Immunophenotype of pediatric-onset mastocytosis does not correlate with clinical course.

BACKGROUND: Pediatric mastocytosis differs from adult mastocytosis in its presentation and clinical course. However, the data regarding the immunophenotypic characterization of mast cells in children are limited. Our objective was to evaluate the immunophenotype of mast cells in pediatric mastocytosis and correlate it with the clinical course. METHODS: Biopsy specimens of children with cutaneous mastocytosis were retrieved from the institutions of pathology and were stained for CD25, CD2, and CD30. The percentage of mast cells and the staining intensity were correlated with the clinical data. RESULTS: Twenty-five biopsy specimens were included in the study. Patients' average age was 15.4 at presentation and 37.5 months at biopsy performance. Clinical presentations included maculopapular cutaneous mastocytosis in 79% and mastocytoma in 21% of cases. CD25, CD2, and CD30 were positive in 60%, 44%, and 84% of the biopsy specimens, respectively. The staining score was significantly higher for CD30 as compared to those for CD25 and CD2 (P = 0.02). No correlation was found between the immunophenotype and the clinical form or course of disease. CONCLUSIONS: Our results confirm that CD30 is a sensitive marker for pediatric-onset mastocytosis. Nevertheless, its expression does not correlate with clinical subtype or clinical course. The sensitivity of CD25 is higher than that of CD2 in skin lesions.

Tumour-induced osteomalacia.

Tumour-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare paraneoplastic disorder caused by tumours that secrete fibroblast growth factor 23 (FGF23). Owing to the role of FGF23 in renal phosphate handling and vitamin D synthesis, TIO is characterized by decreased renal tubular reabsorption of phosphate, by hypophosphataemia and by low levels of active vitamin D. Chronic hypophosphataemia ultimately results in osteomalacia (that is, inadequate bone mineralization). The diagnosis of TIO is usually suspected when serum phosphate levels are chronically low in the setting of bone pain, fragility fractures and muscle weakness. Locating the offending tumour can be very difficult, as the tumour is often very small and can be anywhere in the body. Surgical removal of the tumour is the only definitive treatment. When the tumour cannot be located or when complete resection is not possible, medical treatment with phosphate salts or active vitamin D is necessary. One of the most promising emerging treatments for unresectable tumours that cause TIO is the anti-FGF23 monoclonal antibody KRN23. The recent identification of a fusion of fibronectin and fibroblast growth factor receptor 1 (FGFR1) as a molecular driver in some tumours not only sheds light on the pathophysiology of TIO but also opens the door to a better understanding of the transcription, translocation, post-translational modification and secretion of FGF23, as well as suggesting approaches to targeted therapy. Further study will reveal if the FGFR1 pathway is also involved in tumours that do not harbour the translocation.

The diagnostic dilemma of tumor induced osteomalacia: a retrospective analysis of 144 cases.

Diagnostic delay of tumor induced osteomalacia (TIO) is common in clinic practice. To investigate the diagnostic condition of TIO in China and raise clinicians' awareness of TIO, we retrospectively analyzed clinical manifestations, biochemical features, and specially evaluated missed diagnoses and misdiagnoses among 144 TIO patients from Peking Union Medical College Hospital during December 1982 to December 2014. Clinical presentations of TIO mainly included bone pain, difficulty in walking, pathological fractures, muscle weakness, and height loss. TIO patients demonstrated hypophosphatemia (0.48±0.13 mmol/L), elevated serum alkaline phosphatase (277.9±152.6 U/L), reduced tubular maximum for phosphorus/glomerular filtration rate (0.39±0.14) and markedly elevated serum fibroblast growth factor 23 (FGF23) (median level 302.9 pg/mL). The average time from onset to a correct diagnosis was 2.9±2.3 years while the mean duration from onset to tumor resection was 5.4±4.2 years. The initial misdiagnosis rate was 95.1% (137/144) and 240 case-times of misdiagnoses occurred among the 144 cases. The most frequent misdiagnoses were intervertebral disc herniation, spondyloarthritis (including ankylosing spondylitis) and osteoporosis. A total of 43.1% (62/144) cases with hypophosphatemia presented on their laboratory sheets were neglected and missed diagnosed. Our study showed that TIO was frequently misdiagnosed and missed diagnosed due to its rarity, insidious onset, nonspecific clinical manifestations and clinicians' poor recognition. It is necessary to test serum phosphorus in patients with musculoskeletal symptoms and difficulty in walking. The measurement of serum FGF23 is rather valuable. Once hypophosphatemia is discovered, TIO should be suspected and it is highly recommended to search for tumors and perform curative surgery.

