[Medication-related osteonecrosis of the jaws associated with the use of bone-modifying agents]. / Medikamentoznyi osteonekroz chelyustei, svyazannyi s priemom osteomodifitsiruyushchikh preparatov.

The relevance of the study is associated with the widespread use of osteomodifying agents in patients with bone metastases and osteoporosis. Bisphosphonates and other osteo-modifying agents are widely used in oncology and prevention of age-related changes in the human bone system. The use, therapeutic effects and complications of therapy with osteo modifying agents are being investigated all over the world. However, the etiology and pathogenesis of drug-induced osteonecrosis of the jaws (MONCH) have not been fully studied, in this regard, the study of risk factors and mechanisms of its development remains relevant. New data on the etiology and pathogenesis of drug-induced osteonecrosis are presented. The literature review is carried out on the electronic resource PubMed.

Case report: golimumab-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw is an uncommon but highly morbid adverse event of certain medical therapies. Although classically induced by bisphosphonates, the recent advent of monoclonal antibodies is contributing to a rise in cases. In this case report, we present a rare case of golimumab-associated medication-related osteonecrosis of the jaw and discuss the possible mechanisms of pathogenesis.

Osteonecrose dos maxilares relacionada ao uso demedicamentos: características patológicas, diagnóstico,prevenção e estratégias terapêuticas / Medication-related osteonecrosis of the jaws: pathological characteristics, diagnosis, prevention and therapeutic strategies

Objetivo: Este trabalho tem como propósito fornecer uma análise abrangente das características clínicas, etiológicas, radiográficas e histopatológicas da osteonecrose dos maxilares relacionada ao uso de medicamentos, além de abordar os métodos de diagnóstico, prevenção e estratégias terapêuticas. Materiais e métodos: foi realizada uma busca por artigos científicos publicados no período de 2015 a 2023, utilizando as bases de dados Scientific Electronic Library Online (SciELO), US National Library of Medicine (PubMed) e ScienceDirect. Conclusão: Embora infrequente, há um considerável potencial de ocorrência de osteonecrose dos maxilares em pacientes submetidos a terapia prolongada com medicamentos antirreabsortivos e antiangiogênicos, especialmente quando não são adotadas medidas preventivas adequadas. A implementação de práticas preventivas, a vigilância das condições bucais e a colaboração de uma equipe multidisciplinar são fundamentais para reduzir os riscos associados a essa condição patológica.(AU)

Objective: This work aims to provide a comprehensive analysis of the clinical, etiological, radiographic and histopathological characteristics of Medication-Related Jaw Osteonecrosis, in addition to addressing diagnostic methods, prevention and therapeutic strategies. Materials and methods: A search was carried out for scientific articles published between 2015 and 2023, using the Scientific Electronic Library Online (SciELO), US National Library of Medicine (PubMed) and ScienceDirect databases. Conclusion: Although infrequent, there is a considerable potential for osteonecrosis of the jaw to occur in patients undergoing prolonged therapy with antiresorptive and antiangiogenic medications, especially when adequate preventive measures are not adopted. The implementation of preventive practices, surveillance of oral conditions and the collaboration of a multidisciplinary team are essential to reduce the risks associated with this pathological condition.(AU)

A historical review of 'phossy jaw'.

The aim of this article is to stimulate interest and discussion on the pathogenesis of 'phossy jaw'. Historical evidence from newspapers and articles of the time is presented, as other scientific evidence is largely absent. It has stimulated considerable interest in present-day media due to the struggles of nineteenth century reformers to improve working conditions against an apathetic government and weak enforcement of regulation. Those afflicted were often young women who suffered severe pain, loss of segments of jaw, and disfigurement.

Effects of Soft Tissue Closure on Medication-Related Osteonecrosis of the Jaw in a Rabbit Model with Tooth Extraction: A Pilot Study.

