Pre-existing Bone Lesion Research Articles

Spontaneous fractures and hypocuprosis in pen-backgrounded Holstein calves

Bone fractures are a frequent cause of limp in cattle, being pre-existing bone lesions among the predisposing factors. However, there is scant information about the natural occurrence of bone disease. This report aimed to describe an outbreak of spontaneous fractures associated with hypocuprosis in pen-backgrounded calves. Hind limp and irreversible recumbency were noticed in 9-month-old calves of a dairy farm from Córdoba province (Argentina). The issue was only evident in males fed a diet composed (DM) of 57% wet corn, 24% dry corn distiller grains, and 19% corn silage. No mineral mix was supplied. Accumulated morbidity and fatality rates were 5.8 and 100%, respectively. Two autopsies were performed, observing multiple femoral and rib fractures. Severe hypocupremia, very low copper levels in the liver and plasma, deficient dietary copper levels, normocalcemia, marginal hypophosphatemia, and high sulfate concentrations in the water supply were determined. Except for the decreased bone quantity and the multiple fractures, no bone lesion was observed, confirming osteoporosis as the pathological diagnosis, and hypocuprosis as the etiology.

PATHOLOGICAL MANDIBULAR FRACTURES: A RETROSPECTIVE STUDY

Pathological mandibular fractures occur in regions with previously damaged bone structure due to different etiologies. The purpose of the study is to present a retrospective review of patients with pathological mandibular fractures who passed through the Clinic of Oral and Maxillofacial Surgery of St. George University Hospital, Plovdiv, for the period 2005-2019 and to compare the results with published literature. Material and methods: The study includes1328 patients with pathological fractures of the mandible with different etiology. Data were collected on age, gender, pre-existing bone damage and lesions, history of any interventions of the lower jaw and treatment approach. Results: Patients with pathological mandibular fractures are 5,1% of all patients who passed through the clinic for this period. Two hundred of them are associated with benign or malignant bone tumors, 161 with osteomyelitis, 202 with other causes: third molar extraction, implant placement, osteonecrosis. Conclusion: Pathological mandibular fractures have different etiologies. Diagnosis and treatment of this condition are challenging, and the treatment plan should be decided individually, according to the underlying disease.

Prognostic significance of increased bone marrow microcirculation in newly diagnosed multiple myeloma: results of a prospective DCE-MRI study.

Aim of this prospective study was to investigate prognostic significance of increased bone marrow microcirculation as detected by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for survival and local complications in patients with multiple myeloma (MM). We performed DCE-MRI of the lumbar spine in 131 patients with newly diagnosed MM and analysed data according to the Brix model to acquire amplitude A and exchange rate constant kep. In 61 patients a second MRI performed after therapy was evaluated to assess changes in vertebral height and identify vertebral fractures. Correlation analysis revealed significant positive association between beta2-microglobulin as well as immunoparesis with DCE-MRI parameters A and kep. Additionally, A was negatively correlated with haemoglobin levels and kep was positively correlated with LDH levels. Higher baseline kep values were associated with decreased vertebral height in a second MRI (P = 0.007) and A values were associated with new vertebral fractures in the lower lumbar spine (P = 0.03 for L4). Pre-existing lytic bone lesions or remission after therapy had no impact on the occurrence of vertebral fractures. Multivariate analysis revealed that amplitude A is an independent adverse risk factor for overall survival. DCE-MRI is a non-invasive tool with significance for systemic prognosis and vertebral complications. • Qualitative parameters from DCE-MRI are correlated with established factors of disease activity • Increased marrow microcirculation might be a risk factor for loss of vertebral height and fractures • Amplitude A is an independent predictor for shortened overall survival.

Bilateral aneurysmal bone cyst of the mandible: A case report

An aneurysmal bone cyst (ABC), usually considered a reactive lesion of bone rather than a cyst or true neoplasm, is believed to represent an exaggerated, localized, proliferative response of vascular tissue in bone. The case described here is of a 40-year-old female patient presenting with gradually increasing bilateral mandibular swelling of more than 1 year duration. The radiographic and cone beam computed tomography (CBCT) images showed bilateral, multilocular expansile radiolucent lesions in the mandible in the premolar-molar region. On considering the blood aspirate obtained and the histopathologic findings, the patient was diagnosed with bilateral aneurysmal bone cysts in the mandible, with probable pre-existing bone lesion.

