Multiple Lytic Lesions Research Articles

Unusual spinal tuberculosis in an Avar Age skeleton (Csongrád-Felgyő, Ürmös-tanya, Hungary): A morphological and biomolecular study

The paleopathological analysis of a well-preserved young adult female skeleton from the AD 7-8th century (Avar Age) in Hungary revealed multiple lytic lesions in all of the thoracic and lumbar vertebral bodies. The lesions were characterized by smooth marginal zones and space-occupying mass appearance. The considerable loss of spongy bone in the thoracolumbar vertebrae resulted in angular deformity and fusion, characteristic of the healing stage of TB. Osteolytic lesions were also observed on the vertebral processes, ribs and sternum. On the endocranial surface, abnormal blood vessel impressions were revealed, indicating some kind of meningitis. The X-ray and CT analysis of the affected bones detected abnormal structures and cystic zones of destruction. The lesions were however not always bordered by areas of increased density, which is typical in cystic TB. Vertebral remains were also subjected to biomolecular analysis in two different laboratories, which attested the presence of Mycobacterium tuberculosis complex (MTBC) DNA and supported the paleopathological diagnosis of TB. Spoligotyping analysis confirmed the presence of MTBC DNA and more specifically an infection caused by bacteria belonging to the M. tuberculosis lineage. This case study provides new data for the paleoepidemiology of TB in this geographical area and historical period, and draws attention to the great variability of TB lesions in the human skeleton.

Atypical Presentation of Childhood Leukemia.

To, The Editor, Leukemia is the most common childhood cancer worldwide [1]. Acute lymphoblastic leukemia (ALL) usually manifests with pallor, hepatosplenomegaly, lymphadenopathy, fever, bone pain, and bleeding [2]. Presence of frank osteolytic lesions with hypercalcemia is infrequent [3].We describes here a case of paediatric ALL who presented with multiple lytic lesions, hypercalcemia and absence of blasts in the peripheral blood film. A 10-year-old boy presents with generalised weakness, pain in right hypochondriac region which was non radiating, aggravated by coughing, associated with vomiting which was non bilious and non projectile for last 15 days. On examination, mild pallor was present with no icterus and lymphadenopathy. Liver was palpable 2 cm below the right costal margin. On investigations, complete hemogram showed Hb of 9.2g/ dl, WBC count of 8.0×109 /L with neutrophils 54%, lymphocyte 36%, monocyte 7%, eosinophil 2%, myelocyte 1% and platelet count 271 ×109 /L. Peripheral blood film showed mild anisocytosis with microcytes and hypochromia. His serum biochemistry studies were as follows: sodium: 134.8 mmol/L, potassium: 4.2 mmol/L, Crealinium: 0.93mg/dl, Calcium: 14.2 mg/dl, Phosphorous 6.4 mg/dl, uric acid: 7.6 mg/dl, LDH: 654 IU/L, Alkaline phosphatase: 110U/L, Albumin: 3.6g/dl. His ESR was 100 mm/h. Serum vitamin D3 level was 16.3 (15-30ng/ml). His serum parathyroid hormone (PTH) level was 7.2 (13.7-77.2 pg/ml). His abdominal ultrasound was normal except for hepatomegaly. The skeletal survey showed multiple lytic lesions in skull [Table/Fig-1] and ill defined translucent areas in pelvic bone. In view of anemia and multiple lytic lesions, bone marrow examination was done. Bone marrow examination revealed hypercellular marrow with 55% blasts which were positive for CD 10, CD 19, CD 22 and negative for myeloperoxidase confirming to diagnosis of precursor B acute lymphoblastic leukemia. Cytogenetic analysis of bone marrow showed 46XY karyotype. Molecular analysis for t (9; 22), t (12; 21), t (1; 19), and t (4; 11) using PCR method were negative. Patient was started on aggressive hydration, bisphosphonate and frusemide with monitoring of tumour lysis markers. For ALL, he was started with chemotherapy as per BFM 2002 protocol. His serum calcium levels decreased to 11.0 mg/dl after 48 hrs. Currently he is undergoing chemotherapy and his Day +15 marrow was hypocellular with 3% blasts (M1 marrow). Hypercalcemia is a rare finding in paediatric ALL ranging in frequency from 0.6- 4.8% [4]. Hypercalcemia of malignancy can occur due to two mechanisms. First is localized bone destruction by invasive cancer cells and second mechanism involves osteoclastic bone resorption after the release of humoral derived factors from tumour cells. Although hypercalcemia is assumed to be linked with high tumour bulk, a series of 22 patients showed no difference in event free survival in children with hypercalcemia at presentation. It has been reported that t (17;19), which is associated with poor prognosis, is frequently seen in patients with hypercalcemia due to humoral factors [5]. In our patient, hypercalcemia was due to direct bone invasion and cytogenetics was normal. The presence of multiple lytic lesions and hypercalcemia with no blasts in the peripheral blood are uncommon findings in ALL, which has prompted us to report this case. [Table/Fig-1]: X-ray Skull showing multiple lytic lesions

Abstract PR14: In vivo targeting of stromal-derived factor-1 as a strategy to prevent myeloma cell dissemination to distant bone marrow niches

