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..     

Compressive Strength of Iliac Bone ECM Is Not Reduced in Osteogenesis Imperfecta and Increases With Mineralization

Osteogenesis imperfecta (OI) is an inheritable, genetic, and collagen-related disorder leading to an increase in bone fragility, but the origin of its “brittle behavior” is unclear. Because of its complex hierarchical structure, bone behaves differently at various length scales. This study aims to compare mechanical properties of human OI bone with healthy control bone at the extracellular matrix (ECM) level and to quantify the influence of the degree of mineralization. Degree of mineralization and mechanical properties were analyzed under dry conditions in 12 fixed and embedded transiliac crest biopsies (control n = 6, OI type I n = 3, OI type IV n = 2, and OI type III n = 1). Mean degree of mineralization was measured by microcomputed tomography at the biopsy level and the mineral-to-matrix ratio was assessed by Raman spectroscopy at the ECM level. Both methods revealed that the degree of mineralization is higher for OI bone compared with healthy control. Micropillar compression is a novel technique for quantifying post-yield properties of bone at the ECM level. Micropillars (d = 5 μm, h = 10 μm) were fabricated using focused ion beam milling and quasi-statically compressed to capture key post-yield properties such as ultimate strength. The qualitative inspection of the stress–strain curves showed that both OI and healthy control bone have a ductile response at the ECM level. The quantitative results showed that compressive strength is not reduced in OI bone and is increasing with OI severity. Nanoindentation measurements revealed that OI bone tends to have a higher Young's modulus, hardness, and dissipated energy compared with healthy bone. Micropillar strength and indentation modulus increased linearly and significantly (p < .0001) with mineral-to-matrix ratio. In conclusion, this study indicates that compressive mechanical properties of dry OI bone at the iliac crest are not inferior to healthy control at the ECM level and increase with mineralization. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).     

Functional imaging of memory retrieval in deficit vs nondeficit schizophrenia

BACKGROUND: Neuroimaging studies have provided evidence of abnormal frontal and temporal lobe function in schizophrenia. Frontal cortex abnormalities have been associated with negative symptoms and temporal lobe abnormalities with positive symptoms. The deficit and nondeficit forms of schizophrenia were predicted to differ in prefrontal cortical activity, but not in medial temporal lobe activity. METHODS: Regional cerebral blood flow was studied using oxygen 15 positron emission tomography during 3 different memory retrieval conditions in 8 control subjects, 8 patients with the deficit syndrome, and 8 patients without the deficit syndrome. Behavioral and positron emission tomography data were analyzed using a mixed-effects model to test for population differences. RESULTS: In all memory conditions, frontal cortex activity was higher in patients without the deficit syndrome than in patients with the deficit syndrome. During the attempt to retrieve poorly encoded words, patients without the deficit syndrome recruited the left frontal cortex to a significantly greater degree than did patients with the deficit syndrome. The 2 schizophrenia subtypes did not differ in the activity or recruitment of the hippocampus during memory retrieval. CONCLUSION: Frontal cortex function during memory retrieval is differentially impaired in deficit and nondeficit schizophrenia, whereas hippocampal recruitment deficits are not significantly different between the 2 schizophrenia groups.     

Risk factors accelerating cerebral degenerative changes, cognitive decline and dementia

OBJECTIVES: Factors accelerating cerebral degenerative changes represent potentially modifiable risks for cognitive decline. Putative risk factors accelerating subtle cognitive decline and dementia were correlated with repeated measures of cerebral atrophy, CT densitometry, perfusions and cognitive testing among neurologically and cognitively normative ageing volunteers. METHODS: Two hundred and twenty-four normative subjects at increased risk for cognitive decline were admitted to the study. Mean entry age was 59. 5+/-15.8 years. Mean follow-up is 4.3+/-3.1 years. At follow-up, 22 developed subtle cognitive decline (deltaCCSE>/=-3), 19 became demented, eight with vascular type (VAD) and 11 with Alzheimer's type (DAT) and 183 remain cognitively unchanged. Standardized questionnaires, medical, neuropsychological, neurological and blood work examinations were obtained. Cerebral atrophy, tissue densities and perfusions were measured by xenon-enhanced CT. RESULTS: After age 60, cerebral atrophy, ventricular enlargement, polio- and leuko-araiosis geometrically increased as perfusions declined. Risk factors accelerating perfusional decline, cerebral atrophy, polio-araiosis and leuko-araiosis (thinning of grey-white matter densities) were: transient ischaemic attacks (TIAs), hypertension, smoking, hyperlipidemia, male gender. At age 71.5+/-11.9, subtle cognitive decline began, accelerated by TIAs, hypertension and heart disease. Leuko-araiosis began before cognitive decline. TIAs, hypertension and hyperlipidemia correlated with VAD. Excessive cortical perfusional decreases and cerebral atrophy correlated with cognitive decline. Family history of neurodegenerative disease correlated with DAT. CONCLUSION: TIAs, hypertension, hyperlipidemia, smoking and male gender accelerate cerebral degenerative changes, cognitive decline and dementia.     