Effect of Everolimus on Bone Marker Levels and Progressive Disease in Bone in BOLERO-2

Breast Cancer Trials of Oral Everolimus 2 (BOLERO-2), a phase III study in postmenopausal women with estrogen receptor-positive breast cancer progressing despite nonsteroidal aromatase inhibitor therapy, showed statistically significant benefits with adding everolimus to exemestane. Moreover, in preclinical studies, mammalian target of rapamycin inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of everolimus on bone marker levels and progressive disease in bone. Patients were treated with exemestane (25mg/day) and randomized (2:1) to everolimus (10mg/day; combination) or placebo (exemestane only). Exploratory endpoints included changes in bone turnover marker levels vs baseline and progressive disease in bone, defined as unequivocal progression of a preexisting bone lesion or the appearance of a new bone lesion. Baseline disease characteristics were well balanced between arms (N = 724); baseline bisphosphonate use was not (43.9% combination vs 54.0% exemestane only). At a median of 18 months of follow-up, median progression-free survival (primary endpoint) was statistically significantly longer with the combination vs exemestane only (Cox proportional hazard ratio = 0.45, 95% confidence interval = 0.38 to 0.54; log-rank, 1-sided P < .0001). Bone marker levels at 6 and 12 weeks increased with exemestane only, as expected, but decreased with the combination. The cumulative incidence rate of progressive disease in bone was lower in the combination arm. Bone-related adverse events occurred with similar frequency in both arms (3.3% combination vs 4.2% exemestane only). These exploratory analyses suggest that everolimus has beneficial effects on bone turnover and progressive disease in bone in patients receiving exemestane for hormone receptor-positive breast cancer progressing during/after nonsteroidal aromatase inhibitor therapy.

Effects of everolimus (EVE) on disease progression in bone and bone markers (BMs) in patients (pts) with bone metastases (mets).

102 Background: BOLERO-2, a multinational, double-blind, placebo-controlled, phase III study in postmenopausal women with estrogen-receptor–positive breast cancer (BC) refractory to nonsteroidal aromatase inhibitors (NSAIs), showed significant clinical benefits with the addition of EVE to exemestane (EXE) (Baselga J et al. NEJM2011 Epub). As bone resorption is an important factor in BC mets, it is interesting to study bone-related effects of EVE. In preclinical studies, mTOR inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effects of EVE vs placebo (PBO) on BM levels and BC progression in bone in pts with bone mets at baseline. Methods: Eligible pts were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 mg once daily) or PBO. Bone turnover markers (BMs) were exploratory endpoints analyzed at 6 and 12 wks after treatment initiation and included bone-specific alkaline phosphatase, amino-terminal propeptide of type I collagen, and C-terminal cross-linking telopeptide of type I collagen. Progressive disease in bone (PDB) was defined as worsening of a preexisting bone lesion or a new bone lesion. Results: Baseline disease characteristics, including bone mets at baseline (n = 370, 76% EVE vs n = 184, 77% PBO), were well balanced between arms (N = 724), and baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo median follow-up, progression-free survival (primary endpoint), overall response rate, and clinical benefit rate (p &lt; 0.0001, all) were significantly higher with EVE (n = 485) vs PBO (n = 239). BM levels at 6 and 12 wks increased vs baseline with PBO but decreased with EVE. The cumulative incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 6.16%, respectively), and this trend was sustained beyond 6 months. Updated results will be presented. All bone-related adverse events reported were grade 1-2 and occurred with similar frequency in EVE (2.9%)- and PBO (3.8%)-treated patients. Conclusions: Exploratory analyses from BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover and BC progression in bone in pts receiving EXE therapy for NSAI-refractory BC.

Effects of everolimus (EVE) on disease progression in bone and bone markers (BM) in patients (pts) with bone metastases (mets).

