Burosumab for the Treatment of Tumor-Induced Osteomalacia

Tumor-induced osteomalacia (TIO) is caused by phosphaturic mesenchymal tumors producing fibroblast growth factor 23 (FGF23) and is characterized by impaired phosphate metabolism, skeletal health, and quality of life. UX023T-CL201 is an ongoing, open-label, phase 2 study investigating the safety and efficacy of burosumab, a fully human monoclonal antibody that inhibits FGF23, in adults with TIO or cutaneous skeletal hypophosphatemia syndrome (CSHS). Key endpoints were changes in serum phosphorus and osteomalacia assessed by transiliac bone biopsies at week 48. This report focuses on 14 patients with TIO, excluding two diagnosed with X-linked hypophosphatemia post-enrollment and one with CSHS. Serum phosphorus increased from baseline (0.52 mmol/L) and was maintained after dose titration from week 22 (0.91 mmol/L) to week 144 (0.82 mmol/L, p < 0.0001). Most measures of osteomalacia were improved at week 48: osteoid volume/bone, osteoid thickness, and mineralization lag time decreased; osteoid surface/bone surface showed no change. Of 249 fractures/pseudofractures detected across 14 patients at baseline, 33% were fully healed and 13% were partially healed at week 144. Patients reported a reduction in pain and fatigue and an increase in physical health. Two patients discontinued: one to treat an adverse event (AE) of neoplasm progression and one failed to meet dosing criteria (receiving minimal burosumab). Sixteen serious AEs occurred in seven patients, and there was one death; all serious AEs were considered unrelated to treatment. Nine patients had 16 treatment-related AEs; all were mild to moderate in severity. In adults with TIO, burosumab exhibited an acceptable safety profile and was associated with improvements in phosphate metabolism and osteomalacia. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research..     

Clinical and genetic features of variegate porphyria in a Chinese patient

Acute porphyria is rare in orientals. We describe a Chinese woman with recurrent generalised tonic-clonic seizures and abdominal pain. Genomic DNA studies identified a heterozygous base substitution from guanine to adenine at nucleotide position 503, resulting in substitution of arginine by histidine at position 168 of the protein (R168H). This genetic abnormality is similar to the mutation reported in Caucasians with variegate porphyria. To the best of our knowledge, this is the first report in the English literature a Chinese patient with variegate porphyria with an identifiable mutation. A brief review of porphyria is presented.     

A simple chest radiograph score to predict chronic lung disease in prematurely born infants

A simple scoring system has been evaluated with regard to its ability to characterize the pre-term infant's chest radiograph appearance at 28 days and predict oxygen dependency beyond 36 weeks post-conceptional age (PCA). Chest radiographs taken at approximately 1 month of age in 42 infants (median gestational age 28 weeks) were assessed by the scoring system for the presence of fibrosis/interstitial shadows, cystic elements and degree of hyperinflation (maximum score 8). The system's results were then compared with those obtained using two previously published scoring systems. Using all three systems, there were significant differences in the scores of infants who were and were not oxygen dependent at 28 days (p < 0.001) and 36 weeks PCA (p < 0.001). For the three systems, the positive predictive values of a score of 3 or more to predict oxygen dependency at 36 weeks (PCA) were between 67% and 80% and similar receiver operating characteristic curves were obtained. We conclude that scoring only three abnormalities of the 28 day chest radiograph appearance of pre-term infants gives useful predictive information.     

Gas movement in the nonventilated lung at the onset of single-lung ventilation for video-assisted thoracoscopy

To assess the potential for atmospheric nitrogen to enter the nonventilated lung following the initiation of single-lung ventilation, the nonventilated lung of 10 patients undergoing video-assisted thoracoscopy was connected to the air in a water-filled spirometer, and gas movement out of and back into the lung was measured. Airway pressure from both lungs and pleural pressure from the nonventilated side were also measured. With each breath of positive-pressure ventilation to the ventilated lung prior to the thoracic cavity being opened to the atmosphere, the pressure transmitted to the opposite hemithorax generated a mean (range) tidal movement of gas in the nonventilated lung of 134 (65-265) ml. In addition, ongoing gas exchange resulted in a progressive influx of gas from the spirometer over the 110-120 s measurement period of a mean (range) volume of 155 (70-320) ml. This easily preventable influx of atmospheric nitrogen could, in theory, predispose to arterial desaturation and to delayed lung collapse after the parietal pleura is opened.     