OBJECTIVES: The study investigated the effect of soft tissue closure after tooth extraction on the prevention of medication-related osteonecrosis of the jaw in a rabbit model. MATERIALS AND METHODS: Twenty female New Zealand white rabbits were randomly assigned into the experimental group administrated with zoledronic acid (ZA) and control groups treated with saline. Bilateral lower premolar extraction was performed 4 weeks after ZA/saline administration. Immediately after extraction, the wound on the right mandible was closed by suture while the other side was left open. Animals were sacrificed 4 weeks and 8 weeks after tooth extraction. Fluorochrome labeling solutions were injected subcutaneously to evaluate the bone growth rates. The mandibles were harvested and subjected for microcomputed tomography, confocal microscope, and histomorphological examinations. RESULTS: All extraction sites healed well without any signs of infection. Trabecular thickness (Tb.Th) was significantly higher in the ZA-treated group than in the control group at both week 4 and week 8, while no significant difference was detected in the rest of the assessed parameters. The bone growth rate in mandibles showed gradual reduction in the ZA-treated group. Histological analysis showed that at week 8, the animals in the ZA-treated group had significantly higher incidence of osteonecrosis than that in the control group, while no significance was revealed between the sutured and nonsutured side. CONCLUSIONS: ZA treatment significantly reduces bone growth rates but does not reveal a significant effect on bone mineral density and bone microarchitecture. Soft tissue closure of the extraction socket does not reduce the incidence of ONJ in the ZA-treated rabbit model.

Oral mucosal pseudotumor - Novelty complication in patient undergoing bevacizumab therapy.

Medication-related osteonecrosis of the jaw (MRONJ) is a manifestation of bone exposure in the maxillofacial region due to use of drugs such as bisphosphonates, anti-resorptive agents and anti-angiogenic agents. This G1- humanized monoclonal antibody neutralizes the activity of the Vascular Endothelial Growth Factor (VEGF), thus reducing the vascularity of the tumor, which in turn, results in the inhibition of its growth. This case report is of a 53-year-old man with metastatic cholangiocarcinoma who received bevacizumab therapy for the past 11 months. Delayed healing of extraction sockets, osteosclerosis, and exposed bone in the mandible with a mucosal swelling was noted a month after extractions were done. The present case reinforces recent observations that the anti-angiogenic properties of bevacizumab may present a source of osteonecrosis of the jaw. To reduce the incidences of MRONJ, it is imperative to emphasize on preventive dental care, strict oral hygiene maintenance, and regular dental follow ups.

Osteonecrosis of the jaw: a rare but possible side effect in thyroid cancer patients treated with tyrosine-kinase inhibitors and bisphosphonates.

Osteonecrosis of the jaw (ONJ) is a rare but very serious disease that can affect both jaws. It is defined as exposed bone in the maxillofacial region that does not heal within 8 weeks after a health care provider identification. ONJ can occur spontaneously or can be due to drugs like bisphosphonates (BPS) and anti-RANK agents, in patients with no history of external radiation therapy in the craniofacial region. Although in phase 3 trials of tyrosine kinase inhibitors (TKIs) used in thyroid cancer (TC) the ONJ was not reported among the most common side effects, several papers reported the association between ONJ and TKIs, both when they are used alone and in combination with a bisphosphonate. The appearance of an ONJ in a patient with metastatic radio-iodine refractory differentiated TC, treated with zoledronic acid and sorafenib, has put us in front of an important clinical challenge: when a ONJ occurred during TKIs treatment, it really worsens the patients' quality of life. We should consider that in the case of ONJ a TKI discontinuation becomes necessary, and this could lead to a progression of neoplastic disease. The most important aim of this review is to aware the endocrinologists/oncologists dealing with TC to pay attention to this possible side effect of BPS and TKIs, especially when they are used in association. To significantly reduced the risk of ONJ, both preventive measures before initiating not only antiresorptive therapy but also antiangiogenic agents, and regular dental examinations during the treatment should always be proposed.

[Thoughts on the prevention, clinical diagnosis and treatment of osteonecrosis of the jaw and future research directions].

With the progress and development of society, osteonecrosis of the jaw has appeared some new features and new problems in oral clinical work. The prevention, early diagnosis, and early treatments of osteonecrosis of the jaw are of great significance. This article describes the current clinical diagnosis and treatment status of osteoradionecrosis of the jaw and medication-related osteonecrosis of the jaw, and puts forward some thoughts on the prevention, clinical diagnosis and treatment and future research direction of osteonecrosis of the jaw.

[Myelodysplastic syndrome, osteoporosis and medication-related osteonecrosis of the jaw: a case report]. / Síndrome mielodisplásico, osteoporosis y osteonecrosis maxilar asociada a medicamentos antirresortivos: reporte de un caso.