512 Background: BOLERO-2, a multinational, double-blind, placebo-controlled, phase III study in postmenopausal women with estrogen-receptor–positive breast cancer (BC) refractory to non-steroidal aromatase inhibitors (NSAIs), showed significant clinical benefits with the addition of EVE to exemestane (EXE) (Baselga J, et al. NEJM. 2011 Epub). As bone resorption is an important factor in BC mets, it is interesting to study bone-related effects of EVE. In preclinical studies, mTOR inhibition was associated with decreased osteoclast survival and activity. Exploratory analyses in BOLERO-2 evaluated the effect of EVE vs placebo (PBO) on BM levels and BC progression in bone in pts with bone mets at baseline. Methods: Eligible pts were treated with EXE (25 mg once daily) and randomized (2:1) to EVE (10 mg once daily) or PBO. Bone turnover markers were exploratory endpoints analyzed at 6 and 12 wks after treatment initiation, and included bone-specific alkaline phosphatase, amino-terminal propeptide of type I collagen, and C-terminal cross-linking telopeptide of type I collagen. Progressive disease in bone (PDB) was defined as worsening of a pre-existing bone lesion or a new bone lesion. Results: Baseline disease characteristics, including bone mets at baseline (n = 370, 76% EVE vs n = 184, 77% PBO), were well balanced between arms (N = 724), and baseline bisphosphonate use was not (44% EVE vs 55% PBO). At 12.5 mo median follow-up, progression-free survival (primary endpoint), overall response rate, and clinical benefit rate (P &lt; .0001, all) were significantly higher with EVE (n = 485) vs PBO (n = 239). BM levels at 6 and 12 wks increased vs baseline with PBO, but decreased with EVE. The cumulative incidence rate of BC PBD was lower for EVE vs PBO at day 60 (3.03% vs 6.16%, respectively) and this trend was sustained beyond 6 months. Updated results will be presented. All bone-related adverse events reported were grade1/2 and occurred with similar frequency in EVE- (2.9%) and PBO- (3.8%) treated patients. Conclusions: Exploratory analyses from BOLERO-2 suggest that adding EVE has beneficial effects on bone turnover and BC progression in bone in pts receiving EXE therapy for NSAI-refractory BC.

Histology of peri-implant bone in a failed implant retrieved from an area of osteonecrosis of the jaw in a patient suffering from multiple myeloma and treated with intravenous bisphosphonates

Background Osteonecrosis of the jaw (ONJ) has been reported in the past few years in patients undergoing treatment with bisphosphonates (BP). Few published histological studies of ONJ can be found in the literature and no study has been reported on the peri-implant bone around a dental implant retrieved from an area of ONJ. The aim of the present case was to report the histology of the peri-implant bone around an implant retrieved from an area of ONJ. Materials and methods Multiple myeloma was diagnosed to a 72-year-old male. The patient underwent treatment with intravenous pamidronate for 2 years and with intravenous zoledronate for additional 3 years. Five years after the diagnosis, 7 immediately loaded dental implants were inserted in the mandible. A preoperative panoramic radiography did show no pre-existing bone lesions. No healing of the post-extraction sockets of the right third molar and of the left second molar was observed. Three years after the implant insertion a breakdown of the oral mucosa covering the implants was observed. The most distal implant was retrieved with a trephine bur, due to mobility. Discussion The histological findings showed some areas with osseointegration in patients undergoing BP treatment for malignant disease. Conclusion There is certainly a temporal association between BP use and development of ONJ, but a correlation does not necessarily mean causation. Moreover, generalisations about this complex relationship cannot be made on the basis of a single case report. In patients undergoing intravenous treatment, clinicians must be aware of the increased risk of implant failure and, probably, implant insertion should be avoided at all, until more conclusive data are available.

The importance of radiographic imaging in the microscopic assessment of bone tumors