Abstract Background. Multiple myeloma (MM) patients present with multiple lytic lesions at diagnosis, indicating the presence of continuous dissemination of MM cells from the primary site of tumor development to multiple distant bone marrow (BM) niches. We hypothesized that stromal-derived factor-1 (SDF1) may represent a target for preventing transition from MGUS (micrometastatic-stage) to active-MM (macrometastatic-stage). We therefore evaluated SDF1 expression in the BM of patients with MGUS, MM, compared to healthy individuals; and tested NOX-A12, a high affinity L-oligonucleotide binder to SDF1, looking at its ability to modulate MM cell tumor growth and homing to the BM in vivo and in vitro. Methods. SDF1 levels were evaluated by immunohistochemistry on BM specimens of patients with MGUS, active-MM, or healthy individuals; and confirmed by ELISA, using conditioned-medium of BM-mesenchymal stromal cells (BM-MSCs) from MGUS, active-MM and healthy individuals. BM metastatic lesions from primary epithelial tumors were also evaluated. Co-localization of SDF1 with MM cell (MM.1S-GFP+)-enriched BM niches was evaluated using in vivo confocal microscopy. Effect of NOX-A12 on modulating MM cell dissemination was tested in vivo, by using in vivo MM metastasis model. In vivo homing and in vivo tumor growth of MM cells (MM.1S-GFP+/luc+) was assessed by using in vivo confocal microscopy and bioluminescence, in mice treated with 1) vehicle; 2) NOX-A12; 3) bortezomib; 4) NOX-A12+bortezomib. Effects of drug combination on dissemination of MM cells to distant BM niches was evaluated ex vivo by immunofluorescence on explanted femurs. DNA synthesis and adhesion of MM cells in the context of NOX-A12 treated primary MM BM-MSCs in presence or absence of bortezomib were tested by thymidine uptake and adhesion in vitro assay, respectively. Synergism was calculated by using CalcuSyn software. Results. Patients with active-MM present with higher BM SDF1 expression vs MGUS patients and healthy individuals. Similarly, BM presenting with metastasis from epithelial primary tumors had higher SDF1 levels compared to healthy subjects, thus suggesting the importance of SDF1 in favoring tumor cell metastasis to BM niches. SDF1 co-localized at BM level with MM tumor cells in vivo. In vitro, NOX-A12 induced a dose-dependent de-adhesion of MM cells from the BMSCs supported by inhibition of BM-MSC-mediated phosphorylation of ERK1/2 and cofilin. Importantly, NOX-A12 induced MM cell mobilization from the BM to the peripheral blood (PB) as shown ex vivo by reduction of MM cells in the BM and increased number of MM cells within the PB compared to control mice (P<.05). This was supported by inhibited homing and dissemination of MM cells to the BM of those mice pre-treated with NOX-A12. NOX-A12 enhanced MM cell sensitivity to bortezomib, in vivo: tumor burden was similar between NOX-A12- and control mice whereas bortezomib-treated mice showed significant reduction in tumor growth vs. control (P<.05); importantly, significant reduction of tumor burden in those mice treated with sequential administration of NOX-A12 and bortezomib was observed, compared to bortezomib-treated mice (P <.05). Similarly, NOX-A12+bortezomib combination induced significant inhibition of MM cell homing, as shown by in vivo confocal microscopy. In vitro studies confirmed synergism between NOX-A12 and bortezomib in modulating MM cell survival and adhesion to BM-MSCs. Conclusion. SDF-1 represents a valid target for inhibiting MM cell dissemination to distant BM niches, thus providing the evidence for using the SDF1 inhibiting spiegelmer NOX-A12 to target MM cells at the stage of micrometastasis (MGUS), thus preventing development of macrometastatic MM. This abstract is also presented as Poster B80. Citation Format: Aldo M. Roccaro, Antonio Sacco, Michele Moschetta, Patricia Maiso, Yuji Mishima, Yosra Aljawai, Fabio Facchetti, Anna Kruschinski, Giuseppe Rossi, Irene M. Ghobrial. In vivo targeting of stromal-derived factor-1 as a strategy to prevent myeloma cell dissemination to distant bone marrow niches. [abstract]. In: Abstracts: AACR Special Conference on Cellular Heterogeneity in the Tumor Microenvironment; 2014 Feb 26-Mar 1; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2015;75(1 Suppl):Abstract nr PR14. doi:10.1158/1538-7445.CHTME14-PR14

POEMS syndrome with pulmonary nocardiosis: A unique presentation.

POEMS syndrome with pulmonary nocardiosis: A unique presentation.

Bone multicentric epithelioid hemangioendothelioma of the lower and upper extremities with pulmonary metastases: A case report

The present study reports a rare case of bone multicentric epithelioid hemangioendothelioma (EH) involving the upper and lower extremities simultaneously, with visceral involvement of the lung. Osteolytic lesions were first identified in the right distal femur and proximal tibia. Slight increased radionuclide uptake was observed in the right shoulder joint on bone scintigraphy, however, this was ignored, as no clinical symptoms were present. The patient was initially misdiagnosed with multifocal chondroblastoma, and an extra-articular curettage of lesions was performed in the proximal tibia and medial femoral condyle, which was filled with bone cement. The histopathological diagnosis was corrected post-operatively following immunohistochemical analysis, which indicated EH, and subsequently, an amputation of the right leg at thigh level was performed. In addition, multiple lytic lesions in the right shoulder joint and pulmonary metastases were identified on whole-body radiological examination. Radiotherapy was administered to the right shoulder joint, however, the patient refused chemotherapy or further surgery. At 15 months after the initial surgery, the patient currently remains alive. This case indicates that an improved understanding with regard to the clinical features of this disease may prevent misdiagnosis and improve EH treatment.

