Severe Skeletal Complications Research Articles

Bone Marrow Mastocytosis: A Diagnostic Challenge.

Bone marrow mastocytosis (BMM) represents a provisional, indolent subvariant of systemic mastocytosis (SM). Utilizing WHO criteria, BMM requires bone marrow (BM) involvement and the absence of mastocytosis skin lesions. BMM is characterized by male sex prevalence, a slight increase of serum tryptase levels, low BM mast cells (MC) burden, and an indolent clinical course. BMM shows a strong correlation with severe anaphylaxis, mainly due to an IgE-mediated allergy to bee or wasp venom and, less frequently, to unexplained (idiopathic) anaphylaxis. Furthermore, BMM is often associated with osteoporosis which could be the only presenting symptom of the disease. BMM is an undervalued disease as serum tryptase levels are not routinely measured in the presence of unexplained osteoporosis or anaphylaxis. Moreover, BMM patients are often symptom-free except for severe allergic reactions. These factors, along with typical low BM MCs infiltration, may contribute to physicians overlooking BMM diagnosis, especially in medical centers that lack appropriately sensitive diagnostic techniques. This review highlights the need for a correct diagnostic pathway to diagnose BMM in patients with suspected symptoms but lacking typical skin lesions, even in the case of normal serum tryptase levels. Early diagnosis may prevent potential life-threatening anaphylaxis or severe skeletal complications.

Bone Metastases in Neuroendocrine Neoplasms: From Pathogenesis to Clinical Management.

Bone represents a common site of metastases for several solid tumors. However, the ability of neuroendocrine neoplasms (NENs) to localize to bone has always been considered a rare and late event. Thanks to the improvement of therapeutic options, which results in longer survival, and of imaging techniques, particularly after the introduction of positron emission tomography (PET) with gallium peptides, the diagnosis of bone metastases (BMs) in NENs is increasing. The onset of BMs can be associated with severe skeletal complications that impair the patient’s quality of life. Moreover, BMs negatively affect the prognosis of NEN patients, bringing out the lack of curative treatment options for advanced NENs. The current knowledge on BMs in gastro-entero-pancreatic (GEP) and bronchopulmonary (BP) NENs is still scant and is derived from a few retrospective studies and case reports. This review aims to perform a critical analysis of the evidence regarding the role of BMs in GEP- and BP-NENs, focusing on the molecular mechanisms underlining the development of BMs, as well as clinical presentation, diagnosis, and treatment of BMs, in an attempt to provide suggestions that can be used in clinical practice.

Prognosis after Upfront Radiation Therapy in Plasma Cell Myeloma: Analysis of the National Cancer Data Base

