Fatty Marrow Replacement Research Articles

Using Longitudinal MRI to Manage Proton Range Uncertainty for Pediatric Proton Craniospinal Irradiation

Clinical evidence has shown that proton therapy can effectively reduce side effects for pediatric patients undergoing vertebral body-sparing craniospinal irradiation (VBS CSI), compared to conventional photon treatment modalities. However, radiation-induced growth impairment remains challenging for VBS CSI due to proton range uncertainty, compromising vertebral body sparing for growing children. Previous studies have shown that fatty marrow replacement can be observed in vertebral bodies 4-48 weeks after treatment is complete. This study aims to detect and quantify the fatty marrow replacement in vertebral bodies using longitudinal magnetic resonance (MR) to manage proton range uncertainty. A prospective clinical trial of proton VBS CSI was designed, and ten pediatric patients were enrolled with prescribed doses of 15-36 Gy. The thecal sac and neural foramina were the clinical target volumes, and a Monte Carlo planning system was used to robustly optimize treatment plans with a 3.5% range margin. We analyzed patients' T1/T2 MR images acquired before, during, and after proton treatment to investigate the hematopoietic marrow transformation induced by irradiation. A metric was defined to calculate the ratio of fatty and hematopoietic marrow based on relative MR intensity histograms. We proposed a machine learning method via Gaussian fitting process (ML-GFP) to explore hidden correlations between marrow transition and radiation dose to 2 cm3 of the bone marrow (D2cc). We also leveraged this method to embed uncertainty to support potential proton range management for VBS enhancement. The results indicated that fatty marrow replacement could be observed during inter-fractional treatment. For instance, an individual patient showed that the fatty marrow generation ratios were 0.54, 0.74, and 0.45, corresponding to 11, 18, and 65 days after the treatment started. Using ML-GFP, the fatty marrow transition was found to be quadratically correlated to treatment fractions, and the maximum transformation ranged from 40 to 50 days. Then marrow regeneration was observed due to the decrease in fatty marrow ratios. The fatty marrow ratios were also positively correlated to the D2cc doses ranging from 10 Gy to 36 Gy. Limited by insufficient low-dose data, the ML-GFP model extrapolated the data to predict the marrow transformation below 10 Gy. We demonstrated the feasibility of using non-invasive longitudinal MR to quantify the fatty marrow transition from inter-fractional treatment. Based on this prospective study, the method can detect early fatty marrow generation in vertebrae caused by proton irradiation due to the conservative range margin used for robust optimization. The proposed method could be used to validate the actual proton range, allowing an accurate range margin to be defined to preserve bone marrow. Future investigation will likely focus on clinical implementation to improve life quality for pediatric CSI patients.

Early in vivo Radiation Damage Quantification for Pediatric Craniospinal Irradiation Using Longitudinal MRI for Intensity Modulated Proton Therapy

Proton vertebral body sparing craniospinal irradiation (CSI) treats the thecal sac while avoiding the anterior vertebral bodies in an effort to reduce myelosuppression and growth inhibition. However, robust treatment planning needs to compensate for proton range uncertainty, which contributes unwanted doses within the vertebral bodies. This work aimed to develop an early in vivo radiation damage quantification method using longitudinal magnetic resonance (MR) scans to quantify the dose effect during fractionated CSI. Ten pediatric patients were enrolled in a prospective clinical trial of proton vertebral body sparing CSI, in which they received 23.4 to 36 Gy. Monte Carlo robust planning was used, with spinal clinical target volumes defined as the thecal sac and neural foramina. T1/T2-weighted MR scans were acquired before, during, and after treatments to detect a transition from hematopoietic to less metabolically active fatty marrow. MR signal intensity histograms at each time point were analyzed and fitted by multi-Gaussian models to quantify radiation damage. Fatty marrow filtration was observed in MR images as early as the fifth fraction of treatment. Maximum radiation-induced marrow damage occurred 40 to 50 days from the treatment start, followed by marrow regeneration. The mean damage ratios were 0.23, 0.41, 0.59, and 0.54, corresponding to 10, 20, 40, and 60 days from the treatment start. We demonstrated a noninvasive method for identifying early vertebral marrow damage based on radiation-induced fatty marrow replacement. The proposed method can be potentially used to quantify the quality of CSI vertebral sparing and preserve metabolically active hematopoietic bone marrow.

