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Acute tubular necrosis associated with mTOR inhibitor therapy: a real entity biopsy-proven.

BACKGROUND: The protein kinase mTOR (mammalian target of rapamycin) is a critical regulator of cellular metabolism, growth, and proliferation. Inhibitors of mTOR have immunosuppressive and anti-cancer effects, but their effects on the progression of kidney disease are not fully understood. Their most common side-effects include stomatitis, rash, dyslipidemia, hyperglycemia, fatigue, and pneumonitis. However, to the best of our knowledge these agents have not been previously reported to cause severe acute kidney injury (AKI). CASE PRESENTATION: We describe four cases of patients with cancer wh

Direct effect of dasatinib on proliferation and cytotoxicity of natural killer cells in in vitro study.

Lymphocytosis predominantly due to natural killer (NK) cells has been reported in nearly a half of chronic myelogenous leukemia (CML) patients who were being treated with dasatinib. Besides, dasatinib-treated patients with lymphocytosis have a better prognosis than patients without lymphocytosis. In order to elucidate the effects of dasatinib on the proliferation of lymphocyte subset, dasatinib was added to the culture of peripheral blood mononuclear cells with IL-2 (lymphokine-activated killer culture) or a low dose of IL-2 with zoledronate (γδ T-cell culture). In both culture conditions, NK

Cellular interactions of synovial fluid γδ T cells in juvenile idiopathic arthritis.

The pathogenesis of juvenile idiopathic arthritis (JIA) is thought to involve multiple components of the cellular immune system, including subsets of γδ T cells. In this study, we conducted experiments to define the functional roles of one of the major synovial fluid (SF) T cell subsets, Vγ9(+)Vδ2(+) (Vγ9(+)) T cells, in JIA. We found that as opposed to CD4(+) T cells, equally high percentages (∼35%) of Vγ9(+) T cells in SF and peripheral blood (PB) produced TNF-α and IFN-γ. Furthermore, stimulation with isopentenyl pyrophosphate (IPP), a metabolite in the mevalonate pathway, which is a specif

Awareness and education of patients receiving bisphosphonates.

BACKGROUND: Bisphosphonates are used to fight osteoporosis and for treating malignancies. In 2003, the first case reports appeared that described bisphosphonate-induced osteonecrosis of the jaw (BONJ). The aim of this study was to assess patient awareness of the adverse effects of bisphosphonates in order to improve cooperation among doctors and between doctors and patients. METHODS: Patients with symptoms of osteoporosis, prostate cancer, or breast cancer were surveyed to determine their knowledge of bisphosphonates. The questionnaire comprised 12 questions that covered sociographic data, ki

Multiple myeloma vs. breast cancer patients with bisphosphonates-related osteonecrosis of the jaws: a comparative analysis of response to treatment and predictors of outcome.

BACKGROUND: Multiple myeloma (MM) and breast cancer (BC) are the two most common diseases associated with bisphosphonates-related osteonecrosis of the jaws (BRONJ), for which different therapeutical approaches have been proposed. The aim of this study was to compare the clinical behaviour of BRONJ in patients with MM vs. BC and the time of healing in terms of clinical and symptomatological remission, following a standardized therapeutic protocol. METHODS: Twenty-six BRONJ patients (13 men with MM and 13 women with BC) were prospectively enroled and treated with a specific systemic and topical

Postmenopausal osteoporosis: fracture risk and prevention.

In the estrogen-regulated RANK ligand (RANKL)/RANK/osteoprotegerin (OPG) pathway, estrogen deficiency favors osteoclast maturation, leading to increased bone resorption compared with bone formation. Treatment of low bone mineral density (BMD) should be based on fracture risk, assessed using the WHO Fracture Risk Algorithm (FRAX(R)). Criteria for treatment are 10-year overall fracture risk ≥ 20% or 10-year hip fracture risk ≥ 3%. Vitamin D supplementation at levels higher than those traditionally recommended may be appropriate for healthy menopausal women. Multiple strategies are needed to effe

Bisphosphonate-related osteonecrosis of the jaws: a single-center study of 101 patients.

PURPOSE: Osteonecrosis of the jaw (ONJ) is a devastating side effect of long-term bisphosphonate (BP) use. We present the largest case series from a single department. MATERIALS AND METHODS: This case series included 101 ONJ patients. Data on demographics, medical background, type and duration of BP use, possible triggering events, mode of therapy, and outcome were recorded. RESULTS: ONJ was associated with intravenous BPs in 85 patients and with oral BPs in 16 patients. It was diagnosed after 48, 27, and 67 months of pamidronate, zoledronic acid, and alendronate use, respectively. Long-term

Screening for Cardiac Amyloidosis When Conducting Carpal Tunnel Surgery.