IntroductionSystemic therapy with corticosteroids, immunomodulatory agents and/or proteasome inhibitors is the principal treatment modality for plasma cell myeloma. However, some patients with advanced bone disease may start treatment with radiation therapy (RT) to control pain from lytic lesions, fractures, or spinal cord compression. The degree of bone involvement may correlate with cytogenetic lesions, gene expression profile, and prognosis in myeloma (Zhan et al., Blood 2006; Kumar and Rajkumar, Nat Rev Clin Oncol 2018), yet the prognostic relevance of upfront RT use has not been previously studied. We hypothesized that the need for upfront RT may be associated with worse long-term outcomes, as an indicator of late-stage diagnosis or a biologically aggressive disease with bone destruction. Our objective was to examine patterns of use, factors associated with upfront RT, and survival outcomes among myeloma patients treated with upfront RT.MethodsFrom the National Cancer Data Base (NCDB), a nationwide registry containing records of >70% of incident cancers in the United States, we selected adult patients with histologically confirmed myeloma diagnosed between 2004 and 2015, who received chemotherapy within 12 months of diagnosis. We excluded patients with solitary plasmacytoma, those treated outside of the reporting facility, or those receiving palliative RT as the only therapy. We defined upfront RT as RT delivered before or within 14 days of the start of chemotherapy. We examined factors associated with upfront RT in a multivariable logistic model. We then examined the association between upfront RT and overall survival (OS) in a proportional hazard model adjusting for age, sex, race, income, insurance status, comorbidity index, year of diagnosis, type of treating hospital, and time from diagnosis to start of therapy.ResultsOf the 88,995 patients with myeloma, 15,223 (18%) received upfront RT, at median 15 days from diagnosis. Median radiation dose was 3000 cGy delivered over median 10 fractions, with the most common targets being spine/skull (59%), hips/pelvis (12%), and other bones (11%). Among patients receiving upfront RT, 73% started it before chemotherapy, while 27% started RT within 14 days of chemotherapy initiation.Use of upfront RT was significantly less common in academic than community hospitals (16% versus 20%, P<.0001). In the multivariable model, patients receiving upfront RT were significantly younger (odds ratio [OR] for a 10-year age increment: 0.92, 95% CI: 0.91-0.94), more likely to be male (OR: 1.11, 95% CI: 1.07-1.15), white non-Hispanic than black (OR: 1.13, 95% CI: 1.08-1.19), uninsured than privately insured (OR: 1.17, 95% CI: 1.06-1.29), and treated at a community rather than an academic hospital (OR: 1.28, 95% CI: 1.24-1.33). Receipt of upfront RT was also inversely associated with median income in the area of residence, distance to the hospital, and number of comorbidities (P<.0001).Median OS for the entire cohort was 4.2 years (95% CI, 4.1-4.2), longer for those treated with upfront systemic therapy (4.3 years, 95% CI, 4.2-4.3) than those receiving upfront RT (3.7 years, 95% CI, 3.6-3.8; Fig. A). After adjusting for baseline patient characteristics, treatment with upfront RT was associated with significantly worse OS (hazard ratio [HR]: 1.09, 95% CI: 1.07-1.12). This association was consistent in sensitivity analyses limited to patients who survived >1 year from diagnosis (HR: 1.15, 95% CI: 1.11-1.19), those who underwent autologous stem cell transplantation (HR: 1.11, 95% CI, 1.02-1.22; Fig. B), or accounting for baseline mortality rate using the endpoint of relative survival rather than OS (HR: 1.10, 95% CI: 1.07-1.14).ConclusionsIn this large nationwide cohort, nearly 1 in 5 of newly diagnosed myeloma patients received upfront RT. The association between socio-economic variables like income or insurance status and the use of upfront RT suggests that a delay in diagnosis may lead to severe skeletal complications of myeloma requiring RT. Worse survival with upfront RT may similarly correspond to more advanced disease, but persistent association in sensitivity analyses supports the hypothesis that a presentation with skeletal complications reflects a more aggressive myeloma biology. Further research should aim at disentangling the socio-economic, clinical, and molecular reasons underpinning this association. [Display omitted] DisclosuresOlszewski:Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding.

Ichthyosis linearis circumflexa with bamboo hair: challenges in the diagnosis and management

A 15-year-old boy had persistent and refractory erythroderma since early childhood. His parents noticed polycyclic skin lesions and hair fragility around the age of 5 years. He was treated by...

A new framework for evaluating the health impacts of treatment for Gaucher disease type 1