Utility of selected sequence MRI imaging of the axial skeleton in the diagnosis of axial spondyloarthritis

BackgroundWhole body MRI has been used to evaluate inflammatory lesions associated with axial spondyloarthritis (SpA). These sequences are extensive, time consuming and add to the cost of the investigation. We aimed to determine the utility of selected sequence MRI imaging of the axial skeleton including spine, pelvis and sacroiliac (SI) joints to identify features of (SpA). MethodsA retrospective study was conducted on 76 patients diagnosed with SpA that underwent a selective sequence MRI imaging of the axial skeleton. The MRI were reported by two musculoskeletal trained radiologists were reviewed. The MRI sequences included whole spine sequences of sagittal STIR (short tau inversion recovery), T1 weighted and T2 weighted sequences. Coronal STIR and T1 weighted images were studied for SI joints and pelvis. The MRI were assessed based on the guidelines outlined by the Assessment of SpondyloArthritis International Society (ASAS) for features of spondylitis, spondylodiscitis, enthesitis, synovitis, capsulitis, bone marrow edema, fatty marrow replacement, erosions and bony ankylosis. Inflammatory lesions were documented in the spine, sacroiliac, facet, hip and costovertebral joints. ResultsThe mean scan duration was 28 min. SI joint involvement was noted in 74 (97.3%) of patients. The other most prevalent findings were spondylitis in 44 (57.8%) patients, costovertebral joint involvement in 31 (40.7%), facet joint lesions in 32 (42.1%), spondylodiscitis in 21 (27.6%), enthesitis in 13 (17.1%), hip lesions in 16 (21%) and ankylosis in 10 (13.1%). ConclusionsThis selective sequence imaging of the pelvis and spine was able to identify typical lesions of SpA in a shorter time period. Fifty-five percent patients had lesions in the posterior elements including facet joints and costovertbral joints that would be missed on traditional SI joint imaging.

Modic Change: An Emerging Complication in the Aging Population.

This was a literature review. The objective of this study was to review the pathogenesis, prevalence, clinical associations, diagnostic modalities, and treatment options for patients with lower back pain (LBP) associated with Modic change (MC). Vertebral body endplates are located between the intervertebral disk and adjacent vertebral body. Despite their crucial roles in nutrition and biomechanical stability, vertebral endplates are extremely susceptible to mechanical failure. Studies examining the events leading to disk degeneration have shown that failure often begins at the endplates. Endplate degeneration with subchondral bone marrow changes were originally noticed on magnetic resonance imaging. These magnetic resonance imaging signal changes were classified as MC. A literature review was conducted on the history, etiology, risk factors, diagnostic modalities, and treatment of LBP with MC. Type 1 MC refers to the presence of increased vascularization and bone marrow edema within the vertebral body. Type 2 MC involves fatty marrow replacement within the vertebral body. Type 3 MC reflects subchondral bone sclerosis. Despite the original classification, research has supported the notion that MCs possess a transitional nature. Furthermore, type 1 MCs have been strongly associated with inflammation and severe LBP, while types 2 and 3 tend to be more stable and demonstrate less refractory pain. With a strong association to LBP, understanding the etiology of MC is crucial to optimal treatment planning. Various etiologic theories have been proposed including autoimmunity, mechanics, infection, and genetic factors. With the aging nature of the population, MC has emerged as an extremely prevalent issue. Research into the pathogenesis of MC is important for planning preventative and therapeutic strategies. Such strategies may include rehabilitation, surgical fixation, stabilization, steroid or cement injection, or antibiotics. Improved diagnostic methods in clinical practice are thus critical to properly identify patients suffering from MC, plan early intervention, and hasten return to functioning.

MR imaging findings of vertebral involvement in Gorham-Stout disease, generalized lymphatic anomaly, and kaposiform lymphangiomatosis.

To assess the MR imaging findings of vertebral involvement in Gorham-Stout disease (GSD), generalized lymphatic anomaly (GLA), and kaposiform lymphangiomatosis (KLA). Nine patients (three patients with GSD, three with GLA, and three with KLA) who underwent whole-spine MR examinations were included. MR findings of fatty marrow replacement and prolonged T1 and T2 lesions of the vertebrae were retrospectively assessed. Prolonged T1 and T2 lesions were defined as well-defined and round-, oval-, or geographic-shaped areas. Six patients [one (33%) patient with GSD, two (67%) with GLA, and three (100%) with KLA] showed both fatty marrow replacement and prolonged T1 and T2 lesions. Fatty marrow replacement was seen in the cervical spine of two (33%) patients, thoracic spine of six (100%), lumbar spine of six (100%), and sacral spine of two (33%). Prolonged T1 and T2 lesions were seen in the cervical spine of three (50%) patients, thoracic spine of three (50%), lumbar spine of six (100%), and sacral spine of three (50%). Both fatty marrow replacement and prolonged T1 and T2 lesions of the vertebrae could be observed in GSD, GLA, and KLA. The most commonly affected site was the lumbar spine, followed by the thoracic spine.