BMPR2 inhibition induced apoptosis and autophagy via destabilization of XIAP in human chondrosarcoma cells.

Bone morphogenetic proteins (BMPs) are multifunctional proteins, and their receptors (BMPRs) have crucial roles in the process of signaling. However, their function in cancer is somewhat inconsistent. It has been demonstrated that more prevalent expression of bone morphogenetic protein receptor 2 (BMPR2) has been detected in dedifferentiated chondrosarcomas than conventional chondrosarcomas. Here, we find that BMPR2 inhibition induces apoptosis and autophagy of chondrosarcoma. We found that BMPR2 expression was correlated with the clinicopathological features of chondrosarcomas, and could predict the treatment outcome. Knockdown of BMPR2 by small interfering RNA results in growth inhibition in chondrosarcoma cells. Silencing BMPR2 promoted G2/M cell cycle arrest, induced chondrosarcoma cell apoptosis through caspase-3-dependent pathway via repression of X-linked inhibitor of apoptosis protein (XIAP) and induced autophagy of chondrosarcoma cells via XIAP-Mdm2-p53 pathway. Inhibition of autophagy induced by BMPR2 small interfering RNA (siBMPR2) sensitized chondrosarcoma cells to siBMPR2-induced apoptotic cell death, suggesting that autophagy has a protective role for chondrosarcoma cells in context of siBMPR2-induced apoptotic cell death. In vivo tumorigenicity assay in mice indicated that inhibition of BMPR2 reduced tumor growth. Taken together, our results suggest that BMPR2 has a significant role in the tumorigenesis of chondrosarcoma, and could be an important prognostic marker for chondrosarcoma. BMPR2 inhibition could eventually provide a promising therapy for chondrosarcoma treatment.

Six-year follow-up of a characteristic osteolytic lesion in a patient with tumor-induced osteomalacia.

OBJECTIVE: Tumor-induced osteomalacia is a rare paraneoplastic syndrome characterized by hypophosphatemia and inappropriately normal or low 1,25-dihydroxyvitamin D. CLINICAL CASE: Here, we report a 6-year postoperative follow-up of a patient with oncogenic osteomalacia with a distinctive skeletal manifestation. The latter was characterized by an almost linear lytic lesion of a few millimeters with irregular borders, mainly involving the trabecular compartment but extending into cortical shell, located in the middle third of the right fibula. Six years after tumor resection, a sclerotic repair with a complete recovery was observed. Furthermore, we monitored a striking increase in bone mineral density throughout the observation period, reaching a peak of 73% over basal values at lumbar spine after 2 years; at total femur and radius, the peak was 47.5 and 4.6% respectively, after 4 years from tumor resection. CONCLUSIONS: We report for the first time that an osteolytic lesion may be part of the skeletal involvement in tumor-induced osteomalacia.

In vitro evaluation of chondrosarcoma cells and canine chondrocytes on layer-by-layer (LbL) self-assembled multilayer nanofilms.

Short-term cell-substrate interactions of two secondary chondrocyte cell lines (human chondrosarcoma cells, canine chondrocytes) with layer-by-layer self-assembled multilayer nanofilms were investigated for a better understanding of cellular-behaviour dependence on a number of nanofilm layers. Cell-substrate interactions were studied on polyelectrolyte multilayer nanofilms (PMNs) of eleven different biomaterials. Surface characterization of PMNs performed using AFM showed increasing surface roughness with increasing number of layers for most of the biomaterials. LDH-L and MTT assays were performed on chondrosarcoma cells and canine chondrocytes, respectively. A major observation was that 10-bilayer nanofilms exhibited lesser cytotoxicity towards human chondrosarcoma cells than their 5-bilayer counterparts. In the case of canine chondrocytes, BSA enhanced cell metabolic activity with increasing number of layers, underscoring the importance of the multilayer nanofilm architecture on cellular behaviour.

Anesthesia for oncogenic osteomalacia--a rare paraneoplastic syndrome.