Background: Carpal tunnel syndrome (CTS) has emerged as an early indicator of cardiac amyloidosis (CA) caused by transthyretin-associated (ATTR) mutations, possibly linked to adverse cardiovascular outcomes. This case series examines the relationship between idiopathic CTS and CA imaging diagnosis. Methods: Twenty-two patients from the cross-sectional study CarPoS (NCT05409833) were included. These patients underwent physical evaluation, laboratory exams, electrocardiography, echocardiography, cardiac magnetic resonance (CMR) imaging, and scintigraphy with 99mTc-3,3-diphosphono-1,2-propanodica

[18F]sodium fluoride positron emission tomography: a systematic bibliometric review from 2008 to 2022.

BackgroundAs a noninvasive diagnostic tool, fluorine-18-labelled sodium fluoride positron emission tomography ([18F]NaF PET) has been increasingly applied in clinical practice due to its excellent imaging performance, attracting more attention from clinical practitioners. However, with the continuous development of technology and growth of knowledge, the field of [18F]NaF PET is changing. Nevertheless, few studies have conducted quantitative analyses of the literature in this field. Therefore, in this study, we used bibliometric methods to analyze the trends, content distribution, and frontier

Metabolic effects of pamidronate in patients with metastatic bone disease.

We have evaluated the value of specific bone resorption markers in monitoring metastatic bone disease to define the duration of action of a single high-dose pamidronate infusion. Twenty patients received a single infusion of pamidronate 120 mg for painful bone metastases. Ten out of these 20 patients also received a second infusion. They were evaluated at baseline, 2, 4 and 8 weeks after each infusion. A composite pain questionnaire, serum and urine tests were carried out at these time points. Bone resorption markers measured included urinary calcium, hydroxyproline and two new markers: pyridi

Mevalonates restore zoledronic acid-induced osteoclastogenesis inhibition.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ) is likely to be caused by continuous imperfection of bone healing after surgical treatments in patients with long-term administration of nitrogen-containing bisphosphonates (NBPs). NBPs inhibit osteoclastic bone resorption by impairing the mevalonic acid sterol pathway in osteoclasts. Thus, we hypothesized that exogenous mevalonic acid metabolites restore the inhibitory effects of NBPs on osteoclastogenesis and bone remodeling. To clarify the effects of mevalonic acid metabolites, especially geranylgeranyl pyrophosphate (GGPP) and geranyl

Adjuvant zoledronic acid in patients with early breast cancer: final efficacy analysis of the AZURE (BIG 01/04) randomised open-label phase 3 trial.

BACKGROUND: The role of adjuvant bisphosphonates in early breast cancer is uncertain. We therefore did a large randomised trial to investigate the effect of the adjuvant use of zoledronic acid on disease-free survival (DFS) in high-risk patients with early breast cancer. METHODS: In the AZURE trial, an open-label, international, multicentre, randomised, controlled, parallel-group phase 3 trial, women (age ≥18 years) with stage II or III breast cancer were randomly assigned (1:1) by a central automated 24-h computer-generated telephone minimisation system (balanced for number of involved axill

New approach to analyze genetic and clinical data in bisphosphonate-induced osteonecrosis of the jaw.

OBJECTIVES: Osteonecrosis of the jaw (ONJ) is a major complication associated with long-term use of bisphosphonates (BP). We aimed to investigate the effect of CYP2C8 rs1934951 SNP and its relationship to a number of clinical and biochemical factors in 46 Hungarian subjects with bisphosphonate-induced ONJ. METHODS: Blood samples were collected from each subject and genomic DNA was extracted. SNP analysis of CYP2C8 gene was carried out by predesigned TaqMan primer/probe sets. The genetic data together with clinical and biochemical variables were evaluated by chi-square test, logistic regressio

Dental abnormalities in a mouse model for craniometaphyseal dysplasia.

Mice carrying a knock-in mutation (Phe377del) in the Ank gene replicate many skeletal characteristics of human craniometaphyseal dysplasia, including hyperostotic mandibles. Ank (KI/KI) mice have normal morphology of erupted molars and incisors but excessive cementum deposition with increased numbers of Ibsp- and Dmp1-positive cells on root surfaces. The cervical loops of adult Ank (KI/KI) lower incisors are at the level of the third molars, while they are close to the mandibular foramen in Ank (+/+) mice. Furthermore, Ank (KI/KI) incisors show decreased eruption rates, decreased proliferation

Osteonecrosis of the jaw in patients with cancer who received zoledronic acid and bevacizumab.