IntroductionPrimary bone tumors are rare and require a multidisciplinary approach. Diagnosis involves primarily the radiologist and the pathologist. Bone lesions are often heterogeneous and the microscopic diagnostic component(s) may be in the minority, especially on core needle biopsies. Reactive processes, benign, and malignant tumors may have similar microscopic aspects. For these challenging cases, the correlation of microscopic and radiologic information is critical, or diagnostic mistakes may be made with severe clinical consequences for the patient. The purpose of this article is to explain how pathologists can best use imaging studies to improve the diagnostic accuracy of bone lesions. DiagnosisMany bone lesions are microscopically and/or radiographically heterogeneous, especially those with both lytic and matrix components. Final diagnosis may require specific microscopic diagnostic features that may be present in the lesion, but not the biopsy specimen. A review of the imaging helps assess if sampling was adequate. The existence of a pre-existing bone lesion, syndrome (such as Ollier disease or multiple hereditary exostosis), or oncologic history may be of crucial importance. Finally, imaging information is very useful for the pathologist to perform accurate local and regional staging during gross examination. ConclusionClose teamwork between pathologists, radiologists, and clinicians is of utmost importance in the evaluation and management of bone tumors. These lesions can be very difficult to interpret microscopically; imaging studies therefore play a crucial role in their accurate diagnosis.

Osteonecrosis of the Posterior Mandible after Implant Insertion: A Clinical and Histological Case Report

In the past few years, the occurrence of an oral lesion, called osteonecrosis of the jaw (ONJ), has been increasingly reported in patients undergoing treatment with bisphosphonates (BPs); however, few published histological studies of ONJ can be found in the literature. The aim of the present case was to report an occurrence of ONJ after implant insertion. Multiple myeloma was diagnosed to a 65-year-old female. After 5 years of treatment with intravenous clodronate, two dental implants were inserted in the mandibular molar region. No preexisting bone lesions were present at a preoperative panoramic radiography. Before implant insertion, the patient had suspended the treatment with clodronate for 3 months. Four months after the implant insertion, a breakdown of the oral mucosa covering the implants occurred with a purulent discharge; periapical radiolucency was present around both implants. An en-block resection on the alveolar bone including the two implants was performed. No signs of recurrence of the lesion were observed after a follow-up of 20 months. At the interface of one of the implants, a gap was observed between bone and implant. This bone was nonvital, and many osteocyte lacunae were empty. Moreover, this bone appeared to be partially demineralised. No newly formed bone or osteoblasts were present. Bone trabeculae were observed, on the other hand, within the apical implant threads of the other implant. A close connection was observed between this bone and the implant surface. The histological findings showed some areas with osseointegration in patients undergoing BP treatment for malignant disease; however, any invasive procedure can determine the onset of osteonecrosis. In conclusion, there is certainly a temporal association between BP use and development of ONJ, but a correlation does not necessarily mean causation. Moreover, generalizations about this complex relationship cannot be made on the basis of a single case report. In patients undergoing intravenous treatment, clinicians must be aware of the increased risk of implant failure and, probably, implant insertion should be avoided at all until more conclusive data are available.

Osteosarcoma Radioinduced After Adenoid Cystic Tumor of the Parotid Gland

Osteosarcoma can develop secondary to malignant transformation within a preexisting benign bone lesion, such as Paget disease, osteonecrosis, fibrous dysplasia, and chronic infection, or it can arise in previously irradiated areas. This article presents the case of a 36-year-old woman who was affected by a radioinduced osteosarcoma after radiotherapy for an adenoid cystic carcinoma of the left parotid gland treated when she was 24 years old.

Efficacy of targeted therapy in patients with renal cell carcinoma with pre-existing or new bone metastases

This single-centre retrospective analysis of data from three randomised studies and two expanded-access studies compared the effect of interferon (IFN)-alfa, sunitinib, and sorafenib on the occurrence and progression of metastatic bone lesions in patients with renal cell carcinoma (RCC). The analysis included 292 patients: 107 received sunitinib 50 mg/day in 6-week cycles (Schedule 4/2), 147 received sorafenib 800 mg/day, and 38 received placebo or IFN-alfa 9 MU t.i.w. Pre-existing metastatic bone lesions were reported in 82 patients, of which 30 experienced progression. Twenty-three of 210 patients developed new bone lesions. Overall, sunitinib appeared slightly more effective than sorafenib or IFN-alfa at extending mean time to progression of pre-existing bone lesions (P = 0.057). Compared with sorafenib, sunitinib significantly decreased formation (P = 0.034) and prolonged time to occurrence of new bone lesions (P = 0.047). Further evaluation of the effect of these therapies on bone metastases in RCC is warranted.