Evaluation of Outcome of Transpedicular Decompression and Instrumented Fusion in Thoracic and Thoracolumbar Tuberculosis.

Study DesignRetrospective analysis.PurposeWe evaluated the functional, neurological, and radiological outcome in patients with thoracic and thoracolumbar tuberculosis operated through the transpedicular approach.Overview of LiteratureFor surgical treatment of thoracic and thoracolumbar tuberculosis, the anterior approach has been the most popular because it allows direct access to the infected tissue, thereby providing good decompression. However, anterior fixation is not strong, and graft failure and loss of correction are frequent complications. The transpedicular approach allows circumferential decompression of neural elements along with three-column fixation attained via pedicle screws by the same approach.MethodsA total of 47 patients were diagnosed with tuberculosis of the thoracic or thoracolumbar region from August 2012 to August 2013. Of these, 28 patients had progressive neurological deterioration or increasing back pain despite conservative measures and underwent transpedicular decompression and pedicle screw fixation with posterior fusion. Antituberculosis therapy was given till signs of radiological healing were evident (9–16 months). Functional outcome (visual analog scale [VAS] score for back pain), neurological recovery (Frankel grading), and radiological improvement were evaluated preoperatively, immediate postoperatively, and at 3 months, 6 months, and 1 year.ResultsMean VAS score for back pain improved from 8.7 preoperatively to 1.1 at 1 year follow-up. Frankel grading preoperatively was grade B in 7, grade C in 11, and Grade D in 10 patients, which improved to grade D in 6 and grade E in 22 patients at the last follow-up. Radiological healing was evident in the form of reappearance of trabeculae formation, resolution of pus, fatty marrow replacement, and bony fusion in all patients. Mean correction of segmental kyphosis postoperatively was 10.5°. Mean loss of correction at final follow-up was 4.1°.ConclusionsTranspedicular decompression with instrumented fusion is a safe and effective approach for management of patients with thoracic and thoracolumbar tuberculosis.

Evaluation of Outcome of Posterior Decompression and Instrumented Fusion in Lumbar and Lumbosacral Tuberculosis.

BackgroundFor surgical treatment of lumbar and lumbosacral tuberculosis, the anterior approach has been the most popular approach because it allows direct access to the infected tissue, thereby providing good decompression. However, anterior fixation is not strong, and graft failure and loss of correction are frequent complications. The posterior approach allows circumferential decompression of neural elements along with three-column fixation attained via pedicle screws by the same approach. The purpose of this study was to evaluate the outcome (functional, neurological, and radiological) in patients with lumbar and lumbosacral tuberculosis operated through the posterior approach.MethodsTwenty-eight patients were diagnosed with tuberculosis of the lumbar and lumbosacral region from August 2012 to August 2013. Of these, 13 patients had progressive neurological deterioration or increasing back pain despite conservative measures and underwent posterior decompression and pedicle screw fixation with posterolateral fusion. Antitubercular therapy was given till signs of radiological healing were evident (9 to 16 months). Functional outcome (visual analogue scale [VAS] score for back pain), neurological recovery (Frankel grading), and radiological improvement were evaluated preoperatively, immediately postoperatively and 3 months, 6 months, and 1 year postoperatively.ResultsThe mean VAS score for back pain improved from 7.89 (range, 9 to 7) preoperatively to 2.2 (range, 3 to 1) at 1-year follow-up. Frankel grading was grade B in 3, grade C in 7, and grade D in 3 patients preoperatively, which improved to grade D in 7 and grade E in 6 patients at the last follow-up. Radiological healing was evident in the form of reappearance of trabeculae formation, resolution of pus, fatty marrow replacement, and bony fusion in all patients. The mean correction of segmental kyphosis was 9.85° postoperatively. The mean loss of correction at final follow-up was 3.15°.ConclusionsPosterior decompression with instrumented fusion is a safe and effective approach for management of patients with lumbar and lumbosacral tuberculosis.