Two patients with a diagnosis of oncogenic osteomalacia are described. This rare disease, characterized by secretion of fibroblast growth factor-23 by the tumor cells, causes myopathy, extreme debilitation and severe osteopathy because of severe hypophosphatemia. Both patients presented with severe bone pain, pathological fractures and proximal muscle weakness. Multiple diagnostic tools had to be utilized to settle the diagnosis of this rare disease. Although supplemental therapy for hypophosphatemia is usually started preoperatively, surgical excision of the causative tumor is the only definite treatment. Surgery is almost always curative; however, there is a lack of discourse in the literature regarding the anesthetic implications for the disease. The complete pathophysiology of the disease, clinical picture, its diagnostic intricacies as well as the salient points in its anesthetic management are discussed in this report.

Coexistence of tumor-induced osteomalacia and primary hyperparathyroidism.

OBJECTIVE: To present an unusual case of coexisting tumor-induced osteomalacia (TIO) and primary hyperparathyroidism (PHPT). METHODS: We report the clinical features, imaging studies, and the results of laboratory investigations before and after surgical resection of both a soft-tissue tumor and a parathyroid adenoma. RESULTS: A 44-year-old woman was referred to the endocrinology department with a diagnosis of PHPT accompanied by unusually severe hypophosphatemia, despite having received treatment with cinacalcet. Debilitating muscle weakness and bone pain, severe phosphaturia and hypophosphatemia, inappropriately normal calcitriol, and elevated fibroblast growth factor-23 and intact parathyroid hormone levels raised the suspicion of coexisting TIO and PHPT. Imaging studies were negative, but histologic characteristics of a palpable subcutaneous mass from the patient's thigh revealed a phosphaturic mesenchymal tumor. Complete remission after surgical removal of both the soft-tissue tumor and the parathyroid adenoma confirmed the diagnosis. CONCLUSION: The coexistence of TIO and PHPT has not been described before and can cause life-threatening hypophosphatemia. Diagnosis and localization of the tumor is of paramount importance since surgery is the treatment of choice for both TIO and PHPT.

Molecular alterations of monophasic synovial sarcoma: loss of chromosome 3p does not alter RASSF1 and MLH1 transcriptional activity.

Differential diagnosis of monophasic synovial sarcoma requires the detection of specific biological markers. In this study we evaluated the presence of molecular alterations in 15 monophasic synovial sarcomas. Multiple changes affecting chromosome arms were detected by CGH-array in all microdissected cases available, and an association between gain or loss of specific regions harbouring cancer progression-associated genes and aneuploid status was found. The most frequent alteration was loss of 3p including 3p21.3-p23 region that, however, did not involve the promoter regions of the corresponding genes, RASSF1 and MLH1. Using Real-Time PCR, mRNA levels of both resulted moderately high compared to normal tissue; however, the weak to absent protein expression suggests RASSF1 and MLH1 post-transcription deregulation. Moreover, immunohistochemical analysis revealed that both mesenchymal and epithelial antigens were present in diploid tumours. These findings confirm the genetic complexity of monophasic synovial sarcoma and underline the need to integrate different analyses for a better knowledge of this tumour, essential to investigate new diagnostic and prognostic markers.

Usefulness of ultrasonic strain measurement-based shear modulus reconstruction for diagnosis and thermal treatment.

We previously reported an ultrasonic strain measurement-based one-dimensional (1-D) shear modulus reconstruction technique using a regularization method for differential diagnosis of malignancies on human superficial tissues (e.g., breast tissues). Here, ultrasonic strain measurement-based 2-D and 3-D shear modulus reconstruction techniques are described, and the 1-D technique is reviewed and subsequently applied to various human in vivo tissues, including deeply situated tissues (e.g., liver). Because soft tissues are deformed in 3-D space by externally situated arbitrary mechanical sources, the accuracy of the low-dimensional (i.e., 1-D or 2-D) reconstructions is lower to that of 3-D reconstruction due to occurrence of erroneous reconstruction artifacts (i.e., the reconstructed modulus is different than reality). These artifacts are confirmed on simulated inhomogeneous cubic phantoms containing a spherical homogenous inclusion using numerically calculated deformation data. The superiority of quasi-real-time imaging of the shear modulus is then demonstrated by comparing it with conventional B-mode imaging and strain imaging from the standpoints of monitoring the effectiveness of minimally invasive thermal therapy as well as differential diagnosis. Because the 2-D and 3-D techniques require special ultrasonic (US) equipment, the 1-D technique using conventional US imaging equipment is used, even though erroneous artifacts will occur. Specifically, the 1-D technique is applied as a diagnostic tool for differentiating malignancies in human in vivo liver and breast tissue, and a monitoring technique for determining the effectiveness of interstitial electromagnetic wave (micro and rf) thermal therapy on human in vivo liver and calf in vitro liver. Even when using the 1-D technique, reconstructed shear moduli were confirmed to be a suitable measure for monitoring thermal treatment as well as differential diagnosis. These results are encouraging in that they will promote use of 2-D and 3-D reconstruction techniques.