BackgroundThe Disease Severity Scoring System (DS3) is a validated measure for evaluating Gaucher disease type 1 (GD1) severity. We developed a new framework, consisting of health states, transition probabilities between those states, and preferences for those states (utilities) based on the DS3 to predict long-term outcomes of patients starting treatment. We defined nine mutually exclusive (alive) health states based on three DS3 categories: mild (0 ≤ DS3 ≤ 3.5) without symptoms of bone disease; mild with bone pain, mild with severe skeletal complications (SSC) defined as lytic lesions, avascular necrosis, or fracture; moderate (3.5 < DS3 ≤ 6.5) without SSC; moderate with SSC; marked (6.5 < DS3 ≤ 9.5) without SSC; marked with SSC; severe (9.5 < DS3 ≤ 19) without SSC; and severe with SSC. Health-state transition probabilities and utilities were estimated from a longitudinal sample of patients with GD1 who started enzyme replacement therapy (the DS3 Score Study). Age dependent GD1-specific mortality was derived from published data. We used a Markov state-transition model to illustrate how to estimate time spent in each health state.ResultsThe average predicted utilities for each health state ranged from 0.76 for mild disease with no clinical symptoms of bone disease to 0.52 with severe disease with SSC. Transition probabilities depended on disease severity (DS3 score) at treatment initiation and whether patients had undergone a total splenectomy or had an intact spleen/partial splenectomy prior to starting treatment. Patients who started treatment with intact or residual spleens spent more time in better health states than those who started treatment with total splenectomy.ConclusionsThis new framework, which is based on the DS3, can be used to project the long-term outcomes of GD1 patients starting treatment. The framework could also be used to compare the long-term outcomes of different GD1 treatment options.Trial registrationNCT01136304. Registered: May 31, 2010 (retrospectively registered).

Biochemical markers of bone metabolism in breast cancer.

The relationship between biochemical markers of bone resorption (C-terminal telopeptide, deoxypyridinoline, tartrate-resistant acid phosphatase 5b) and osteosynthesis (bone alkaline phosphatase) and clinical manifestations of bone metastases were studied in 239 patients with breast cancer with and without signs of bone involvement. High levels of C-terminal telopeptide and bone alkaline phosphatase were associated with poor prognosis: more severe skeletal complications and lesser survival values. These biochemical markers can be used for prognosis and optimization of therapy for bone metastases in patients with breast cancer.

Management of bone metastases

The skeleton is the most common site to be affected by advanced breast, prostatic, lung, kidney, thyroid and other solid tumors (in addition to myeloma multiplex). Bone metastases cause significant morbidity with nearly always fatal outcome. Over 600 000 new patients diagnosed in the developed countries yearly. On average every 4-6 months patients suffer from series of severe skeletal complications such as pathologic fractures, spinal cord compression, hypercalcemic events, etc., besides the permanent pain. Local external beam radiotherapy, systemic radioisotope-, endocrine-, and chemotherapy, oral and i.v. bisphosphonates and recently s.c. denosumab are the mainstays of treatment, in addition to pain-killers and other usual "classical" interventions. The modern treatments singificantly reduce the probability of skeletal complications and improve the patients' quality of life and, sometimes, they extend the survival as well. The authors briefly summarize the available treatment options.

Pathological fracture and pyogenic osteomyelitis in a patient with type 2 Gaucher disease

In Gaucher disease (GD), enzyme replacement therapy (ERT) results in the alleviation of hematological abnormalities and visceral infiltration as well as improvement in quality of life and life-span. However, several years may be required for skeletal manifestations, which are usually observed in type 1 and 3 GD, to respond to ERT. Infants with type 2 GD rarely present skeletal manifestations because most of these patients die within the first 2 years of life before they develop skeletal involvement. The use of ERT may prolong the lifespan of these patients and influence the natural history of the disease. The present study reports a new natural history of treated GD in which a 2-year and 7-month-old girl with type 2 GD who was receiving ERT developed valproate-induced Fanconi syndrome, pathological fractures, and pyogenic osteomyelitis. In conclusion, skeletal disease may occur in any type of GD, and Fanconi syndrome may lead to severe skeletal complications in patients with GD.