Fullerol nanoparticles suppress inflammatory response and adipogenesis of vertebral bone marrow stromal cells—a potential novel treatment for intervertebral disc degeneration

Background contextIntervertebral disc degeneration, leading to chronic back pain, is a major health problem in western societies. Vertebral bone marrow has been considered to play an important role in nutrition supply and metabolic exchange for discs. Vertebral bone marrow lesions, including fatty marrow replacement and inflammatory edema, noted on magnetic resonance imaging were first described in 1988. PurposeTo investigate the potential of a free radical scavenger, fullerol nanoparticles, to prevent vertebral bone marrow lesion and prevent disc degeneration by inhibiting inflammation and adipogenic differentiation of vertebral bone marrow stromal cells (vBMSCs). Study design/settingFullerol nanoparticle solutions were prepared to test their in vitro suppression effects on mouse vBMSC inflammation and adipogenic differentiation compared with non–fullerol-treated groups. MethodsWith or without fullerol treatment, vBMSCs from Swiss Webster mice were incubated with 10 ng/mL interleukin-1 β (IL-1 β). The intracellular reactive oxygen species (ROS) were measured with fluorescence staining and flow cytometry. In addition, vBMSCs were cultured with adipogenic medium (AM) with or without fullerol. Gene and protein expressions were evaluated by real-time polymerase chain reaction and histologic methods. ResultsFluorescence staining and flow cytometry results showed that IL-1 β markedly increased intracellular ROS level, which could be prevented by fullerol administration. Fullerol also decreased the basal ROS level to 77%. Cellular production of matrix metalloproteinase (MMP)-1, 3, and 13 and tumor necrosis factor alpha (TNF-α) induced by IL-1 β was suppressed by fullerol treatment. Furthermore, adipogenic differentiation of the vBMSCs was retarded markedly by fullerol as revealed by less lipid droplets in the fullerol treatment group compared with the adipogenic group. The expression of adipogenic genes PPARγ and aP2 was highly elevated with AM but decreased on fullerol administration. ConclusionsThese results suggest that fullerol prevents the catabolic activity of vBMSCs under inflammatory stimulus by decreasing the level of ROS, MMPs, and TNF-α. Also, fat formation in vBMSCs is prevented by fullerol nanoparticles, and, therefore, fullerol may warrant further in vivo investigation as an effective biological therapy for disc degeneration.

Downregulation of GATA-2 and overexpression of adipogenic gene-PPARγ in mesenchymal stem cells from patients with aplastic anemia

Aplastic anemia (AA) is characterized by a reduced number of hematopoietic stem cells and fatty replacement in the bone marrow. Transcriptional factor GATA-2 plays several important roles in both hematopoiesis and adipogenesis. Decreased levels of GATA-2 compromise the proliferation and survival of hematopoietic stem cells. GATA-2 suppresses adipocyte differentiation through direct inhibition of adipogenic factors, including peroxisome proliferator-activated receptor-gamma (PPARgamma). Previous studies have shown that expression of GATA-2 is decreased in marrow CD34-positive cells in AA. To elucidate the mechanisms of fatty marrow replacement, we evaluated the mRNA expression for GATA-2 and PPARgamma in mesenchymal stem cells (MSCs) from patients with AA by quantitative real-time polymerase chain reaction. GATA-2 expression by MSCs from AA patients was significantly lower than in normal subjects. Conversely, expression of PPARgamma was significantly higher in AA patients. Western blot analysis demonstrated that protein levels of GATA-2 were lower in AA patients than those in normal subjects. Moreover, incubation with interferon-gamma induced downregulation of GATA-2 levels in MSCs from normal subjects. These findings indicate that fatty marrow replacement in AA patients can be explained by downregulation of GATA-2 and overexpression of PPARgamma in MSCs. Decreased expression of GATA-2 might be responsible for the pathogenesis and development of the clinical features of the disease.

Down Regulation of GATA-2 and the Inversely-Correlated Expression of Adipogenic Specific Gene-PPARγ in Mesenchymal Stem Cells from Patients with Aplastic Anemia.