Effect of age and breast density on screening mammograms with false-positive findings

OBJECTIVE: The objective of this study was to examine the effect of breast density and age on screening mammograms with false-positive findings. MATERIALS AND METHODS: The study sample was taken from the Washington State Mammography Tumor Registry, which links data from participating radiologists with the Puget Sound Cancer Surveillance System and the Washington State Cancer Registry. Participants (n = 73,247) were women 35 years old and older who underwent screening mammography for which an assessment and a four-category density rating were coded. A total of 46,340 mammograms were sampled to avoid interpreter bias. In this study of false-positive mammograms, only women with no diagnosis of breast cancer within 12 months of the index mammogram were included. Logistic regression was used to estimate the odds ratios of a false-positive mammogram being associated with each category of breast density or age, adjusting for the other factor as a covariate. RESULTS: After controlling for breast density, we found that the risk of a false-positive mammogram was not affected by age (p = 27). However, the trend of increasing risk of a false-positive mammogram with increasing breast density was highly significant (p < .001). Women with extremely dense breast tissue were almost two times more likely to have a false-positive mammogram than were women with fatty breast tissue. This effect persisted after controlling for age. CONCLUSION: Breast density, not age, is an important factor when predicting risk of a false-positive mammogram. Breast density should be considered when educating individual women on the risks and benefits of screening mammography.     

New and old antipsychotics versus clozapine in a monkey model: adverse effects and antiamphetamine effects

Rationale: Neuroleptic primed Cebus apella monkeys have proven reliable in screening antipsychotics for extrapyramidal side effect (EPS) potential in humans, and the ratio EPS liability/antiamphetamine efficacy [“therapeutic index” (TI)] has fit well with clinical results. Objectives: 1) To find the TIs of one new (quetiapine), three potential [NNC 756 (dopamine (DA) D₁ antagonist), NNC 22-0031 (alpha-1 adrenergic/5-HT₂ serotonergic/DA D₁ and D₂ antagonist) and DOD 647 (DA D₁ and D₂ antagonist)] and three old antipsychotics (haloperidol, melperone and clozapine), 2) to test the model further and 3) to gain more insight as to clozapine’s neuropharmacology. Methods: Seven monkeys received haloperidol daily for 2 years; all were sensitized to dystonia. All drugs were given SC, in increasing doses until two animals had dystonia/other adverse effects (AE), and in decreasing doses with a fixed dose of dextroamphetamine producing motor unrest and stereotypies, to find the minimum significant antiamphetamine dose (AA). The ratio AE/AA = TI. Results: Excepting clozapine and DOD 647, all drugs induced dystonia. At 2–4 mg/kg, clozapine caused uncoordinated movements, myoclonic jerks and rough tremor; unlike dystonia, the syndrome was not alleviated but worsened by the anticholinergic, biperiden. DOD 647 up to 2 mg/kg had no adverse effects. The TIs of the new and potential antipsychotics were 3–5 versus 4 for clozapine and 1 for haloperidol and melperone, suggesting that like clozapine, these new drugs will not produce EPS at antipsychotic doses. Received: 31 October 1997/Final version: 9 November 1998     

Risk factors in calcium stone disease of the urinary tract.

The concept that calcium stone formation may be explained on the basis of a number of risk factors is developed. The main risk factors involved are shown to be calcium, oxalate, pH, acid mucopolysaccharides and uric acid. A method is described for calculating and combining the individual risk factors into a measure of the "relative probability" of forming stones (PSF). PSF values are generally lower in normal subjects than in stone-formers. Amongst the normals, PSF values are lower in children and women than in men. Recurrent stone-formers have the highest PSF values and these correlate well with the severity of the diseases as defined by the stone episode rate of the patient. Single stone-formers have PSF values intermediate between those of normal men and those of recurrent stone-formers.     

Lower Limb Swelling Due to Femoral Aneurysms

A man of 53 presented with left lower limb swelling, which was found to be caused by compression of the femoral vein by a common femoral artery aneurysm. Seven years later a similar situation developed in the opposite limb. On each occasion the diagnosis was confirmed radiologically and the symptoms resolved rapidly following surgery.

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