Prognostic Value of Bone Scintigraphy in Cancer Patients With Osteonecrosis of the Jaw

identifying imaging predictors of healing of osteonecrosis of the jaw (ONJ) in cancer patients may assist in better stratification of treatment strategies. MATERIALS AND METHODS: patients with ONJ were followed prospectively and underwent bone scintigraphy, both planar and single-photon emission computed tomography (SPECT) imaging. End points were time to healing and the number of recurrences. Studied parameters included lesion visibility, pattern of uptake, and quantification of uptake relative to the unaffected side. RESULTS: a total of 22 patients were recruited (3 men; 19 women) with a stage 1 ONJ lesion in 8, stage 2 in 9, and stage 3 ONJ in 5 patients. Median duration of follow-up was 12 months (range, 6-37). SPECT acquisitions proved superior over planar images in detecting ONJ lesions (P = 0.03). Quantification of tracer uptake in the ONJ lesion relative to the unaffected side showed increasing uptake with higher stages of ONJ: mean, 1.67 (95% confidence interval [CI], 1.17-2.18) in stage 1, 2.72 (95% CI, 2.24-3.20) in stage 2, and 4.62 (95% CI, 3.98-5.26) in stage 3. In addition, this relative ratio of uptake was found to be an independent predictor of ONJ healing (hazard ratio, 0.24; 95% CI, 0.07-0.82; P = 0.02). Neither ONJ stage nor relative ratio of uptake were predictors of the occurrence of ONJ relapses. CONCLUSIONS: bone scintigraphy in patients with ONJ is feasible and SPECT acquisitions are preferred over planar images. Relative quantification of tracer uptake provides prognostic information independent of clinical stage that may assist in identifying patients with a poor prognosis

Osteonecrosis of the Jaw After Bisphosphonates Treatment in Patients with Multiple Myeloma

Bone lytic lesion in Multiple myeloma are the most commonly presented symptoms which require treatment with bisphosphonates (BPs). BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. Osteonecrosis of the jaw (ONJ) has been associated recently with the use of BPs. The aim of these study is to evaluate the incidence of ONJ in patients with MM treated with mixed biphosphonates. We analyzed total 296 myeloma patients (150 male and 146 female). Mostly effected age group with 58,1% is age more than 60 years up to 88 years, diagnosed in our institution in the period 2005-2015. We used intravenous or oral forms of biphosphonates such as pamidronate, ibandronate, clodronate and zolendronic acid. The patients were evaluated for ONJ. The incidence of ONJ in our group of patients treated with Bps was 4,6% from our group of 260 patients 87,8% received BPs therapy and patients which haven’t received BPs 12,2%. From this group, 95,4% (248) didn’t show ONJ, and 4,6% (12) showed ONJ. The period of this treatment with BPs is an important risk factor for development of ONJ, average duration of BPs therapy in patients which show adverse effects is 26.8±13.7 months, from the total number of 12 patients that developed ONJ adverse effects, we have 8 patients which received treatment with Zolendronic acid and the remaining 4 patients which were treated with other BPs combinations without Zolendronic acid. All patients treated for MM must continue with the therapy with Zolendronic acid and Pamidronate, each patient must be individually treated according to his response of the treatment (dose, frequency and duration of therapy)

A 5-year retrospective longitudinal study on the incidence and the risk factors of osteonecrosis of the jaws in patients treated with zoledronic acid for bone metastases from solid tumors

Background: The aim of this study was to evaluate the incidence and the risk factors of osteonecrosis of the jaw (ONJ) in a group of patients treated with zoledronic acid (ZA) for bone metastases from solid tumors and enrolled in a preventive dental program. Material and Methods: This 5-year retrospective longitudinal study included all consecutive oncological patients who underwent at least one infusion with ZA between 2004 and 2011 for bone metastases due to solid neoplasms. Results: Of the 156 patients enrolled in the study, 17 developed ONJ (10.89%). At the multivariate analysis, severe periodontal disease (P=0.025), tooth extraction (P<0.0001) and starting the preventive dental program after the beginning of ZA therapy (P=0.02) were the only factors which showed a significant association with the occurrence of ONJ. Conclusions: This study demonstrated the importance of beginning dental prevention before zoledronic acid exposure in reducing ONJ occurrence, especially in the long term. The results of this research show that control of periodontal disease and an increase in the time between tooth extraction and the first ZA administration are recommended in order to reduce the risk of ONJ developmen