(Introduction) Aplastic anemia (AA) is characterized by a reduced number of hematopoietic stem cells resulting in peripheral pancytopenia and fatty marrow replacement. Although immune-mediated suppression of hematopoiesis is considered to play an important role in most patients with AA, the mechanism of fatty marrow replacement remains unclear. Transcription factor GATA-2 is known to play important roles in hematopoiesis. Gene Chip analysis has implicated the decreased expression of GATA-2 in AA CD34 cells, a finding confirmed by quantitative real-time PCR analysis. In a mouse stromal preadipocyte cell line, the suppression of GATA-2 expression accelerated the differentiation of stromal preadipocytes. In order to explore the impact of GATA-2 expression on adipogenesis in AA, the expression of GATA-2, the adipogenic specific gene adipsin, CCAAT/enhancer binding protein alpha (C/EBPα), and peroxisome proliferator-activated receptor γ (PPARγ) was examined in mesenchymal stem cells (MSCs) derived from bone marrow from AA patients and normal individuals.(Patients and methods) Thirty-four AA patients and 15 healthy individuals were included in this study. The median patient age was 10 years, ranging from 2 to 21 years. Twelve patients were studied before immunosuppressive therapy (IST) or bone marrow transplantation. Twenty-two patients were studied after treatment, of whom 11 responded to IST and 11 did not respond. Mononuclear cells were separated from bone marrow aspirates and 1x107 cells used for MSCs culture. MesenCult (StemCell Technologies, USA) was used to culture and expand the MSCs in vitro, after which the cells retain their ability to differentiate along various lineages upon the addition of the appropriate stimulatory supplements. Total RNA was extracted from the third passage of MSCs and synthesis of cDNA was performed using the Thermoscript RT-PCR system. Quantitative real-time PCR was conducted using Taqman primers and probes. The K562 cell line for GATA-2, the EOL1 cell line for adipsin and the MOLM-13 cell line for C/EBPα and PPARγ were used as controls.(Results) GATA-2 expression by MSCs from patients with AA at diagnosis was significantly decreased compared with normal individuals (p=0.031). However, one of the adipogenic specific genes, PPARγ, was significantly increased in MSCs in AA at diagnosis (p=0.017). The expression of adipsin and C/EBPα in MSCs did not differ significantly between AA patients and healthy volunteers. Notably, in the 22 AA patients who received IST, the expression of GATA-2 and PPARγ did not significantly decrease if the patient had responded and hematopoiesis had improved (n=11). However, after the IST the 11 non-responders still had significantly lower GATA-2 and higher PPARγ expression compared to normal individuals.(Conclusion) The mechanism of fatty replacement in the bone marrow in AA may be explained by the down regulation of GATA-2 and the inversely-correlated expression of PPARγ in MSCs. The decreased expression of GATA-2 may be responsible for the pathogenesis and development of the clinical features of this disease.

Physiologic and Radiographic Evidence of the Distal Edge of the Proton Beam in Craniospinal Irradiation

Fatty replacement of bone marrow resulting from radiation therapy can be seen on T1-weighted magnetic resonance (MR) images. We evaluated the radiographic appearance of the vertebral bodies in children treated with proton craniospinal irradiation (CSI) to illustrate the distal edge effect of proton radiotherapy. The study cohort consisted of 13 adolescents aged 12-18 years who received CSI with proton radiotherapy at Massachusetts General Hospital. Ten of these patients had reached maximal or near-maximal growth. Proton beam radiation for these 10 patients was delivered to the thecal sac and exiting nerve roots only, whereas the remaining 3 patients had a target volume that included the thecal sac, exiting nerve roots, and entire vertebral bodies. Median CSI dose was 27 [range, 23.4-36] cobalt gray equivalent (CGE) given in 1.8-CGE fractions. Magnetic resonance images of the spine were obtained after completion of radiotherapy. Magnetic resonance images of patients who received proton radiotherapy to the thecal sac only demonstrate a sharp demarcation of hyperintense T1-weighted signal in the posterior aspects of the vertebral bodies, consistent with radiation-associated fatty marrow replacement. Magnetic resonance images of the patients prescribed proton radiotherapy to the entire vertebral column had corresponding hyperintense T1-weighted signal involving the entire vertebral bodies. The sharp delineation of radiation-associated fatty marrow replacement in the vertebral bodies demonstrates the rapid decrease in energy at the edge of the proton beam. This provides evidence for a sharp fall-off in radiation dose and supports the premise that proton radiotherapy spares normal tissues unnecessary irradiation.