[Neuroendocrine dysfunction in female patients with systemic dysplasia of the connective tissue]. / Neiroéndokrinnaia difunktsiia u zhenshchin s sistemnoi displaziei soedinitel'noi tkani.

The study covered 119 women with systemic undifferentiated dysplasia of the connective tissue (DCT) aged 14-39 years. All the examinees had vegetative disorders, 26.1% had a neuroendocrine-metabolic form of hypothalamic syndrome (HS), 51.3%--premenopausal syndrome, 65.5%--dysmenorrhea. It was found that women with DCT and HS develop symptoms of neuroendocrine disorders at earlier age than those with HS but free of DCT. Arterial hypertension was registered in 96.8% of patients with DCT and HS, 80.3% of DCT patients with premenopausal syndrome. Central hemodynamics was different in DCT patients without neuroendocrine disorders and with neuroendocrine dysfunction evidencing the role of the latter in development of arterial hypertension in DCT.

Gastrointestinal stromal tumors: their origin and cause.

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the gastrointestinal tract. Recently, we found that GISTs expressed KIT, a receptor tyrosine kinase encoded by the protooncogene c-kit. We propose that GISTs may originate from interstitial cells of Cajal (ICCs), which are considered to be pacemaker cells for the autonomous movement of the gastrointestinal tract. There are major two reasons for this proposal: one is that both GISTs and ICCs are double-positive for KIT and CD34, and the other is that multiple GISTs appear to develop from diffuse ICC hyperplasia in germline mutations of the c-kit gene. Because somatic gain-of-function mutations of the c-kit gene are observed in solitary GISTs, and because the germline gain-of-function mutations of the c-kit gene are observed in familial and multiple GISTs, the gain-of function mutations of the c-kit gene are considered to be a cause of the development of GISTs.

Gastrointestinal stromal tumors the assessment of malignant potential.

GISTS are the largest category of non-epithelial neoplasms of stomach and small bowel. Numerous immunohistochemical, ultrastructural and flow cytometry studies have been carried out for evaluation of prognostic factors which could predict malignant behaviour of these neoplasms. Tumor size of 5 cm and mitosis of 2/10 hpf were suggested as two important parameters which could predict the chances of recurrence and clinically aggressive course. The aim of this study is to examine predictive value of these two important parameters in assigning the tumors as high, intermediate and low risk groups. Using these two parameters we categorized 30 cases of GIST over a period of 6 years (1990-95) into low, intermediate and high risk groups and examined other features of these cases. Based on these two parameters alone we found that 4 cases each in low and intermediate group could be assigned to a higher risk group clinically as there were presence of adjacent organ infiltration, lymphatic emboli, serosal nodules, lymph node metastasis and transmural infiltration. Hence, other features like hemorrhage, necrosis and anaplasia should also be included in risk assessment. Metaplastic tissues like bone, cartilage and adipose tissues were seen only in high-risk categories.

Merging the old skeletal biology with the new. I. Intramembranous ossification, endochondral ossification, ectopic bone, secondary cartilage, and pathologic considerations.

Skeletogenesis and chondrogenesis result from a sequence of events involving epithelial-mesenchymal interaction, condensation, and differentiation. Types of bone and cartilage formation include: (1) intramembranous ossification, (2) endochondral ossification, (3) combined endochondral and intramembranous ossification, (4) heterotopic bone and cartilage formation, and (5) secondary cartilage formation. Pathologic conditions with bone and cartilage include: (1) benign and malignant tumors and (2) reactive osseous and cartilaginous metaplasia.