Cystic angiomatosis: a rare cause of osteolytic lesions and pathological fracture - a case report

Cystic angiomatosis is an uncommon benign multifocal disorder in which there is proliferation of endothelial lined vessels in bone. Angiomatous malformation results in progressive loss of bone. Bony cystic lesion affects the axial and proximal appendicular skeleton. Patients usually presents with pain. We report a case of 58 year old man who presented with pain and pathological fracture. X-Ray imagery showed multicystic lesions involving the whole length of multiple ribs. Rib biopsy showed the proliferating capillary network growing in to the bone marrow spaces associated with destruction of bone. Cystic angiomatosis should be kept as one of the rare differential diagnosis in a case presenting with multiple lytic lesions of bone.

Une fracture pathologique de la hanche chez un adulte révélant une ostéomalacie hypophosphorémique oncogénique secondaire à une dysplasie fibreuse des os.

Oncogenic hypophosphatemic osteomalacia is a rare acquired condition (about 160 reported cases). The initial abnormality is the unregulated secretion of FGF-23 by small growth mesenchymal tumors. Fibrous dysplasia is a well-known cause of oncogenic osteomalacia, with the polyostotic form complicated in 50% of cases with severe hypophosphatemia. We report here the case of a 43 years-old man, admitted for diffuses bone pain and muscular proximal weakness, evolving for 2 years, complicated with a pathological femoral neck fracture. Lab studies found severe hypophosphatemia and an elevation of alkaline phosphatases with normal levels of serum calcium, 25OH-vit D3 and PTH. X-Rays revealed a diffuse bone demineralization with multiple vertebral fractures and a fracture of the femoral neck associated with multiple lytic lesions of the femoral diaphysis. Histological examination has concluded fibrous dysplasia. Main etiologies, such as iatrogenic causes and Fanconi syndrome, have not been considered. Treatment with phosphorus associated with 1,25OH-Vit D3 has been installed, associated with intravenous infusions of bisphosphonates.

CD166 Identifies Multiple Myeloma Cells That Preferentially Home to the Bone Marrow Microenvironment and Promote Disease Progression and Bone Lytic Disease

Multiple myeloma (MM) is an incurable malignancy characterized by the proliferation of neoplastic plasma cells in the bone marrow (BM) and by multiple lytic lesions throughout the skeleton. We previously reported that CD166 is a functional molecule on normal hematopoietic stem cells that plays a critical role in HSC homing to the BM and engraftment (Blood. 2014; 124(4):519-29.), suggesting that CD166 is involved in trafficking and lodgment of HSC. CD166, which is a member of the immunoglobulin superfamily capable of mediating both homophilic and heterophilic (CD6) interactions, has been shown to enhance metastasis and invasion in several tumors including breast cancer and melanoma. However, whether CD166 is involved in MM and whether it plays a role in MM progression or the bone lytic disease has not been addressed. H929-GFP MM cells were injected intravenously into NSG mice and GFP cells were recovered from the BM 14hr later. While only 29.9%±1.4% of total H929-GFP cells were CD166+, the frequency of CD166+ cells contained in BM-homed H929-GFP cells was significantly higher (80.0%±2.5%, n=9, p<0.01). Knocking-down (KD) CD166 expression on H929-GFP cells with shRNA reduced the homing of MM cells to the BM. The number of BM-homed GFP cells was significantly decreased for CD166KD cells (5658±904, n=6) compared to mock cells (8551±848, n=6; p<0.05). To examine the potential role of CD166 in osteolytic lesions, we used a novel Ex Vivo Organ Culture Assay (EVOCA) in which MM cells are co-cultured over calvariae from 10d-old pups for 7 days creating an in vitro 3D system for the interaction of MM cells with the bone microenvironment. EVOCA data from two MM cells lines, H929 and OPM2 as well as from three primary MM patients’ CD138+ BM cells demonstrated that bone osteolytic lesions were significantly reduced when CD166 was absent on either MM cells (sorted CD166- fraction) or osteoblast lineage cells (calvariae from CD166-/- mice). Osteolytic lesions can be caused by decreased osteoblastogenesis or increased osteoclastogenesis. Co-culturing BM stromal cells (BMSC) from WT or CD166-/- mice with mock or CD166KD H929 cells in osteoblastogenic media revealed that loss of CD166 on either MM cells or BMSC released the inhibition of mRNA expression of RUNX2, a critical transcriptional factor for early osteoblast differentiation, suggesting that interactions through CD166 suppresses osteoblastogenesis. Gene analysis of calvariae co-cultured with mock or CD166KD H929 cells revealed that the ratios of mRNA levels of RANKL to that of OPG, an important inhibitor of osteoclastogenesis, were elevated in cultures containing a CD166+ component suggesting that CD166 enhances osteoclastogenesis. Furthermore, co-cultures of BM monocytes (BMM) from WT or CD166-/- mice with mock or CD166KD H929 cells in the presence of RANKL and MCSF confirmed that the absence of CD166 on either BMM or MM cells results in significantly reduced osteoclast differentiation as evidenced by TRAP staining. Given that Akt signaling is regulated by CD166 and that Akt pathway is important in osteoclast differentiation, we examined whether or not the Akt pathway is involved in CD166-induced osteoclastogenesis in MM. Western blot analysis of BMM from WT or CD166-/- mice starved then stimulated with either mock or CD166 KD H929 cells revealed that phospho-Akt was significantly down-regulated in the absence of CD166 on either BMM or MM cells indicating that CD166 can activate the Akt pathway and promote MM-induced osteoclast differentiation. Finally, we compared in NSG mice the progression of MM initiated with control, mock or CD166KD H929-GFP cells (n=7-13/group, 2 independent experiments). Compared to control and mock groups, NSG mice transplanted with CD166KD cells showed delayed disease progression and prolonged survival as evidenced by serum levels of human IgA (kappa) and Kaplan-Meier survival curves (p<0.05), respectively. Meanwhile, the inhibition of osteocalcin mRNA expression in calvariae of NSG mice was significantly reduced in the presence of CD166KD cells compared to that with control or mock cells, suggesting again that expression of CD166 on MM cells inhibits osteoblastogenesis. These results suggest that CD166 directs MM cell homing and retention in the BM and promotes MM disease progression and propose that CD166 may induce osteoclastogenesis in MM through the Akt pathway. CD166 may serve as a therapeutic target in the treatment of MM. DisclosuresNo relevant conflicts of interest to declare.