Introduction: Medication-related osteonecrosis of the jaw is a frequent collateral effect found in patients under antiresorptive treatments. Malignancies such as multiple myeloma, breast and prostate cancer as well as bone-metabolic disorders such as osteoporosis, lead the indications for these antiresorptive therapies. Even with a low frequency, myelodysplastic syndromes are also entities that have previously been associated with the development of jaw osteonecrosis. Objective: the aim of this study is to present a case of a 78-year-old male patient with myelodysplastic syndrome and secondary osteoporosis, treated with high-dose Zoledronic Acid and who developed a clinical scenario compatible with medication-related osteonecrosis of the jaw during its evolution. Methodology: : the case was recorded and treated in the Oral Medicine Department, Facultad de Odontología, Universidad Nacional de Córdoba, during a two-years period with a partial resolution, which recurred fourteen months later, where finally therapeutic success was achieved through a conservative management. Conclusion: Due to the increasingly use of antiresorptive drugs, the development of jaw osteonecrosis is possible associated with less frequent pathologies, such as myelodysplastic syndrome. Treatment success in these patients depends on interdisciplinary management and a rigorous clinical, medical and dental follow-up.

Introducción: La osteonecrosis maxilar asociada a medicamentos es una complicación encontrada en pacientes bajo tratamiento con drogas antirresortivas. Patologías oncológicas como mieloma múltiple, cáncer de mama y próstata y alteraciones óseas-metabólicas como la osteoporosis lideran las indicaciones para estas terapias antirresortivas. Aún con una baja frecuencia, los síndromes mielodisplásicos también son entidades que previamente han sido vinculadas al desarrollo de osteonecrosis. Objetivo: el objetivo de este trabajo es presentar un caso de un paciente masculino de 78 años con síndrome mielodisplásico y osteoporosis secundaria, tratado con Ácido Zoledrónico a altas dosis y que en su evolución desarrolló un cuadro clínico compatible con osteonecrosis maxilar asociada a medicamentos. Metodología: el caso fue registrado y tratado en la Cátedra de Estomatología "A" de la Facultad de Odontología, Universidad Nacional de Córdoba, durante un periodo de dos años con una resolución parcial del cuadro, el cual recurrió a los catorce meses, donde finalmente se llegó al éxito terapéutico mediante terapéuticas conservadoras. Conclusión: debido al uso cada vez más extendido de fármacos antirresortivos, es posible el desarrollo de osteonecrosis maxilar asociada a patologías menos frecuentes, como el síndrome mielodisplásico. El éxito del tratamiento en estos pacientes depende del manejo interdisciplinario y de un riguroso seguimiento clínico médico y odontológico.

Determination of the molecular mechanism by which macrophages and γδ-T cells contribute to ZOL-induced ONJ.

OBJECTIVE: This study aims to explore the molecular mechanism of macrophages and γδ-T cells in the ZOL drug-induced osteonecrosis of jaws based on the IFN-γ involved osteoblast differentiation signaling pathway. RESULTS: The number and apoptotic rate of CD11b+Gr1hi cells and γδ-T cells in the ONJ group were significantly higher. The TNF-α, IL-1ß, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were significantly higher in the ONJ group. The expression of CTSK and FGFR3 was lower in the ONJ group, but was higher in the NF-κB and ERBB2IP group. CONCLUSION: The proliferation of macrophages and γδ-T cells promote the inflammation in ZOL-induced jaw necrosis. METHODS: A total of 20 patients with osteonecrosis of the jaw from January 2016 to March 2018 were collected and assigned into the observation group, while 20 healthy subjects were assigned into the control group. Furthermore, 40 SD rats were selected and assigned into observation group, while 10 non-treatment SD rats were selected and assigned as controls. The distribution and proportion of CD11b+Gr1hi cells and γδ-T cells in the necrotic tissues of the jaw were analyzed. Then, the TNF-α, IL-1ß, IFN-γ, CCL3, CCL4, IL-12 and IL-13 levels were measured. Afterwards, the expression of CTSK, FGFR3, NF-κB and ERBB2IP in the necrotic tissues of the jaw in the animal models were analyzed.

Osteonecrosis of the jaw induced by treatment with anti-PD-1 immunotherapy: a case report.