Pharmacogenetics of Bisphosphonate-associated Osteonecrosis of the Jaw

Osteonecrosis of the jaws (ONJ) is a potentially severe disorder that develops in a subgroup of individuals who have used bisphosphonate (BP) medications. Several clinical risk factors have been associated with the risk of ONJ development, but evidence is limited and in most instances ONJ remains an unpredictable adverse drug reaction. Interindividual genetic variability can contribute to explaining ONJ development in a subset of BP users and the discovery of relevant associated gene variants could lead to the identification of individuals at higher risk. No genetic variant has been found to be robustly associated with susceptibility to ONJ

A multicenter case registry study on medication-related osteonecrosis of the jaw in patients with advanced cancer

PURPOSE: This observational case registry study was designed to describe the natural history of cancer patients with medication-related osteonecrosis of the jaw (ONJ) and evaluate the ONJ resolution rate. METHODS: Adults with a diagnosis of cancer and with a new diagnosis of ONJ were enrolled and evaluated by a dental specialist at baseline and every 3 months for 2 years and then every 6 months for 3 years until death, consent withdrawal, or loss to follow-up. The primary endpoint was the rate and time course of ONJ resolution. Secondary endpoints included frequency of incident ONJ risk factors, ONJ treatment patterns, and treatment patterns of antiresorptive agents for subsequent ONJ. RESULTS: Overall, 327 patients were enrolled; 207 (63%) were continuing on study at data cutoff. Up to 69% of evaluable patients with ONJ had resolution or improvement during the study. ONJ resolution (AAOMS ONJ staging criteria) was observed in 114 patients (35%); median (interquartile range) time from ONJ onset to resolution was 7.3 (4.5-11.4) months. Most patients (97%) had received antiresorptive medication before ONJ development, 9 patients (3%) had not; 68% had received zoledronic acid, 38% had received denosumab, and 10% had received pamidronate (56% had received bisphosphonates only, 18% had received denosumab only, and 21% had exposure to both). CONCLUSIONS: These results are consistent with those observed in clinical trials evaluating skeletal-related events in patients with advanced malignancy involving bone. Longer follow-up will provide further information on ONJ recurrence and resolution rates between medically and surgically managed patients

The dental management of patients at risk of medication-related osteonecrosis of the jaw: New paradigm of primary prevention

Medication-related osteonecrosis of the jaw (MRONJ) is a serious adverse reaction of antiresorptive and antiangiogenic agents; it is a potentially painful and debilitating condition that can considerably affect the quality of life of patients. Furthermore, even if its epidemiology and pathogenesis have still not been fully clarified, several risk factors related to MRONJ have been recognized in prevention protocols. Three main risk factors are as follows: (i) the type of ONJ-related medications: antiresorptive (e.g., Bisphosphonates, Denosumab) and antiangiogenic drugs (e.g., Bevacizumab, Sunitinib); (ii) the category of patient at MRONJ risk: cancer versus non-cancer patient; (iii) the typologies and timing of dental treatments (e.g., before, during, or after the drug administration). The aim of this paper is to describe the new paradigm by the Italian Society of Oral Pathology and Medicine (SIPMO) on preventive dental management in patients at risk of MRONJ, prior to and during/after the administration of the aforementioned ONJ-related drugs. In reducing the risk of MRONJ, dentists and oral hygienists are key figures in applying a correct protocol of primary prevention for pre-treatment and in-treatment patients. However, the necessity of a multidisciplinary standardized approach, with a sustained dialogue among specialists involved, should be always adopted in order to improve the efficacy of preventive strategies and to ameliorate the patient\u2019s quality of life

Analysis of different therapeutic protocols for osteonecrosis of the jaw associated with oral and intravenous bisphpsphonates