Oncogenic osteomalacia — Hypophosphataemic spectrum from “benignancy” to “malignancy”

Though case reports and case series about oncogenic osteomalacia due to benign mesenchymal tumours and much more rarely, secondary to malignant ones exist in the literature, there has not been any series reported from a single department spanning the gamut of causes from benign to malignant. We present 3 patients who were seen at the department of endocrinology of our hospital between 2010 and 2012 with hypophosphataemia and severe skeletal complications. All of them were found to have oncogenic osteomalacia otherwise known as tumour induced osteomalacia (TIO) — a paraneoplastic syndrome characterised by renal phosphate wasting and severe hypophosphataemia. The implicating tumours in our patients ranged from a subcutaneous mesenchymal tumour in the heel to a mixed connective tissue variant within the nasal cavity to metastatic prostate cancer. All our patients had protracted periods before the diagnosis was made, during which time the burden of their metabolic and skeletal pathology had increased. A timely recognition of the clinical features and biochemical findings of this rare but potentially debilitating disease is critical. Physicians should be cognizant of the presence of the disease and its localising and treatment strategies.

Skeletal implications of isolated bone marrow mastocytosis

In the article on the isolated bone marrow mastocytosis (IBMM) as an underestimated subvariant of indolent systemic mastocytosis (ISM), Zanotti et al.1 reported that 54.7% of patients with unexplained/recurrent anaphylaxis or severe allergic reactions were found to be suffering from IBMM. They conclude that the incidence of IBMM can be frequently underestimated, especially in the face of a lack of collaboration among medical specialities, while early recognition can potentially reduce life-threatening events and/or severe skeletal complications. Although this is an extremely interesting finding depicting the problem of unrecognized IBMM, the Authors do not provide an acceptable level of information regarding the skeletal problems of the patients. Since bone densitometry (BMD) was performed in all patients and X-rays in selected cases, it would be helpful for the reader to know the skeletal implications of these subjects. Osteoporosis or osteopenia is by far the most frequently observed pathological skeletal sign in systemic mastocytosis reported in more than one-third of all patients, while osteolysis and osteosclerosis can occur, even simultaneously, in the same patient. In addition, osteoporosis can be the only presentation in IBMM; specifically among men IBMM can be found in up to 9% of patients with idiopathic osteoporosis.2 Furthermore, fractures, mostly vertebral, have been reported in approximately 15% of all patients with systemic mastocytosis.3 Serum tryptase is currently considered the test of choice in the initial assessment of suspected systemic mastocytosis cases.4 However, its cost-effectiveness in the evaluation of secondary osteoporosis is yet to be defined due to the lack of data regarding the real incidence of the disease among osteoporotic patients. It would be very important to know whether the Authors can confirm or not a low BMD and/or pathological fractures in patients with IBMM, especially among young patients. In the former case, the importance of considering the diagnosis of IBMM in subjects with a low BMD and/or fractures and a history of recurrent allergic reactions would be highlighted.

Inhibition of RANKL increases the anti-tumor effect of the EGFR inhibitor panitumumab in a murine model of bone metastasis

Bone metastases cause severe skeletal complications and are associated with osteoclast-mediated bone destruction. RANKL is essential for osteoclast formation, function, and survival, and is the primary effector of tumor-induced osteoclastogenesis and osteolysis. RANKL inhibition by its soluble decoy receptor osteoprotegerin (OPG) prevents tumor-induced osteolysis and decreases skeletal tumor burden. Because osteoclast-mediated bone resorption releases growth factors from the bone matrix, the host bone microenvironment induces a vicious cycle of bone destruction and tumor proliferation and survival. A prediction of this vicious cycle hypothesis is that targeting the host bone microenvironment by osteoclast inhibition would reduce tumor growth and survival and may enhance the anti-tumor effects of targeted therapies. The epidermal growth factor receptor (EGFR) pathway regulates critical processes such as cell growth and survival, and anti-EGFR therapies can cause tumor cell arrest and apoptosis. We evaluated whether reduction of osteolysis by RANKL inhibition could enhance the anti-tumor effects of an anti-EGFR antibody (panitumumab) in a novel murine model of human A431 epidermoid carcinoma bone metastasis. Skeletal tumor progression was assessed longitudinally by bioluminescence imaging. RANKL inhibition by OPG-Fc treatment resulted in a reduction in tumor progression in bony sites. OPG-Fc treatment also caused a dose-dependent reduction in tumor-induced osteolysis, supporting the essential role of RANKL in this process. In combination, RANKL inhibition increased the anti-tumor efficacy of an anti-EGFR antibody, and completely blocked tumor-induced bone breakdown, demonstrating that addition of the indirect anti-tumor effect of RANKL inhibition increases the anti-tumor efficacy of panitumumab, a targeted anti-EGFR antibody.