Bortezomib Induced Pulmonary Toxicity

Background:Bortezomib (BTZ), a proteasome inhibitor, is a promising agent against Multiple Myeloma (MM). BTZ induced lung injury (BLI), although not appreciated during the introductory time of the medication, has now been highlighted in multiple case reports. Two primary hypotheses for the cause of pulmonary toxicity are:A. BTZ withdrawal leads to reactivation of Nuclear Factor (NF)- κB causing inflammatory changes in the lungs, which explains the rapid improvement of BLI with steroid therapy reported in several cases.B. BTZ not only affects NF- κB, but also various other unclear signaling pathways. Its metabolite may accumulate in lungs causing direct toxicity. It may explain cases, which don’t improve with steroid therapy.Some anecdotes claim that genetic predisposition (especially Japanese population) and history of prior Stem Cell Transplant (SCT) might be risk factors for BLI. The objective of this study is to report a case of BLI, review current literature, and determine the predictors of mortality in BLI.Case report:A 64-year-old male with chronic low back pain presented to the emergency department with new onset severe mid back pain radiating to bilateral shoulders. CT scan, performed to rule out aortic dissection, demonstrated multiple lytic lesions throughout the bony skeleton and a compression fracture at T7 vertebral body with epidural extension of soft tissue. A bone survey confirmed CT scan findings, and subsequent bone marrow biopsy confirmed the diagnosis of MM. He received radiation therapy to the thoracic spine and completed 2 cycles of CyBorD regimen (Cyclophosphamide 300 mg/m2 by mouth, BTZ 1.5 mg/m2 sub-cutaneous, and Dexamethasone 40 mg by mouth each on day 1, 8, 15 and 22). Three days after the completion of the second cycle, he was admitted to hospital with respiratory distress. CT chest (Image 2) showed new interval appearance of bilateral perihilar groundglass opacities, peribronchial and interstitial thickening predominantly in the upper lobes not seen in prior scan (Image 1). There were no other signs or symptoms of pneumonia such as leukocytosis, fever or cough. After some benefit from oral prednisone, he was discharged with a tapering dose of the same. Unfortunately, patient was readmitted with worsening respiratory distress 4 days later. A repeat CT scan of the chest showed resolution of previously well-defined areas of perihilar ground glass opacities but development of hazy areas of ground-glass opacification throughout both lungs with more confluent abnormalities in bilateral lower lobes (Image 3). Patient was treated with high dose methyl-prednisone and noninvasive positive pressure ventilation without any improvement. Family requested do-not-resuscitate and do-not-intubate status. Patient died on 10th day of the admission.Methodology:A case report, review of current literature on BLI, and analysis of available data.Results:An extensive Pubmed search for BLI yielded 29 cases, 5 of which occurred with re-administration of BTZ after resolution of a BLI. Mean (Standard Deviation, Minimum, Maximum) age is 60.72 years (10.12, 31, 74). 69% were males, 13.8% have smoking history, 20.7% have history of lung diseases, and 34.5% have underwent SCT for MM. 62.1% patients were on steroids concurrent with or just prior to BTZ and almost 80% were treated with high dose steroids for BLI. Mean total BTZ dose 4.62 mg (2.75, 1,9), mean duration from the 1st dose to onset of BLI 21.77 days (16.72, 0.5, 60), and mean duration from the last dose to onset of BLI was 3.27 days (2.82, 0, 10). 41.4% patients died of BLI. Mann Whitney test showed no significant difference in median age, median number of BTZ doses, and median duration from the 1st dose of BTZ to the onset of BLI between diseased and survivors. But the difference in median duration (Minimum, Maximum) from the last dose of BTZ to the onset of BLI between deceased (1.00 day, 0, 5) and survivors (4.00 days, 0, 10) were found to be statistically significant (p= 0.007). No significant association could be found between the outcome of BLI and different factors like sex, history of SCT, previous lung diseases, history of smoking, concurrent/prior steroids and treatment of BLI with steroids.Conclusion:BLI is a serious condition as 41.4% of the reported cases were fatal. Early onset of respiratory distress after the last dose of BTZ can be a predictor of mortality in BLI. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Giant Cell Lesions Associated with Primary Hyperparathyroidism.