Chemotherapy-associated osteonecrosis of the jaw caused by bisphosphonates is an exposure of necrotic bone with more than eight weeks of evolution that is attributable to bisphosphonates and no prior radiation therapy. Its etiopathogenesis remains unknown, although there are two hypotheses that may explain it: the drug?s mechanism of action, and the risk factors that can lead to osteonecrosis. There is a wide range of treatment options for managing chemotherapy-associated osteonecrosis of the jaw, from conservative treatments to surgical procedures of varying levels of invasiveness, which are sometimes supplemented with adjuvant therapies. The objective of this article is to group the therapeutic options for osteonecrosis of the jaw (ONJ) into seven different protocols and to evaluate their effectiveness in relation to stage of ONJ. A literature review was carried out in PubMed following the PRISMA criteria. A total of 47 were collected after compiling a series of variables that define ONJ, applied treatments, and the clinical results obtained. The 47 articles selected have a low to average estimated risk of bias and are of moderate to good quality. According to the data obtained, Protocol 3 (conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, and adjuvant therapies) is the most favorable approach for ONJ lesions caused by oral bisphosphonates. For lesions caused by intravenous bisphosphonates, Protocol 2 (conservative treatment, clinical and radiological follow-up, minimally invasive surgical treatment, and no adjuvant therapies) is the best approach. When comparing the different stages of ONJ, Protocol 1 (conservative treatment, clinical and radiological follow-up) promotes better healing of Stage 1 ONJ lesions caused by orally administered bisphosphonates, and Protocol 3 is recommended for Stage II. For ONJ lesions attributable to intravenous bisphosphonates, Protocol 7 (conservative treatment, clinical and radiological follow-up, and adjuvant therapies) provides the best results in Stage 0; in Stages I, II, and III, Protocol 1 gives better results

Medication-related osteonecrosis of the jaw: clinical and practical guidelines

Medication-related osteonecrosis of the jaw (MRONJ) is a severe adverse drug reaction, consisting of progressive bone destruction in the maxillofacial region of patients. ONJ can be caused by two pharmacological agents: Antiresorptive (including bisphosphonates (BPs) and receptor activator of nuclear factor kappa-B ligand inhibitors) and antiangiogenic. MRONJ pathophysiology is not completely elucidated. There are several suggested hypothesis that could explain its unique localization to the jaws: Inflammation or infection, microtrauma, altered bone remodeling or over suppression of bone resorption, angiogenesis inhibition, soft tissue BPs toxicity, peculiar biofilm of the oral cavity, terminal vascularization of the mandible, suppression of immunity, or Vitamin D deficiency. Dental screening and adequate treatment are fundamental to reduce the risk of osteonecrosis in patients under antiresorptive or antiangiogenic therapy, or before initiating the administration. The treatment of MRONJ is generally difficult and the optimal therapy strategy is still to be established. For this reason, prevention is even more important. It is suggested that a multidisciplinary team approach including a dentist, an oncologist, and a maxillofacial surgeon to evaluate and decide the best therapy for the patient. The choice between a conservative treatment and surgery is not easy, and it should be made on a case by case basis. However, the initial approach should be as conservative as possible. The most important goals of treatment for patients with established MRONJ are primarily the control of infection, bone necrosis progression, and pain. The aim of this paper is to represent the current knowledge about MRONJ, its preventive measures and management strategies

Robust identification from band-limited data

Consider the problem of identifying a scalar bounded-input/bounded-output stable transfer function from pointwise measurements at frequencies within a bandwidth. We propose an algorithm which consists of building a sequence of maps from data to models converging uniformly to the transfer function on the bandwidth when the number of measurements goes to infinity, the noise level to zero, and asymptotically meeting some gauge constraint outside. Error bounds are derived, and the procedure is illustrated by numerical experiment

From Recommendation Systems to Facility Location Games

Recommendation systems are extremely popular tools for matching users and contents. However, when content providers are strategic, the basic principle of matching users to the closest content, where both users and contents are modeled as points in some semantic space, may yield low social welfare. This is due to the fact that content providers are strategic and optimize their offered content to be recommended to as many users as possible. Motivated by modern applications, we propose the widely studied framework of facility location games to study recommendation systems with strategic content providers. Our conceptual contribution is the introduction of a $\textit{mediator}$ to facility location models, in the pursuit of better social welfare. We aim at designing mediators that a) induce a game with high social welfare in equilibrium, and b) intervene as little as possible. In service of the latter, we introduce the notion of $\textit{intervention cost}$, which quantifies how much damage a mediator may cause to the social welfare when an off-equilibrium profile is adopted. As a case study in high-welfare low-intervention mediator design, we consider the one-dimensional segment as the user domain. We propose a mediator that implements the socially optimal strategy profile as the unique equilibrium profile, and show a tight bound on its intervention cost. Ultimately, we consider some extensions, and highlight open questions for the general agenda