The clinical course of untreated Gaucher disease in 22 patients over 10 years: Hematological and skeletal manifestations

Gaucher disease (GD) is a lysosomal storage disorder characterized by anemia and thrombocytopenia, hepatosplenomegaly, and skeletal involvement. The management of Gaucher disease was improved by the development of enzyme replacement therapy (ERT). However, the bone response to ERT is generally slower compared to other clinical manifestations. Some have recommended the early use of ERT to prevent the development of severe skeletal complications. Because we have access to over 30 untreated patients in Ontario, we questioned the extent to which complications progress in severity over a long period of time. We examined retrospectively the natural history of GD and the extent of skeletal manifestations in 22 untreated type 1 GD adult patients (mean age, 49 ± 3.3; range, 20–81 years). The patients were followed for a median of 9.5 years (range, 3–16 years). Hemoglobin (Hb) concentration did not significantly change over time (mean baseline concentration of 12.8 ± 0.27 g/dL vs. mean recent concentration of 12.6 ± 0.37 g/dL, p = 0.65). Mean platelet count also remained relatively stable over time (mean baseline count of 138 ± 13 × 10 9/L vs. mean recent count of 138.5 ± 18 × 10 9/L, p = 0.98). Mean ferritin and ACE concentrations were elevated and were stable over time. Liver volumes decreased over time (mean baseline liver volume of 1.2 × normal (N) vs. mean recent volume of 1.06 × N, p = 0.27) and 6 of 22 (27%) patients had moderate hepatomegaly (liver volume, 1.25–2.5 × N). Spleen volumes remained stable over time (mean baseline spleen volume of 6.6 × N vs. mean recent volume of 5.2 × N, p = 0.5). None of the changes was statistically significant. Four of 20 (20%) patients had moderate splenomegaly (spleen volume, 5–15 × N), 2 of 20 (10%) had marked splenomegaly (spleen volume, ≥ 15 × N), and 2 of 22 (9%) had had splenectomy. The most common skeletal manifestations were infiltration of the bone marrow in 16 of 22 (73%) patients followed by osteopenia in 15 of 22 (68%), Erlenmeyer flask deformity in 13 of 22 (59%), and infarctions in 6 of 22 (27%) patients. We observed that bone disease remained relatively stable over time in most patients, although three patients developed new infarcts over time, one developed an avascular necrosis (AVN), and four had an increase in the degree of osteopenia. Although GD and its skeletal complications progress in severity in some patients, our results suggest that GD complications, including bony disease, may stabilize over time. Therefore, early use of ERT may not be necessary in all type 1 GD patients.

The Clinical Course of Untreated Gaucher Disease in 22 Patients Over 10 Years: Hematological and Skeletal Manifestations.