BACKGROUND: The authors investigated the incidence of and risk factors for osteonecrosis of the jaw (ONJ) in patients with metastases to the bone who received the bisphosphonate agent zoledronic acid (ZOL) and chemotherapy combined with the antiangiogenic agent bevacizumab (BEV). METHODS: The authors evaluated 59 participants (34 with breast cancer and 25 with nonsmall-cell lung cancer). All of the participants received 4 milligrams of ZOL via intravenous (IV) infusion every four weeks and 15 mg per kilogram of BEV every three weeks. They conducted a dental examination in participants at base

Sterol-regulatory-element-binding protein 2 and nuclear factor Y control human farnesyl diphosphate synthase expression and affect cell proliferation in hepatoblastoma cells.

FDPS (farnesyl diphosphate synthase) catalyses the formation of farnesyl diphosphate, a key intermediate in the synthesis of cholesterol and isoprenylated cellular metabolites. FDPS is also the molecular target of nitrogen-containing bisphosphonates, which are used as bone-antiresorptive drugs in various disorders. In the present study, we characterized the sterol-response element and NF-Y (nuclear factor Y)-binding site in the human FDPS promoter. Using a luciferase assay, electrophoretic mobility-shift assay and chromatin immunoprecipitation assay, we demonstrated that these elements are res

Medical treatment of otosclerosis: rationale for use of bisphosphonates.

Otosclerosis is a bony dyscrasia characterized by histopathological findings of osteoclast production. Osteoclastogenesis explains the pathogenesis of otosclerosis. Basic science research in the experimental animal otic capsule has given insight into the process of evolution of otosclerosis. The normal otic capsule is preserved with very little bone turnover as a result of the production of osteoprotegerin (OPG) by the membranous inner ear that prevents the activation of osteoclasts. Animals genetically unable to produce OPG demonstrated the production of hearing loss and histopathology of the

Vgamma2Vdelta2 T-cell receptor-mediated recognition of aminobisphosphonates.

Aminobisphosphonates, potent derivatives of bisphosphonates, are frequently used for the treatment of conditions such as osteoporosis and bone metastases that are characterized by excessive osteoclastic bone resorption. Using T-cell receptor (TCR) transfer studies, we show that recognition of antigenic aminobisphosphonates that are known to stimulate human gammadelta T cells in vitro and in vivo (potency: risedronate > alendronate > pamidronate) requires expression of the Vgamma2Vdelta2 TCR and is thus Vgamma2Vdelta2 TCR-dependent. Myeloma cells or monocytes pulsed with risedronate and then wa

Left Ventricular Deformation and Myocardial Work Parameters in Patients with Hereditary Transthyretin Amyloidosis Treated with Patisiran: A Single-Center Study.

Background: In recent years, many advances have been made in the treatment of hereditary transthyretin amyloidosis (ATTRv). Patisiran is a small-interfering RNA used to treat ATTRv with only polyneuropathy or polyneuropathy and cardiomyopathy. The aim of our study was to assess the effect of patisiran on cardiac function in ATTRv patients using speckle tracking echocardiography (STE) analysis. Methods: A single-center prospective study was performed enrolling 21 patients with ATTRv (11 M-52% of the population; 10 F-48% of the population; median age 66 ± 8.4 years old). A total of 7 patients ha

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… glucose, and NT-proBNP (N-terminal pro-B-type natriuretic peptide); - Color-Doppler echocardiography with assessment of conventional echocardiographic parameters and myocardial deformation indices of the left ventricle and left atrium; assessment of myocardial work parameters; - Bone scintigraphy with diphosphonates … It was established by meeting echocardiographic and/or cardiac magnetic resonance imaging criteria, combined with a positive uptake of the radiotracer in scintigraphy using 99mTc-pyrophosphate (PYP), 99mTc -3,3-diphosphono-1,2-propanodicarboxylic acid (DPD), or 99mTc-hydroxymethylene diphosphonate (HMDP …

Clinical manifestations and diagnostic approach to metastatic cancer of the mandible.

In a 12-month period, metastatic cancer was diagnosed in eight patients. Six of them presented with pain mimicking toothache, temporomandibular joint disorders or trigeminal neuralgia, while two showed osteopenic bone lesions in the panoramic radiography, and perimandibular swelling. Anesthesia of the lower lip was the only common clinical feature. In seven of the eight patients, a whole body bone scintigraphy and single photon emission computed tomography (SPECT) of the skull in combination with a whole body and SPECT anti-granulocyte (Tc-99m MAK 250/183) bone marrow scintigraphy was performe