Real-World Use of Fostamatinib in Patients with Immune Thrombocytopenia and Thrombotic Risk.

Patients with immune thrombocytopenia (ITP) are at increased risk for bleeding and are paradoxically at increased risk for thrombosis. Many patients with ITP have underlying cardiovascular (CV) disease and/or other thrombotic risk factors for which considerable attention to selecting a therapeutic agent to manage ITP is needed. Fostamatinib, a spleen tyrosine kinase inhibitor, may reduce the risk of thrombosis while not interfering with hemostasis. We present a case series of 5 patients with ITP who had significant CV histories; each had at least 2 thrombotic risk factors. After unsuccessful management of ITP with other treatments, fostamatinib was initiated, was observed to be tolerable, and provided a durable platelet response without associated thromboembolic events. Fostamatinib may be the treatment of choice for patients with ITP in whom use of prothrombotic treatments should be avoided and/or continued use of antiplatelet or anticoagulant medication is needed.

Intranasal deferoxamine provides increased brain exposure and significant protection in rat ischemic stroke.

Deferoxamine (DFO) is a high-affinity iron chelator approved by the Food and Drug Administration for treating iron overload. Preclinical research suggests that systemically administered DFO prevents and treats ischemic stroke damage and intracerebral hemorrhage. However, translation into human trials has been limited, probably because of difficulties with DFO administration. A noninvasive method of intranasal administration has emerged recently as a rapid way to bypass the blood-brain barrier and target therapeutic agents to the central nervous system. We report here that intranasal administration targets DFO to the brain and reduces systemic exposure, and that intranasal DFO prevents and treats stroke damage after middle cerebral artery occlusion (MCAO) in rats. A 6-mg dose of DFO resulted in significantly higher DFO concentrations in the brain (0.9-18.5 microM) at 30 min after intranasal administration than after intravenous administration (0.1-0.5 microM, p < 0.05). Relative to blood concentration, intranasal delivery increased targeting of DFO to the cortex approximately 200-fold compared with intravenous delivery. Intranasal administration of three 6-mg doses of DFO did not result in clinically significant changes in blood pressure or heart rate. Pretreatment with intranasal DFO (three 6-mg doses) 48 h before MCAO significantly decreased infarct volume by 55% versus control (p < 0.05). In addition, post-treatment with intranasal administration of DFO (six 6-mg doses) immediately after reperfusion significantly decreased infarct volume by 55% (p < 0.05). These experiments suggest that intranasally administered DFO may be a useful treatment for stroke, and a prophylactic for patients at high risk for stroke.

Non-destructive studies of tissue-engineered phalanges by magnetic resonance microscopy and X-ray microtomography.

One of the intents of tissue engineering is to fabricate biological materials for the augmentation or replacement of impaired, damaged, or diseased human tissue. In this context, novel models of the human phalanges have been developed recently through suturing of polymer scaffolds supporting osteoblasts, chondrocytes, and tenocytes to mimic bone, cartilage, and tendon, respectively. Characterization of the model constructs has been accomplished previously through histological and biochemical means, both of which are necessarily destructive to the constructs. This report describes the application of two complementary, non-destructive, non-invasive techniques, magnetic resonance microscopy (MRM) and X-ray microtomography (XMT or quantitative computed tomography), to evaluate the spatial and temporal growth and developmental status of tissue elements within tissue-engineered constructs obtained after 10 and 38 weeks of implantation in athymic (nude) mice. These two times represent respective points at which model middle phalanges are comprised principally of organic components while being largely unmineralized and later become increasingly more mineralized. The spatial distribution of mineralized deposits within intact constructs was readily detected by XMT (qCT) and was comparable to low intensity zones observed on MRM hydration maps. Moreover, the MRM-derived hydration values for mineralized zones were inversely correlated with mineral densities measured by XMT. In addition, the MRM method successfully mapped fat deposits, collagenous tissues, and the hydration state of the soft tissue elements comprising the specimens. These results support the application of non-destructive, non-invasive, quantitative MRM and XMT for the evaluation of constituent tissue elements within complex constructs of engineered implants.

Villonodular synovitis (PVNS) of the spine.