Epiphyseal impaction as a cause of severe osteoarticular pain of lower limbs after renal transplantation

A syndrome of severe osteoarticular pain of lower limbs occurring early after renal transplantation (TP) has been recently identified. We describe its prevalence, clinical presentation and outcome. Symptomatic patients have been studied with conventional X-rays, magnetic resonance (MR) imaging, and 99mTechnetium scintigrams of the painful areas. Among 86 patients transplanted over a two-year period, nine (4 men, 5 women; mean age of 40.4 years; range 32 to 59) developed unexplained severe spontaneous osteoarticular pain of lower limbs 19 to 105 (mean 58) days after TP. Pain affected hip(s), knee(s), and/or ankle(s). Clinical examination was usually unremarkable. Favorable outcome was the rule; mean duration of pain was 86 (range 19 to 175) days. Radiographs were abnormal (joint swelling, patchy osteoporosis and/or periosteal reactions) in 41%, MR (epiphyseal fatty marrow replacement by edema and/or hemorrhages) in 83%, and bone scans (one to several epiphyseal foci of increased uptake) in 81% of the symptomatic examined areas. Among joints re-examined 9 to 12 months after resolution of the symptoms, X-rays showed periosteal reactions in 31%, and the bone scans disclosed persistent increased uptake in 53% of the joints, whereas epiphyseal MR abnormalities had completely disappeared in 86%. There was no difference in dialysis duration, post-TP weight gain, evidence of hyperparathyroidism, and steroid and cyclosporine doses between symptomatic and an appropriately selected group of asymptomatic patients. By contrast, serum alkaline phosphatase levels were transiently higher (at the onset of symptoms) in the symptomatic group.(ABSTRACT TRUNCATED AT 250 WORDS)

Benign versus pathologic compression fractures of vertebral bodies: assessment with conventional spin-echo, chemical-shift, and STIR MR imaging.

Differentiation of benign from pathologic compression fractures of vertebral bodies was evaluated with magnetic resonance imaging in a prospective study of 53 patients. Twenty-six patients had 34 benign posttraumatic compression fractures. Twenty-seven patients had metastatic disease to the vertebral column and seven pathologic fractures. T1- and T2-weighted spin-echo (SE) sequences (1.5 T) were performed in all patients. A presaturation technique was used to obtain "fat" and "water" images to better assess the degree of normal fatty marrow replacement in fractured vertebrae. Short inversion-time inversion-recovery (STIR) images were also obtained. Discrimination between benign and pathologic compression fractures was generally possible with the SE sequences. Chronic benign fractures demonstrated isointense marrow signal intensity (SI), compared with that of normal vertebrae with all sequences. Pathologic fractures showed low SI on T1-weighted images and high SI on T2-weighted images. Fat images revealed complete replacement of normal fatty marrow, shown as absent SI in the involved vertebral body. Water and STIR images showed diffuse high SI in pathologic fractures, with STIR images having the highest contrast between abnormal and normal marrow. Acute benign compression fractures also demonstrated high SI on T2-weighted, water, and STIR images, but the SI was less pronounced and the pattern was generally more inhomogeneous than that of pathologic compressions. In general, fat images showed only partial replacement of normal fatty marrow by low SI, in contrast to the complete absence of marrow SI typical of pathologic fractures.

Paget's disease in the maxilla, mandible, and palate: A histologic analysis

Microscopic study of the maxilla, mandible, and palate in Paget's disease revealed the following features: Bone formation, resorption, degeneration, and inactivity heterogeneously distributed in close proximity to each other. Alteration of the previously existing bone pattern and its replacement by a honeycomb of newly formed bone trabeculae. Replacement of fatty marrow by vascular connective tissue in accordance with no regular pattern. Pronounced bone formation associated with connective tissue marrow and absence of formation, associated with fatty marrow. Pronounced osteoclastic activity, and degeneration in zones of bone formation. Scattered areas in which the bone presents a mosaic pattern as the result of recurrent opposition and resorption. Isolated foci of bone degeneration and increased calcification. The changes observed in the maxilla, mandible, and palate were similar to those described in the remainder of the skeletal system in Paget's disease. A comparison of the findings in Paget's disease with those observed in the mandible and maxilla in non-Paget individuals of a similar age group revealed that all of the individual histologic changes observed in Paget's disease could be duplicated in non-Paget individuals. Although Paget's disease is recognizable as a composite histologic entity, it represents an alteration in severity and pattern, but not in the basic nature of the detailed histologic changes which generally occur in the mandible and maxilla in non-Paget individuals.