Odontoid fracture complicating Jaffe–Lichtenstein disease

The authors report the case of a 31-year-old man with polyostotic fibrous dysplasia who suffered a traumatic odontoid fracture in an area of a preexisting bone lesion. Conservative treatment was successfully performed. Jaffe-Lichtenstein disease is discussed along with differential diagnoses and alternative methods of treatment.

Phase I Trial of HuLuc63 in Multiple Myeloma.

Background: HuLuc63 is a humanized monoclonal antibody directed against CS1 that has demonstrated potent in vivo and in vitro activity against myeloma cells in pre-clinical models. CS1 is a cell surface glycoprotein expressed at high levels on myeloma cells, plasma cells and to a lesser extent on a subset of CD8 + lymphocytes and natural killer (NK) cells. A Phase I study was initiated to evaluate the maximum tolerated dose (MTD) of HuLuc63 in a population of relapsed refractory multiple myeloma patients who have been exposed to at least two prior therapies. In a traditional phase 1 design, six potential dosing cohorts are planned with 3 to 6 patients enrolled per cohort to evaluate safety, pharmacokinetics (PK), biologic activity and clinical response. Each course of HuLuc63 is given IV at the same dose every 2 weeks for a total of 4 doses at a level of 0.5, 1, 2.5, 5, 10, 20 mg/kg. An additional 4 doses may be administered if the patient has demonstrated at least stable disease during the initial course of therapy. To date, a total of 7 patients have been treated at 2 dose levels; 3 in the 0.5 mg/kg cohort and 4 in the 1.0 mg/kg cohort. Median patient age is 64 years and the median number of prior therapies is five. An additional patient was enrolled in the 1.0 mg/kg cohort as a patient in that cohort had a 2-week delay in receiving his second dose due to worsening pain at the site of a pre-existing lytic bone lesion. No dose-limiting toxicities have occurred. Infusions were well tolerated, with grade 1 and 2 toxicities occurring during or after the first dose including chills (2 patients), flushing, pyrexia, rigors, dyspnea and fatigue. Patients who reported first dose reactions were pretreated with acetaminophen and diphenhydramine prior to subsequent doses and only one patient reported fatigue after the second dose. Four serious adverse events have occurred in 2 patients which were considered unrelated to HuLuc63. These include migraine headache (twice in the same patient), congestive heart failure and hypercalcemia. Two patients discontinued therapy prematurely due to progressive disease but all other patients have received 4 doses of HuLuc63. No clinical responses have been observed. In xenograft mouse models, a consistent drug level of 10 mcg / mL was required to show minimal biologic activity. Preliminary PK data reveals that peak serum drug levels for the 0.5 mg/kg dosing cohort reached 10 mcg / mL, which was sufficient to achieve CS 1 saturation of at least 70% on the antigen rich NK cell subset. Drug levels dropped below 1 mcg/mL by day 7, however, coinciding with a decrease in saturation. This indicates that the higher doses to be used in subsequent cohorts may achieve and surpass sustained concentrations in patients above this level. Thus far, HuLuc63 appears to be well tolerated in patients with multiple myeloma. Enrollment is continuing to determine the MTD.

Mandibular fracture after third molar removal

Purpose: Mandibular fracture after impacted lower third molar removal is a rare, but major, complication. The factors leading to a mandibular fracture secondary to third molar removal are analyzed retrospectively. Patients and Methods: Six patients who suffered from a mandibular fracture as a complication after third molar removal were examined clinically and radiographically. Results: All fractures occurred an average of 14 days postoperatively. The patients were 42 to 50 years old and were all fully dentulous. All grades of tooth impaction were included. Conclusions: The major risk factor for this complication seems to be advanced age in combination with a full dentition. The degree of tooth impaction is less important. Preexisting bone lesions weaken the mandible and further predispose to a fracture. © 2000 American Association of Oral and Maxillofacial Surgeons

Pathology of Radium-Induced Bone Tumors: New Aspects of Histopathology and Histogenesis