To evaluate the prevalence, clinical features, diagnostic laboratory values and treatment outcome of giant cell lesions (brown tumors) associated with primary hyperparathyroidism (PHPT) in oral and maxillofacial region. A 5year retrospective data was analyzed wherein all histopathologically proven cases of giant cell lesions involving oral and maxillofacial region were evaluated. Out of these cases, those associated with PHPT were tabulated. Correlation was established with other concomitant clinical features and also with the laboratory values of altered serum calcium, phosphate, alkaline phosphate and parathormone. Follow up of these cases after the correction of PHPT was also noted. Out of 85 cases of histopathologically proven giant cell lesions, five cases were associated with PHPT. There was involvement of maxilla and mandible in one case each. Only frontal bone was involved in two cases. Fifth case had multiple lytic lesions in maxilla and frontal bone. All patients consistently showed very high values of alkaline phosphate and parathormone. Hypercalcemia and hypophosphatemia was noted in four cases. All cases showed regression of the lytic lesion after parathyroidectomy obviating the need for surgical excision of the jaw lesions. Giant cell lesions (brown tumors) associated with PHPT in oral and maxillofacial region are rare clinical entities. The prevalence of PHPT associated giant cell lesions is 5.9%. They are clinically, radiologically and histopathologically similar to any other peripheral or central giant cell tumor. Relevant history may alert the clinician and altered biochemical values may help in correlating the oral and maxillofacial findings with the underlying systemic disease. At times, the brown tumor maybe the only presenting sign leading to the diagnosis of PHPT.

Verrucous Carcinoma of Esophagus: A Diagnostic Challenge

Introduction: Verrucous carcinoma of esophagus (VCE) is a rare variant of squamous cell carcinoma; so far less than 23 cases have been reported in literature. VCE is a well-differentiated carcinoma that is slow growing, irregular and wart like in appearance and has a tendency for local invasion. Verrucous squamous cell carcinoma has been reported in the oral cavity, larynx, urogenital and anorectal regions. We present a case of VCE to highlight that high index of suspicion and evaluation with EUS are crucial steps in making an early diagnosis and management of disease. A 64-year-old man referred to our institution for further evaluation of dysphagia and esophageal mass on EGD. He presented with dysphagia to solids and 60 lb. weight loss over a period of 10 months. There was no history of alcohol or tobacco use or ingestion of caustic substances. He had hypertension, diabetes mellitus, and end stage renal disease requiring hemodialysis. Multiple endoscopic evaluations at outside facilities revealed an esophageal mass with inconclusive pathology; squamous atypia without definitive evidence for malignancy was reported. At our institution, EGD and EUS were performed; conventional upper endoscopy revealed a 9cm long near circumferential obstructing mass with a warty/verrucous appearance. On endosonographic evaluation, diffuse thickening of the mucosa and sub-mucosa was noted with invasion through the muscularis propria, without any invasion of surrounding organs and no pathological lymph nodes were noted. Endoscopically obtained biopsy specimens using a jumbo forceps showed abnormally thick hyperplastic squamous mucosa with marked hyperkeratosis, cellular atypia, focal ulceration with heavy inflammatory cells and exhibiting verrucous growth pattern; suggestive of verrucous carcinoma. CT scan of thorax, abdomen and pelvis showed multiple hepatic lesions and lytic lesions in axial and appendicular skeleton suggestive of metastatic disease. EGD was repeated for new onset hematemesis, previously described long circumferential tumor was visualized; given the sub-optimal surgical candidature for palliation and the advanced metastatic disease, a partially covered self-expanding metallic stent was placed for palliation. Diagnosis of VCE is very elusive as is suggested by the current case as well as those described in the literature. A high index of suspicion on the basis of endoscopic features and EUS findings is helpful. Large biopsy specimens to include the sub-mucosa, such as those can be obtained by use of a jumbo forceps, are important for accurate diagnosis. The role of fine-needle aspiration (FNA) during EUS needs to be evaluated in cases with non-diagnostic pathology even with jumbo biopsy forceps.

Profound vitamin D deficiency in coeliac disease and pregnancy

A 23-year-old Turkish woman with known coeliac disease presented to hospital with a fractured left femur (Figure 1 a) sustained when arising from bed. Two years prior, she sustained a fracture at the right humerus (Figure 1 b), caused by lifting the younger of her two children. Hypercalcemia was documented at the time of the first fracture, but she defaulted from follow-up. Figure 1. (a) Plain AP radiograph of the left femur demonstrates a pathological transverse fracture with full diaphyseal width medial displacement of the distal fragment. The underlying bone is abnormal with multiple lytic lesions in a background of …