Capecitabine and vinorelbine in elderly patients (> or =65 years) with metastatic breast cancer: a phase I trial (SAKK 25/99).

BACKGROUND: Few chemotherapy regimens are suitable for the treatment of elderly patients with advanced breast cancer. With the aim of finding a regimen with a low burden of subjective non-overlapping toxic effects, vinorelbine and capecitabine were chosen to be investigated in a phase I dose-finding study. PATIENTS AND METHODS: Thirty-six patients with advanced breast cancer were stratified for the presence of bone and non-bone involvement and treated at four dose levels from capecitabine 800 mg/m2 orally days 1-14 and vinorelbine 20 mg/m2 intravenously days 1 and 8, to capecitabine 1250 mg/m2 orally days 1-14 and vinorelbine 25 mg/m2 intravenously days 1 and 8, for a maximum of six cycles. None of the patients had received prior chemotherapy for metastatic/advanced disease. Fifty-three per cent of patients with bone metastases and 67% of patients without bone metastases had visceral disease. The median age was 70 years for the 15 with bone involvement patients and 73 years for the 21 without bone involvement patients. RESULTS: Twenty-eight patients were fully evaluable for hematological dose-limiting toxicity (DLT), and all patients for other DLTs and for antitumor activity. One DLT with grade 3 venous thrombosis at dose level 2 and two dose-limiting neutropenia events at level 3 occurred in patients without bone involvement. Two dose-limiting neutropenia events were observed at dose level 2 for patients with bone involvement. Thus, the recommended dose was defined at level 1 (capecitabine 1000 mg/m2 days 1-14 and vinorelbine 20 mg/m2 days 1 and 8) for patients with bone involvement. For patients without bone involvement, the recommended dose was at level 2 (capecitabine 1250 mg/m2 days 1-14 and vinorelbine 20 mg/m2 days 1 and 8). For patients without bone involvement the overall response rate was 48% and the time to progression (TTP) was 4.5 months [95% confidence interval (CI) 3.3-6.9]. For patients with bone involvement the overall response rate was 53% and TTP was 5.3 months (95% CI 2.7-7.8). CONCLUSIONS: This regimen of capecitabine and vinorelbine is well tolerated and effective in elderly patients with metastatic breast cancer. Toxicity was mainly hematological and was observed at a lower dose in patients with bone involvement. A phase II study with the two different dose levels for elderly patients with and without bone involvement is currently being conducted.     

Diagnostik des Williams-Beuren-Syndroms

Zusammenfassung Fragestellung: Die Diagnose des Williams-Beuren-Syndroms (WBS) wird durch die klinische Variabilit?t erschwert. Daher sollen der diagnostische Wert sowohl des von Preus aufgestellten klinischen Scores als auch der Elastingenhemizygotie geprüft und miteinander verglichen werden. Methodik: Bei 13 Kindern mit Verdacht auf WBS wurden der Preus-Score erhoben und eine Fluoreszenz-in situ-Hybridisierungs-Analyse des Elastingens sowie eine Chromosomenanalyse durchgeführt. Ergebnisse: Neun der 13 Patienten zeigten eine Deletion eines Elastingens bei normalem Karyotyp. Zwei Patienten wiesen bei normaler Elastingendosis eine Chromosomenaberration auf. Der Preus-Score lag bei allen Patienten mit Elastindeletion >6 und war damit hoch positiv. Bei den übrigen Kindern wurde ein Preus-Score von 0,18; 0,37, 1,00 und 6,4 ermittelt. Schlu?folgerung: Bei allen Patienten mit WBS lagen in dieser Studie eine Elastingendeletion und ein hoch positiver Preus-Score vor. Ein positiver Preus-Score wurde jedoch auch bei Patienten mit Chromosomenaberrationen ermittelt. Unter Berücksichtigung dieser Ergebnisse und der Daten aus der Literatur sollte daher die Diagnose Wiliams-Beuren-Syndrom nur unter Vorbehalt gestellt werden, wenn keine Elastingendeletion nachweisbar ist. Da aber bisher unbekannte Mutationen bei den wenigen Patienten ohne Elastingendeletion denkbar sind, kann ein WBS auf molekularer Ebene nicht mit letzter Sicherheit ausgeschlossen werden. Bei diesen Patienten k?nnte der Preus-Score zur klinischen Diagnose beitragen. Setzt man für die Diagnose eines WBS im Preus-Score einen Endsummenwert von >1 voraus, so wird eine Sensitivit?t von 100% bei einer Spezifit?t von 92% erreicht.      