Recognizing rare but clinically significant toxicity of immunotherapy is critical. Here we describe the first detailed case of severe osteonecrosis of the jaw due to anti-PD-1. A 75-year-old man with metastatic melanoma, with no prior radiation or treatment with bone-targeting agents, experienced jaw pain 1 week after his first dose of nivolumab. Imaging studies were negative, and treatment was resumed after pain was controlled. 4 months later, the patient experienced acute exacerbation of pain and malocclusion of the jaw. Imaging showed bilateral fractures of the angle of mandible with extensive disruption of the normal trabecular architecture, requiring total mandibulectomy. The patient's metastatic melanoma responded to treatment and remains controlled >20 months after treatment cessation without further therapy.

Rechallenge of denosumab in jaw osteonecrosis of patients with unresectable giant cell tumour of bone: a case series analysis and literature review.

OBJECTIVES: Giant cell tumour of bone (GCTB) is a rare tumour, generally managed with surgery. Treatment of the very rare unresectable advanced/metastatic GCTB is challenging and denosumab is the only current available medical option, an anti-RANKL monoclonal antibody inhibiting osteolysis. An uncommon but severe and treatment-limiting adverse event of denosumab is the osteonecrosis of the jaw (ONJ). The clinical management of GCTB patients stopping denosumab for medication-related (MR)-ONJ and the possible reintroduction of denosumab after MR-ONJ resolution is matter of debate. We performed a retrospective study to describe the incidence, clinical features and outcome of MR-ONJ in unresectable GCTB patients treated with denosumab at our Institution. DESIGN AND SETTING: Retrospective, single-institutional study. PARTICIPANTS: Adult patients receiving denosumab as antineoplastic therapy for GCTB and experiencing MR-ONJ at Fondazione IRCCS Istituto Nazionale Tumori of Milan between January 2008 and July 2019. MAIN OUTCOME MEASURES: Incidence, time of onset and clinical features of MR-ONJ. RESULTS: 29 patients with locally advanced and/or metastatic GCTB treated with denosumab were identified. At a median follow-up of 70 months (range 1-125), 4 (13.8%) patients experienced MR-ONJ while on treatment, after 125, 119, 85 and 41 months of denosumab, respectively. All patients showed an ongoing tumour stabilisation with denosumab at the MR-ONJ onset and in all cases denosumab was stopped. All four patients were treated with ozone therapy. Two are waiting for surgery, two were already operated on. Both of them experienced disease progression and were thus rechallenged with denosumab. One is still on therapy after 25 months. The other had an MR-ONJ relapse after 39 months and was treated again with ozone therapy and surgery. She is under surveillance, GCTB being currently stable. CONCLUSION: A clinical algorithm of denosumab rechallenge after complete resolution of MR-ONJ in progressing GCTB patients should be prospectively validated.

Osteonecrosis de los maxilares asociada a medicamentos: revisión de la literatura y propuesta para la prevención y manejo / Osteonecrosis of the jaws

Medication-related osteonecrosis of the jaw is a disease where there is necrotic bone exposed or that can be explored by means of a fistula in the maxillofacial region. It has been associated with the use Biphosphonates and denosumab for osteoporosis. Although its etiology is unclear, it may be related to a decrease in bone turnover produced by these drugs, rendering the bone more prone to generate cell necrosis during invasive dental procedures, especially in the posterior region of the jaw. There is no consensus about the prevention and treatment of this condition. The aim of this paper is to present a review of the literature with the main characteristics of osteonecrosis of the jaws associated with drugs, together with a proposal for prevention and treatment for these patients.

Relationships of opacification in the nasal sinuses, rhinosinusitis, and antiresorptive agent-related osteonecrosis of the jaw.