OBJECTIVE: To describe the imaging features of spinal pigmented villonodular synovitis (PVNS). DESIGN AND PATIENTS: We retrospectively reviewed 15 cases of pathologically proven spinal PVNS. Patient demographics and clinical presentation were reviewed. Radiologic studies were evaluated by consensus of two musculoskeletal radiologists for spinal location, spinal segments affected, lesion center, detection of facet origin and intrinsic characteristics on radiography (n=11), myelography (n=7), CT (n=6) and MR imaging (n=6). RESULTS: Women (64%) were more commonly affected than men (36%) with an average age of 28 years. Clinical symptoms were pain (45%), neurologic (9%) or both (36%). Lesions most frequently affected the cervical spine (53%) followed by the thoracic (27%) and lumbar regions (20%). The majority of lesions (93%) were centered in the posterior elements with frequent involvement of the pedicle (67%), neural foramina (73%), lamina (67%) and facets (93%). No lesions showed calcification. Determination of a facet origin by imaging was dependent on imaging modality and lesion size. A facet origin could be determined in 45% of cases by radiography vs 67% of patients by CT (n=6) and MR (n=6). Large lesions (greater than 3 cm in at least one dimension) obscured the facet origin in all cases with CT and/or MR imaging (44%,n=4). Small lesions (less than 3 cm in any dimension) demonstrated an obvious facet origin in all cases by CT and/or MR imaging (56%,n=5). Low-to-intermediate signal intensity was seen in all cases on T2-weighted MR images resulting from hemosiderin deposition with "blooming effect" in one case with gradient echo MR images. CONCLUSIONS: PVNS of the spine is rare. Large lesions obscure the facet origin and simulate an aggressive intraosseous neoplasm. Patient age, a solitary noncystic lesion centered in the posterior elements, lack of mineralization and low-to-intermediate signal intensity on all MR pulse sequences may suggest the diagnosis in these cases. Small lesions demonstrate a facet origin on CT or MR imaging. This limits differential considerations to synovial-based lesions and additional features of a solitary focus, lack of underlying disease or systemic arthropathy, no calcification as well as low-to-intermediate signal intensity on all MR images should allow spinal PVNS to be suggested as the likely diagnosis.

Functional opioid pathways are necessary for hypocretin-1 (orexin-A)-induced feeding.

We investigated the interaction of the orexigenic neuropeptide, hypocretin-1 (Hcrt-1, also known as orexin-A), with endogenous opioids (also orexigenic neuropeptides). Rats were injected with naltrexone (NTX, nonspecific opioid antagonist) i.p., i.c.v., in the lateral hypothalamus (LH), and in the accumbens shell (AcbSh), and naloxone methiodide (nonspecific opioid antagonist unable to cross the blood brain barrier) was injected i.p. Rats were then injected with Hcrt-1 in the LH. Food intake was measured for up to 4h thereafter. Rats were also pretreated with NTX in the LH, with Hcrt-1 injected in the AcbSh. NTX suppressed Hcrt-1-induced feeding only when injected i.p., i.c.v., and in the AcbSh. These studies reveal the necessity for functional central opioidergic pathways involving the AcbSh, but not the LH in Hcrt-1-induced feeding.

Most osteomalacia-associated mesenchymal tumors are a single histopathologic entity: an analysis of 32 cases and a comprehensive review of the literature.

Oncogenic osteomalacia (OO) is a rare paraneoplastic syndrome of osteomalacia due to phosphate wasting. The phosphaturic mesenchymal tumor (mixed connective tissue variant) (PMTMCT) is an extremely rare, distinctive tumor that is frequently associated with OO. Despite its association with OO, many PMTMCTs go unrecognized because they are erroneously diagnosed as other mesenchymal tumors. Expression of fibroblast growth factor-23 (FGF-23), a recently described protein putatively implicated in renal tubular phosphate loss, has been shown in a small number of mesenchymal tumors with known OO. The clinicopathological features of 32 mesenchymal tumors either with known OO (29) or with features suggestive of PMTMCT (3) were studied. Immunohistochemistry for cytokeratin, S-100, actin, desmin, CD34, and FGF-23 was performed. The patients (13 male, 19 female) ranged from 9 to 80 years in age (median 53 years). A long history of OO was common. The cases had been originally diagnosed as PMTMCT (15), hemangiopericytoma (HPC) (3), osteosarcoma (3), giant cell tumor (2), and other (9). The tumors occurred in a variety of soft tissue (21) and bone sites (11) and ranged from 1.7 to 14 cm. Twenty-four cases were classic PMTMCT with low cellularity, myxoid change, bland spindled cells, distinctive "grungy" calcified matrix, fat, HPC-like vessels, microcysts, hemorrhage, osteoclasts, and an incomplete rim of membranous ossification. Four of these benign-appearing PMTMCTs contained osteoid-like matrix. Three other PMTMCTs were hypercellular and cytologically atypical and were considered malignant. The 3 cases without known OO were histologically identical to the typical PMTMCT. Four cases did not resemble PMTMCT: 2 sinonasal HPC, 1 conventional HPC, and 1 sclerosing osteosarcoma. Three cases expressed actin; all other markers were negative. Expression of FGF-23 was seen in 17 of 21 cases by immunohistochemistry and in 2 of 2 cases by RT-PCR. Follow-up (25 cases, 6-348 months) indicated the following: 21 alive with no evidence of disease and with normal serum chemistry, 4 alive with disease (1 malignant PMTMCT with lung metastases). We conclude that most cases of mesenchymal tumor-associated OO, both in the present series and in the reported literature, are due to PMTMCT. Improved recognition of their histologic spectrum, including the presence of bone or osteoid-like matrix in otherwise typical cases and the existence of malignant forms, should allow distinction from other mesenchymal tumors. Recognition of PMTMCT is critical, as complete resection cures intractable OO. Immunohistochemistry and RT-PCR for FGF-23 confirm the role of this protein in PMTMCT-associated OO.