Intratympanic Gentamicin for Treatment of Intractable Meniere's Disease: A Preliminary Report

Topical administration of aminoglycoside antibiotics in the middle ear can achieve “chemical labyrinthectomy” in patients with intractable Meniere's disease. Herein we report our results of intratympanic gentamicin therapy in 21 patients using two different dosing protocols, twice weekly and twice daily(b.i.d.). Both hearing and vertigo outcome were evaluated. Complete control of episodic vertigo was achieved initially in 20 of 21 patients (95.2%). However, 6 of 20 responders (30%) developed relapsing symptoms within 12 months. Retreatment was successful in 75% of these patients. Overall, hearing was preserved or improved in 62% of cases, worse in 24%, and not yet tested in 14%. When the cumulative dose of gentamicin was ≤4 injections in the first week, only 1 of 14 (7.1%) lost hearing. Intratympanic gentamicin offers better risk/benefit outcome than other invasive therapies for intractable Meniere's disease.     

Toxic cardiogenic shock in a patient receiving weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin

A 54-year-old man was treated with weekly 24-h infusion of high-dose 5-fluorouracil (2600 mg/m2) and leucovorin (100 mg/m2) for metastatic colon cancer. At first, he tolerated the treatment well and no significant toxicity was identified. After a total of eight courses of treatment, a stable disease was observed, but mild shortness of breath was found on occasion. The patient had no previous history of cardiac disease and the heart performance assessed by left ventricular ejection fraction before treatment was normal. Unfortunately, acute pulmonary edema with lethal cardiogenic shock occurred during the ninth course of treatment, in spite of intensive medical treatment. The chest X-ray showed extreme cardiomegaly. Repeated assessment of his heart function by echocardiogram and ventricular ejection fraction revealed a very poor cardiac performance. Toxic cardiogenic shock during weekly 24-h infusion of high-dose 5-fluorouracil and leucovorin is extremely rare. To the best of our knowledge, no case has been reported in the English literature. We report a case and the relevant literature about the incidence, clinical picture and possible pathophysiology on 5-fluorouracil-related cardioxicity is reviewed.      

A randomized phase II trial of capecitabine and two different schedules of irinotecan in first-line treatment of metastatic colorectal cancer: efficacy, quality-of-life and toxicity.

BACKGROUND: To determine the efficacy, impact on quality-of-life (QoL) and tolerability of two different irinotecan administration schedules in combination with capecitabine as first-line treatment of metastatic colorectal cancer. PATIENTS AND METHODS: We carried out a randomized phase II trial to select one of the following treatment regimens for further investigation: weekly irinotecan at a dose of 70 mg/m(2) days 1, 8, 15, 22, 29 (arm A) or 3-weekly irinotecan at a dose of 300/240 mg/m(2) day 1 and days 22 (arm B) in combination with capecitabine 1000 mg/m(2) twice daily days 1-14 and days 22-35 every 6 weeks. RESULTS: Seventy-five patients with good performance status entered the trial. The two arms were well balanced for relevant patient and disease characteristics. The most frequent toxic effects were grade 3/4 diarrhea (arm A: 34%, B: 19%), grade 3/4 neutropenia (A: 5%, B: 19%) and grade 2/3 alopecia (A: 26%, B: 65%). Other grade 3/4 toxic effects were rare (<5%). Response rates were 34% [95% confidence interval (CI) 20% to 51%] in arm A and 35% (95% CI: 20% to 53%) in arm B. Median time to progression was 6.9 (4.6-10.1) and 9.2 (7.9-11.5) months and median overall survival was 17.4 (12.6-23.0+) and 24.7 (16.3-26.4+) months. Patients with an objective tumor response reported better physical well-being (P < 0.01), mood (P < 0.05), functional performance (P < 0.05) and less effort to cope (P < 0.05) compared with the non-responders and stable disease patients. CONCLUSIONS: The primary end point of this study was the objective response rate and based on the statistical design of the trial, the 3-weekly irinotecan schedule was selected over weekly irinotecan administration. The 3-weekly irinotecan schedule also seemed advantageous in terms of grade 3/4 diarrhea, time to progression, overall survival and patient convenience, but the study was not designed to detect differences in these parameters. In addition, tumor response was shown to have a beneficial effect on QoL indicators.