OBJECTIVE: Bone turnover suppression agents are widely used for prophylaxis of bone metastases from cancer and osteoporosis; the occurrence of their side effect, antiresorptive agent-related osteonecrosis of the jaw (ARONJ), has been increasing. We investigated the relationships between opacification in the nasal sinuses, rhinosinusitis, and ARONJ based on data obtained from oral surgeons. METHODS: We examined 132 patients who had been clinically diagnosed with ARONJ based on clinical observations; all patients had undergone treatment at the Departments of Otorhinolaryngology and Oral Surgery. In 16 of the 132 patients, we confirmed a diagnosis of osteonecrosis of the upper jaw and the presence of ipsilateral opacification of the maxillary sinus. We analyzed the data of these 16 patients in detail. RESULTS: Five of the 16 patients had some nasal symptoms and had been diagnosed with rhinosinusitis. The opacification of the rhinosinuses improved, partially improved, and remained unchanged after treatment in 10, three, and two patients, respectively; notably, imaging assessment could not be conducted after treatment in one case. CONCLUSIONS: Although there is no consensus regarding the treatment of sinusitis accompanying ARONJ, attempts to improve the causal foci and conservative treatment may offer favorable results; thorough investigation is necessary in refractory cases before determining the use of surgery.

Medication-related osteonecrosis of the jaws (MRONJ) in cancer patients treated with denosumab VS. zoledronic acid: A systematic review and meta-analysis

BACKGROUND: The aim of the present study was to analyse the incidence, risk ratio (RR) and prognoses of two types of medication-related osteonecrosis of the jaws (MRONJ): denosumab-related osteonecrosis of the jaws (DRONJ) and Bisphosphonate-Related Osteonecrosis of the Jaws (BRONJ) in cancer patients under treatment with deno-sumab or zoledronic acid (ZA). MATERIAL AND METHODS: An electronic and manual search was conducted for randomized controlled trials (RCTs) until May 2019. Assessment of the identified studies, risk of bias and data extraction were performed independently by two reviewers. The incidence of DRONJ and BRONJ and the RR to develop MRONJ were calculated at 1 year, 2 years and 3 years of exposure. It was also calculated the odds ratio (OR) of their respective prognoses. They were calculated normalizing the values of the individual studies to 1 year, 2 years or 3 years when necessary through robust regression models using a statistical program. RESULTS: From 1.277 references identified, 8 RCTs were included, which comprised a total of 13.857 patients with a variety of neoplasms. The incidence of DRONJ in cancer patients under treatment with denosumab ranged from 0.5 to 2.1% after 1 year, 1.1 to 3.0% after 2 years, and 1.3 to 3.2% after 3 years of exposure. The incidence of BRONJ in cancer patients under treatment with ZA ranged from 0.4 to 1.6% after 1 year of exposure, 0.8 to 2.1% after 2 years, and 1.0 to 2.3% after 3 years of exposure. Statistically significant differences were found between de-nosumab and ZA in the risk of developing MRONJ after 1, 2 and 3 years of exposure. Nevertheless, there were no significant differences in terms of patient prognosis. CONCLUSIONS: Denosumab is associated with a significantly higher risk of developing MRONJ compared to ZA. Nevertheless, no differences were found in its prognoses

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Aromatase inhibitors associated osteonecrosis of jaw: signal refining to identify pseudo safety signals.

Background Signal generation through data mining algorithms is an innovative and emerging field in pharmacovigilance. Early detection of safety signals is important for public health safety. However, the possibility of generating pseudo signals should not be overlooked. Objective Our study aimed to identify potential signals of aromatase inhibitors associated Osteonecrosis of Jaw and assess the possibilities of the safety signal to be a pseudo signal/false positive in FDA Adverse Event Reporting System (FAERS). Setting Spontaneously reported data in FAERS database. Methods Data for this study were obtained from the public release of data in FAERS. OpenVigil, a pharmacovigilance analytical tool was used to access FAERS data. Reporting Odds Ratio (ROR) was used to assess the relation between the drug and adverse event. A value of ROR-1.96SE > 1, (SE-standard error) was considered positive. Main outcome measure Signal strength. Results FAERS database had a total of 15,178 reports for Osteonecrosis of Jaw. Amongst which 617 reports were associated with aromatase inhibitors. Signal strength ROR (lower bound of the 95% CI) for letrozole, anastrozole and exemestane associated Osteonecrosis of Jaw without any background correction was 8.34, 6.64 and 15.14 respectively. Upon removing the reports of concomitantly administered drugs (bisphosphonates and denosumab), signal strength drastically decreased to 0.03, 0.36 and 0.47 for letrozole, anastrozole and exemestane respectively. The signal strength of bisphosphonates and denosumab associated Osteonecrosis of Jaw was not changed significantly upon removal of aromatase inhibitors. Conclusion Our study concluded that the signal generated for aromatase inhibitors associated Osteonecrosis of Jaw in FAERS database can be false positive. Careful background corrections with identification of those risk factors are imperative to exclude false positive results.