THE WIDENING SPECTRUM OF PARANEOPLASTIC DISORDERS: TWO CASES

Paraneoplastic neurological syndromes are non-metastatic disorders triggered by an altered immune response to a neoplasm. Uncommon presentations are increasingly reported, widening the recognised spectrum of these disorders. We present two patients with atypical neurological manifestations that heralded malignancy. <b>Case 1</b> A 79 year old woman presented with progressive asymmetrical (R&gt;L) leg weakness. Examination confirmed significant paraparesis (MRC 2/5 bilaterally) with normal muscle bulk and tone, normal sensation and sphincter control, hyporeflexia and downgoing plantars. MRI of the lumbosacral spine was normal. Nerve conduction studies showed an axonal and demyelinating motor neuropathy. CSF was acellular with high protein (2.5 gr/dl) and normal glucose. Body CT revealed a large retrosternal mass consistent with thymoma. Her paraneoplastic motor neuropathy was treated with intravenous immunoglobulin, which clinically stabilised her progression, and referred for surgical removal. <b>Case 2</b> A 72 year old woman presented with painless, progressive left-sided visual loss. Fundoscopy excluded arterial occlusion or vasculitis. Investigations for autoimmune or infective causes were normal. Chest X-ray, echocardiogram, lumbar puncture and a temporal artery biopsy were diagnostically non-contributory. Body CT showed multiple lytic and sclerotic bone lesions, with abnormal lymphadenopathy in the left axilla. Fine needle aspiration of a node showed adenocarcinoma consistent with metastatic oestrogen receptor positive breast cancer. The final diagnosis was non-metastatic paraneoplastic optic neuropathy.

Nasu-Hakola Disease as Suspected Cause for Bone Disease and Dementia

Progressive dementia in conjunction with multiple bone fractures in a previously healthy young man led to the investigation of the underlying cause. The differential diagnoses (most importantly hypoparathyroidism) were limited given basal ganglia calcifications on the brain computed tomographic scan. Electronic search of the key words basal ganglia calcification, osteoporosis, and dementia revealed a rare condition termed Nasu-Hakola disease or polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. This very rare and potentially fatal genetic disease is characterized by pathological fractures, multiple lytic bone lesions, and presenile dementia. We report an Iranian patient with this disease and a review of the literature.

18F-FDG PET/CT Metabolic Variability in Functioning Oncocytic Parathyroid Adenoma With Brown Tumors

A 29-year-old female patient exhibited a solitary neck mass, severe hypercalcemia, and multiple skeletal lytic lesions consistent with metastatic neoplastic disease. Fine-needle aspiration (FNA) cytology of the neck lesion indicated a follicular thyroid neoplasm. CT-guided bone biopsy was non-diagnostic. Subsequent 18F-FDG PET/CT examination demonstrated avid glucose uptake within the neck mass and diffuse bony lesions of variable metabolic activity. Repeat biopsy utilizing PET/CT guidance produced core tissue with classic histologic features of a brown tumor. Postoperative histology revealed an exclusively oncocytic parathyroid adenoma. Atypical radiotracer uptake of this rare functioning adenoma subtype is illustrated with discussion of improved procedural diagnostic yield utilizing PET/CT.

Role Of CD166 In Multiple Myeloma Cell Homing To The Bone Marrow Microenvironment and Disease Progression

Multiple myeloma (MM) is a plasma cell malignancy characterized by multiple lytic lesions throughout the skeleton, suggesting that trafficking of MM cells from the bone marrow (BM) and lodgment of these cells at secondary sites is important in disease progression. CD38+CD138- MM cells were previously characterized as putative MM stem cells (MMSC, Cancer Res. 2008; 68(1):190-7.). We analyzed CD38+CD138- cells contained within the MM cell line H929 and determined that a fraction of these cells (29.9%±1.4%) expresses CD166. CD166 is a member of the immunoglobulin superfamily capable of mediating both homophilic and heterophilic (CD6) interactions and has been shown to enhance metastasis and invasion in several tumors including breast cancer and melanoma. Studies from our laboratory suggest that CD38+CD138-CD166+ MM cells possess many functional properties commonly associated with MMSC including cell cycle quiescence, maintenance and propagation of daughter cells on a stromal substrate and gene expression profile. We hypothesized that CD166 promotes MM cell trafficking to the BM and is critical for disease progression. To test this hypothesis, H929-GFP myeloma cells were injected intravenously into NSG mice and GFP cells were recovered from the BM 14hr later. While only 3.3%±1.5% of total H929-GFP cells express the CD38+CD138- phenotype, the frequency of CD38+CD138- cells contained in BM-homed H929-GFP cells was significantly higher (53.4%±3.7%, n=3, p<0.01), suggesting a preferential homing of MMSC to the marrow microenvironment. Interestingly, whereas only 29.9%±1.4% of CD38+CD138- cells expressed CD166 prior to injection, 84.1%±10.8% of BM-homed H929-GFP CD38+CD138- cells expressed CD166 (n=3, p<0.01), suggesting that CD166 plays a critical role in directing homing of MM cells to the BM. Next, CD166 expression on H929-GFP cells was knocked down (KD) with shRNA in order to examine if reduced CD166 expression inhibit the homing of MM cells to the BM. The number of BM-homed GFP cells was significantly decreased for CD166KD cells (5658±904, n=6) compared to mock control (8551±848, n=6; p<0.05). Interestingly, cells in which suppression of CD166 expression was not achieved with shRNA homed preferentially to the BM (4.3%±0.3% CD166+cells in CD166 KD H929-GFP before injection versus 29.3%±3.6% in BM-homed GFP cells). Then we compared the progression of MM in NSG mice initiated with mock control or CD166 KD H929-GFP cells. Disease progression in mice receiving control cells was more rapid compared to that in mice receiving CD166KD cells as evidenced by serum levels of human IgA (kappa) at 4 weeks post-transplantation (240.5±67.1ng/ml versus 45.1±33.0ng/ml, n=3; p<0.05). We next examined the potential role of CD166 in osteolytic lesions using a novel Ex Vivo Organ Culture Assay (EVOCA) in which MM cells are co-cultured over calvariae from 10d-old pups for 7 days creating an in vitro 3D system for the interaction of MM cells with bone microenvironment. Data from EVOCA with H929 cells showed that bone osteolytic lesions are substantially reduced when CD166 is absent on either MM (CD166- fraction) or osteoblast lineage cells (calvariae from CD166-/- mice). Furthermore, co-culturing CD166+ or CD166- H929 cells with bone marrow stromal cells (BMSC) from WT or CD166-/- mice revealed that mRNA levels of receptor activator of NF-κB ligand (RANKL) are decreased when CD166 is absent on either MM or stromal cells while mRNA levels of osteoprotegerin (OPG), an important inhibitor of osteoclastogenesis, are not altered. This resulted in decreased RANKL/OPG ratios in cultures containing a CD166- component suggesting reduced MM-induced osteoclastogenesis in the absence of CD166. Interestingly, levels of M-CSF and IL-6 were similar in all these cultures suggesting that loss of CD166 may mediate suppression of osteolytic lesions through the downregulation of RANKL. Together, these results suggest that CD166 plays an important role in homing and retention of MM cells in the BM and promotes MM disease progression as well as bone-lytic disease and that CD166 may serve as a therapeutic target in the treatment of MM. Disclosures:No relevant conflicts of interest to declare.