Tenosynovial (extraarticular) chondromatosis: an analysis of 37 cases of an underrecognized clinicopathologic entity with a strong predilection for the hands and feet and a high local recurrence rate.

Tenosynovial chondromatosis is a multinodular cartilaginous proliferation that arises from the tenosynovial membranes. This report describes the clinical, radiologic, and histopathologic findings in 37 cases of this uncommon entity. There were 17 males and 20 females, ranging in age from 20 to 86 years (mean and median age, 46 years). The process involved tenosynovium of the fingers (n = 19), feet (n = 8), wrists (n = 4), ankles (n = 2), hand, not otherwise specified, or palm (n = 2), knee (n = 1), and forearm (n = 1). Signs of disease or symptoms were present for 5 weeks to 18 years (median duration, approximately 2 years) before surgical excision. The two most common complaints were a painless mass and a mass that was mildly tender with pressure. None of the tumors had clinical, radiologic, or histopathologic evidence of articular or bone involvement. Histologically, all tumors consisted of a multinodular cartilaginous proliferation involving tenosynovium and/or subsynovial connective tissue. Mild or moderate atypia, as encountered in chondroma of soft parts and synovial chondromatosis, was a frequent finding. Follow-up information was available for 16 patients (43%). Only two patients with follow-up information remained disease free after their initial surgical procedure. Seven patients had one recurrence and seven patients had two or more recurrences. Tenosynovial chondromatosis appears to be an extraarticular counterpart of synovial (intraarticular) chondromatosis. Our review indicates this process is often confused with chondroma of soft parts, in part, because both entities have a predilection for the hands and feet. Diagnosis of this underrecognized entity is of clinical importance because of the high local recurrence rate.

Synovial-type giant cell tumors of the vertebral column: a clinicopathologic study of 15 cases, with a review of the literature and discussion of the differential diagnosis.

Synovial and tenosynovial giant cell tumors only rarely arise in close proximity to the axial skeleton; to date, fewer than 30 examples have been reported in the English-language medical literature. In this report we describe the clinical, radiologic, histopathologic, and immunohistochemical findings in 15 cases retrieved from our files. The study group comprised 7 males and 8 females, ranging in age from 17 to 44 years (mean age, 32 years). The tumors involved the cervical (n = 11), thoracic (n = 1), lumbar (n = 2), and sacrococcygeal (n = 1) regions and ranged in size from 1.0 to 6.0 cm in greatest dimension (median size, 3 cm). Symptoms were present for 2 months to at least 2 years, with the most common complaint being pain localized to the spinal region (n = 12). Ten patients also had radicular symptoms. Radiologic studies, available for 11 cases, usually demonstrated a mass involving the posterior aspect of adjoining vertebrae. Bony abnormalities (including scalloping, erosion, and destruction), facet joint and soft tissue involvement, and extradural extension were typically present. Histologically, all tumors contained a proliferation of epithelioid (histiocytoid) cells, admixed with varying numbers of osteoclast-like giant cells, siderophages, xanthoma cells, lymphocytes, and some spindled fibroblast-like cells. Only 1 tumor had the classic villiform architecture of pigmented villonodular synovitis. The remaining 14 tumors had a nodular appearance with varying amounts of collagen. Seven of these had definite histological evidence of infiltrative growth, and 6 had some features that warranted concern for possible infiltration. Only 1 tumor had findings fully compatible with a localized synovial-type giant cell tumor/nodular (teno)synovitis. All tumors had mitotic activity, with mitotic counts ranging from 1 to 21 mitotic figures per 50 high-power fields (HPFs) (mean mitotic count, 5 mitotic figures/50 HPFs). Immunohistochemistry was performed on 5 tumors, and immunoreactivity was present for CD68, CD163, and vimentin. Limited immunoreactivity for muscle actin (HUC1-1) was also noted. Follow-up information was available for 9 of the 15 patients (60%). Five patients had no evidence of recurrent or persistent disease 4 months to 9 years after undergoing either a local excision with gross total tumor removal (with or without irradiation) or a wide en bloc resection. Four patients had persistent disease after undergoing either an incomplete resection or biopsy with spinal fusion procedure. All 4 of these patients had additional surgical intervention (accompanied by irradiation in 2 instances), but only one was known to be disease-free at last follow-up (10 years after gross total tumor removal). No patient has experienced a metastasis or died of disease. The best predictor of outcome was gross total tumor removal at the surgical outset.