[Current evidence-based approaches and international guidelines in primary and secondary prevention strategies of medication-related osteonecrosis of the jaws]. / Aktualitások a gyógyszer okozta állcsontelhalás primer és szekunder prevenciójának stratégiájában az evidenciák és a nemzetközi ajánlások tükrében.

Introduction: The presumably multifactorial pathomechanisms of medication-related osteonecrosis of the jaws have not been fully elucidated so far. Management of this rare but serious side effect is a real challenge and requires a multidisciplinary approach. Aim: The aim of the authors was to take stock of our present knowledge about the pathogenesis, risk factors, clinical manifestations and the possibilities of prevention and treatment in the medication-related osteonecrosis of the jaws. In addition, the available international guidelines are compared and the evidence-based, stage-specific conservative and adjuvant therapeutic approaches are also reviewed, having regard to special aspects of medical and dental care. Method: In the last 5 years - due to the increasing number of disorder-oriented database - the number of available systematic reviews, recommendations and meta-analyses has escalated significantly which we reviewed and compared. Results: Since the last Position Paper published by the taskforce of the American Association of Oral and Maxillofacial Surgeons, novel pharmacological groups with the potential to induce osteonecrosis have come in the clinical scope, further elaborating the nomenclature of the disease and further specifying patient groups. The sphere of patients at risk has broadened and novel patient groups (rheumatologic-osteological, immunosuppressed, transplanted or oncological patients treated with monoclonal antibody, known as 'target therapy') are expected to develop this serious side effect. Conclusion: Although a number of issues are still open regarding the treatment of the disorder, evidence-based, individualized, stage-adapted therapeutic approaches have replaced the previous empirical treatment. Orv Hetil. 2020; 161(6): 214-223.

Quantitative bone scan imaging using BSI and BUV: an approach to evaluate ARONJ early.

OBJECTIVE: The usefulness of bone scan index (BSI), a quantitative metric of the area of uptake in computer-aided diagnosis in bone scintigraphy, has been reported for the diagnosis of anti-resorptive-agent-related osteonecrosis of the jaw (ARONJ). The aim of this study is to validate the diagnostic ability of BSI for the early detection of ARONJ. In addition, the Bone uptake value (BUV), another quantitative index obtained from bone scintigraphy that indicates the degree of radioisotope (RI) accumulation, was used to improve the diagnostic ability for early detection of ARONJ. METHODS: A total of 34 patients (11 with ARONJ, 23 without ARONJ) who were administered anti-resorptive-agents for bone metastasis and had incidentally consulted a dental surgeon within 3 months after regular whole-body bone scintigraphy were retrospectively included in the study. The bone scintigraphy data were subjected to semiquantitative analysis of uptake in the jaw using BONENAVI (FUJIFILM Toyama Chemical, Co. Ltd., Tokyo, Japan; EXINI Diagnostics AB, Lund, Sweden) and BUV software (Technical Society for Quantitative Bone Scintigraphy and Fujifilm Toyama Chemical Co., Ltd. Tokyo, Japan). The ROI was set semi-automatically on mandibular hotspots, and the regional BSI was termed BSIJ. Planar anterior and posterior images were then sent to BUV software, with the ROI set manually as for BSI, and the regional BUV was termed BUVJ. RESULTS: Mean BSIJ values for the ARONJ positive and ARONJ negative groups were 0.17 ± 0.83 and 0.03 ± 0.50%, respectively. Mean BUVJ values for the ARONJ positive and ARONJ negative groups were 0.47 ± 0.17 and 0.19 ± 0.11, respectively. BSIJ × BUVJ values for the ARONJ positive versus ARONJ negative groups were 0.088 ± 0.067 vs. 0.007 ± 0.010. The AUC for BSIJ, BUVJ and BSIJ × BUVJ was 0.949, 0.951 and 0.988, respectively. CONCLUSION: The BSI metric of a CAD system for bone scintigraphy was useful for the early detection of ARONJ. Accuracy was improved with the additional use of BUVJ data. We recommend that SPECT imaging be performed when bone scintigraphy reveals focal or diffuse uptake in the mandible with high BSIJ and BUVJ.