Cytogenetic Profile Of Multiple Myeloma In The Inner City: Clinical Presentation and Survival

Multiple Myeloma (MM), a plasma-cell neoplasia characterized by bone marrow (BM) infiltration, monoclonal protein production, and end organ dysfunction, is the most common hematologic neoplasm in blacks. The subclinical syndrome monoclonal gammopathy of undetermined significance (MGUS) precedes MM, and SEER data as well as more recent reports show that blacks have a 2-3-fold higher risk of developing MGUS and MM suggesting a genetic predisposition that causes the marked racial disparity in the incidence of both conditions. In addition, the recent rate of survival improvement observed in Caucasian patients has not been observed in blacks implying that the clinical course and development of resistance are varied between black and Caucasian MM patients. We have recently reported that in our inner-city, largely Caribbean-African patients MM occurs more frequently in women and at a younger age compared to literature. In this report we present cytogenetic information on 146 of these newly-diagnosed MM patients and their survival data.Patients were identified by tumor registries at UH and Kings County Hospital based on tumor histopathology. Data were collected from hospital records of patients treated between 2001-2011 (n=242).Downstate's inner-city MM patients in Brooklyn, NY are largely Caribbean-African individuals and descendants. Demographics, disease indicators, and vital statistics were collected. In 146 patients, baseline cytogenetics by chromosome banding studies were available. In 63 of these patients baseline FISH used locus-specific probes del13 (13q14), IGH translocation (14q32), del17 and t(11;14)(q13;q32). Patients were treated with standard combination therapies.146 patients had active, advanced newly-diagnosed MM. Median age=66 (range 36-91), male/female= 0.8, and evidence for the degree of tumor burden included: median % infiltration with CD138-positive cells within BM=50% (range 7%-99%), median serum M protein 3.3 g/dL (range 0.2-9.1). International Staging System level: Stage II: 28%, Stage III: 72%; median serum creatinine=2 mg/dL (range 0.38-14), median serum beta-2 microglobulin= 5.8 mg/dl (range 0.96-20.2). Further, 58% of patients with cytogenetic information had diffuse skeletal involvement with multiple lytic lesions (48%) and fractures (10%). Contrary to expectations from patients with advanced MM, chromosome banding and FISH showed abnormal cytogenetics (AC) in only 26% (n=38). At present, 50% of the patients have expired in both the normal cytogenetics (NC) and AC groups. In the AC group who expired, average time with MM was 2 years (range 0.5-5.6), whereas in the NC patients, average survival was 3.4 years (range, 0.6-5.2). Frequency of trisomies 5 and 9 indicative of hyperdiploidy, were twice as common in patients who are surviving with AC. In these latter patients as well as in surviving patients with NC, average survival time with MM is 4 years (range 0.4-15). In addition, IGH translocation was twice as common in AC patients who expired compared to the NC group. Other AC findings including hypodiploidy, del13, chr1 loss, and trisomies involving chromosomes 1, 7, 11, 19, and 21 were equally frequent in expired and living patients with AC.Using clinically available methods we found IGH translocation, trisomy 5 and trisomy 9 to be prognostically significant in this cohort of 145 inner-city, largely Carribean-African patients. Subtle presentation of cytogenetic abnormalities suggest that genome-wide analyses are needed to asses this patient populations' MM biology.Cytogenetic Abnormality (frequency)Alive (n)Expired (n)Mean Survival in Years of Expired Patients with AC (Range)del 13 (12.3%)8101.2 (0.1-3.6)IGH translocation (13.0%)7121.7 (0.1-4.1)Chr 1 gain (8.2%)571.1 (0.1-2.4)Chr 1 loss (4.8%)342.3 (0.5-4.1)Hyperdiploidy (19.9%)15141.8 (0.1-5.6)Hypodiploidy (8.9%)761.7 (0.1-4.1)Trisomy 5 (12.3%)1261.7 (0.1-5.6)Trisomy 7 (6.9%)641.2 (0.5-2.3)Trisomy 9 (15.1%)1482.1 (0.1-5.6)Trisomy 11 (12.3%)992.0 (0.1-5.6)Trisomy 15 (11.6%)1161.5 (0.1-5.6)Trisomy 19 (13.7%)1371.7 (0.1-4.1) Disclosures:No relevant conflicts of interest to declare.

