. In situ hybridization was used to provide anatomical localization for the encoded proteins. Results Real-time polymerase chain reaction (RT-PCR) demonstrated significant upregulation of Klotho transcripts in the fourth ventricle of Hyp mice compared to controls. Transcript levels for Fgfr1c were unchanged in Hyp mice. Atp1a1 transcripts encoding the alpha-1 subunit of Na+/K+-ATPase were significantly downregulated in the third and lateral ventricles (LV). Expression levels of the Slc12a2 transcript (which encodes NKCC1) were unchanged in Hyp mice compared to controls. In situ hybridization (ISH) confirmed the presence of all 4 transcripts in the LV ChP both of WT and Hyp mice. Conclusion This is the first study to document a significant change in the level of expression of the molecular machinery required for CSF production in Hyp mice. Whether similar changes occur in patients with XLH, potentially contributing to the cranial and spinal cord abnormalities frequently seen in XLH, remains to be determined.

/pdf/altered-expression-of-several-molecular-mediators-of-3mk3zyn0.pdf

Jared Kaplan

Papers

Clinical and genetic analysis in a large Chinese cohort of patients with X-linked hypophosphatemia

Intratumoral temozolomide in spontaneous canine gliomas: feasibility of a novel therapy using implanted microcylinders.

Selective deletion of the receptor for CSF1, c-fms, in osteoclasts results in a high bone mass phenotype, smaller osteoclasts in vivo and an impaired response to an anabolic PTH regimen

Altered Expression of Several Molecular Mediators of Cerebrospinal Fluid Production in Hyp Mice