A revision of bone tumor pathology in patients treated with multiple injections of the short-lived alpha-particle emitter radium-224, predominantly for tuberculosis and ankylosing spondylitis, revealed an unexpectedly high proportion of bone sarcomas of the fibrous connective tissue type. This included the first case of malignant fibrous histiocytoma of bone described after internal irradiation. A comparison of bone tumor types in the radium-224 patients and bone sarcoma after incorporation of radium-226 and radium-228 and external irradiation and in tumors arising at sites of pre-existing bone lesions showed the same spectrum of tumors. The high incidence of bone tumors of the fibroblastic and fibrohistiocytic type was observed in all these "secondary" bone sarcomas. These results suggest that a close histogenetic relationship exists between disorder of the local milieu caused by deterministic radiation damage accompanied by disturbances of the remodeling process. The reactive proliferation of the predominantly fibroblastic tissue could be the presumptive origin of these special types of radiation-induced bone sarcomas.

Aneurysmal Bone Cyst of the Paranasal Sinuses Associated with Fibrous Dysplasia

An aneurysmal bone cyst (ABC) in the paranasal sinuses is rare with only four previous cases having been described in the sphenoid and ethmoid sinuses. This report describes a case of an ABC involving the sphenoid and ethmoid sinuses as well as the upper nasal fossae. It is currently believed that a preexisting primary bone lesion, such as fibrous dysplasia, initiates an osseous arteriovenous fistula, which creates a secondary reactive lesion of bone, the ABC. These lesions, which are comprised of multiple cysts containing liquid blood and serous fluid, are optimally studied by a combination of CT and MR scans.

Aneurysmal bone cyst of the jaws: Report of a case associated with fibrous dysplasia and review of the literature

A case of aneurysmal bone cyst (ABC) of the mandible, recurring for the third time and arising in conjunction with fibrous dysplasia, is reported. A comprehensive review of the literature and analysis of over 50 cases of ABC of the jaws yielded the following results: ABCs of the jaws constitute 1.5 % of all non-odontogenic and non-epithelial cysts of the jaws, and 1.9 % of all ABCs of the skeleton, The mandible was affected in 55 % of the cases, the maxilla in 45 % of the patients. Females represented 53 % of the patients and males the remaining 47 %n. Seventy-four percent of the ABCs occurred in patients 20 years old and younger. This lesion is regarded as non-neoplastic and as most likely secondary to a pre-existing bone lesion. Our review established that 21 % of the reported cases in the jaws had developed in association with various primary lesions of bone, including fibro-osseous lesions. The primary bone lesion initiates an osseous, arteriovenous fistula which, through its hemodynamic forces, creates a secondary reactive lesion, that is an aneurysmal bone cyst. We also established a recurrence rate of 26 %, based upon previously reported cases as well as our own. The treatment of choice is surgical curettage with cryosurgery and immediate packing with bone chips.

Sarcoma arising in irradiated jawbones. Possible relationship with previous non-malignant bone lesions: Report of 6 cases and review of the literature

Thirty-seven cases of radiation-induced sarcoma of the jaw are reviewed from the literature and six new cases are reported. It appears that irradiation seems to play a significant role in the development of jaw sarcoma: 10% of jaw sarcomas arise in irradiated bone. The initial lesion, however, that required irradiation appears to be equally important: 46% of the cases were found to have fibrous dysplasia as the initial lesion, whereas 18% of the remaining cases included diverse bone lesions. The bone was assumed to be normal in only 36% of the cases where irradiation was administered to adjacent tissue lesions. It seems that the association between irradiation and a pre-existing bone lesion has a definite oncologic effect.

Postradiation Sarcoma of Bone

Thirty-four additional cases of sarcoma developing in previously irradiated bone are documented, bringing the total Mayo Clinic experience in sarcoma appearing after radiation therapy to fifty-five instances. The sarcomas arose in normal bone within the radiation treatment field in eleven patients, while they arose in pre-existing bone lesions in sixteen patients. Osteogenic sarcoma and fibrosarcoma were most commonly diagnosed. The outlook in tumors of this nature is poor, the average survival being 1.14 years, with only two long-term survivors. Although a relationship has been established in experimental animals, a direct relationship between exposure to external radiation and the development of sarcoma is not established in man. There is no absolute proof that ionizing radiation caused any of these sarcomas. However, this and other significantly large series add to the mounting circumstantial evidence that the association between ionizing radiation and sarcoma is a real one. It must also be emphasized that this is a rare complication clinically.