Eosinophilic “candy floss”-like inclusions in myeloma cells

A 60-year-old female presented with weakness and pain in the bones that had persisted for 1 year. Radiological investigations revealed multiple lytic lesions in the skull and vertebrae. Abdominal ultrasound and computerized tomography did not reveal any lesions suggestive of solid organ malignancy. Serum protein electrophoresis revealed an ‘‘M’’ band in the gamma region. Tests of renal function and liver function were within normal limits. Complete blood counts showed anemia, with hemoglobin of 83 g/L. Bone marrow aspirate smears were hypercellular for age, with immature-looking plasma cells accounting for 55 % of all nucleated cells (top left). Myeloma cells were large, frequently bi- or multi-nucleate, and open chromatin with presence of nucleoli. Notably, many cells showed intracytoplasmic single large-round eosinophilic-amorphous inclusions, resembling cotton balls or ‘‘candy floss’’ (top right). In addition, many ‘‘flame cells’’ were also seen, with occasional flame cells exhibiting round inclusions (bottom left). The great majority of myeloma cells were immature with frequent presence of very large bizarre cells (bottom

3:46 PM Abstract No. 47 - Imaging of the thoracic duct using C-arm CT lymphangiography (CTL) following ultrasound guided inguinal nodal injection in children with right to left shunts

Purpose To study the feasibility of C-arm CTL following ultrasound guided inguinal lymph node injection of water soluble contrast media in children with right to left shunts. Materials and Methods Patient 1 : A 4 year old boy with complex congenital heart disease developed recurrent right sided chylothorax which resolved followed by left chylothorax requiring several chest tubes. A lymphangiogram was performed to look for thoracic duct leak. Patient 2 : A 13 year old girl with multiple cutaneous epidermal nevi, simple renal and splenic cysts, multiple lytic bone lesions, bilateral interstitial lung disease, multiple left lower lobe pulmonary AVM’s developed recurrent chylopericardium. This was managed with pericardial drainage and lymphangiogram was performed to look for leak. Technique : Lipiodol could not be used due to the risk of systemic embolization in the presence of right to left shunts. Under ultrasound guidance bilateral inguinal nodes were accessed using 25G needles followed by slow hand injection of Optiray 320. 2D-fluoroscopic visualization of the pelvic and lumbar lymphatics up to L2 level was possible beyond which dilution of contrast from leakage across the wall of the lymphatics precluded visualization. C-arm CT (syngo Dyna CT®, Siemens Medical Solutions USA Inc.) of the chest was performed using 8s DR-body protocol and images were reconstructed. Results Patient 1 : C-arm CTL showed a lobulated pseudoaneurysm of the thoracic duct at the level of T6 adjacent to a surgical clip with normal course and caliber of the rest of the duct to its insertion into the left subclavian vein and no leak. Patient 2 : C-arm CTL showed reflux of contrast into dilated lymphatics in the mediastinum, left hilum and left lower lobe suggestive of lymphangiectasia with uninterrupted course of the rest of the duct to the left subclavian vein. No leak into the pericardium was seen but the study was limited by artifacts from pericardial drainage catheter and nasogastric tube. Conclusion C-arm CTL can successfully demonstrate thoracic duct anatomy and pathology in combination with ultrasound guided inguinal nodal injection of water soluble contrast agent in children with contraindication for oily contrast media.

In the labyrinth of calcium metabolism

The authors present the case of a 27-year-old male patient. In 2010, he suffered from a bone fracture of the pelvis. As imaging techniques showed multiple osseal lytic lesions, diagnostic investigations were performed for multiple myeloma. Later, a mass lesion measuring 37 mm in size was removed from the left side of his mandible. Histology revealed a giant-cell tumour of the bone and oncologic therapy was considered. However, before this planned treatment a PET-CT was performed, which showed numerous distinct lesions with enhanced glucose metabolism in the skeleton as well as in soft tissue behind the right lobe of the thyroid. Hence, the patient was referred to endocrinologists. On the basis of severe hypercalcemia (serum calcium 3.66 mmol/l) and high serum parathyroid hormone level (162.5 pmol/l) the diagnosis of a right sided parathyroid tumour was established. After surgical excision of the parathyroid tumour, high levels of serum calcium and parathyroid hormone returned to normal. Histology failed to show malignancy and the patient recovered soon. This case report may shed some light on the importance of serum calcium measurements and the differential diagnostic significance of primary hyperparathyroidism.