Gaucher disease (GD) is a lysosomal storage disorder characterized by anemia and thrombocytopenia, hepatosplenomegaly, and skeletal involvement. The management of Gaucher disease was improved by the development of enzyme replacement therapy (ERT). However, the bone response to ERT is generally slower compared to other clinical manifestations. Some have recommended the early use of ERT to prevent the development of severe skeletal complications. Because we have access to over 30 untreated patients in Ontario, we questioned the extent to which the bony complications progress in severity over a long period of time. We examined retrospectively the natural history of GD and the extent of skeletal manifestations in 22 untreated type 1 GD adult patients (mean age 49 ± 3.3, range of 20–81 years). Ten patients were N370S homozygotes and twelve were compound heterozygotes. The patients were followed for a median of 9.5 years (range of 3 to 16 years). Assessments included complete blood counts (CBC); levels of angiotensin converting enzyme (ACE), ferritin, and chitotriosidase; liver and spleen volumes; and occurrences of bony complications. Dual Energy X-ray Absorptiometry (DEXA), Magnetic Resonance Imaging (MRI) of femurs, skeletal survey, and plain radiography were utilized to assess bony complications in 21 patients. Hemoglobin (Hb) concentration did not significantly change over time (mean baseline concentration of 12.8 ± 0.27 g/dL vs mean recent concentration of 12.6 ± 0.37 g/dL, p = 0.65). Mean platelet count also remained relatively stable over time (mean baseline count of 138 ± 13 × 109/L vs mean recent count of 138.5 ± 18 × 109/L, p = 0.98). Mean ferritin and ACE concentrations were elevated and were stable over time. Liver volumes decreased over time (mean baseline liver volume of 1.2 × normal (N) vs mean recent volume of 1.06 × N, p = 0.27) and 6/21 (29%) patients had moderate hepatomegaly (liver volume ≥ 1.25 × N). Spleen volumes remained stable over time (mean baseline spleen volume of 6.4 × N vs mean recent volume of 5.1 × N, p = 0.56). None of the changes was statistically significant. Three of 19 (15.8 %) patients had moderate splenomegaly (spleen volume ≥ 5 × N), 2/19 (10.5%) had severe splenomegaly (spleen volume ≥ 15 × N), and 2/22 (9%) had splenectomy. The most common skeletal manifestations were infiltration of the bone marrow in 15/21 (71%) patients followed by osteopenia in 14/21 patients (67%), and infarctions in 6/21 (29%) patients. Other bony complications included osteoporosis in 3/21 (14%), avascular necrosis (AVN) in the left knee and femur in 1/21 (5%), and osteolysis in 1/21 (5%) patients; there were no cases of fractures. Three of 21 (14%) patients developed new infarcts (2N370S homozygous patients) over time, 1/21 (5%) developed AVN, and 4/21 (19%) had an increase in the degree of osteopenia. There were no significant differences observed between the N370S homozygous and compound heterozygous patients. Although GD and its skeletal complications progress in severity in some patients, our results suggest that GD complications including bony disease may stabilize over time. Therefore, early use of ERT may not be necessary in all type 1 GD patients.

312 Pilot study of the use of infliximab for fatigue in advanced cancer

Bone metastases cause severe skeletal complications and are associated with osteoclast-mediated bone destruction. RANKL is essential for osteoclast formation, function, and survival, and is the primary effector of tumor-induced osteoclastogenesis and osteolysis. RANKL inhibition by its soluble decoy receptor osteoprotegerin (OPG) prevents tumor-induced osteolysis and decreases skeletal tumor burden. Because osteoclast-mediated bone resorption releases growth factors from the bone matrix, the host bone microenvironment induces a vicious cycle of bone destruction and tumor proliferation and survival. A prediction of this vicious cycle hypothesis is that targeting the host bone microenvironment by osteoclast inhibition would reduce tumor growth and survival and may enhance the anti-tumor effects of targeted therapies. The epidermal growth factor receptor (EGFR) pathway regulates critical processes such as cell growth and survival, and anti-EGFR therapies can cause tumor cell arrest and apoptosis. We evaluated whether reduction of osteolysis by RANKL inhibition could enhance the anti-tumor effects of an anti-EGFR antibody (panitumumab) in a novel murine model of human A431 epidermoid carcinoma bone metastasis. Skeletal tumor progression was assessed longitudinally by bioluminescence imaging. RANKL inhibition by OPG-Fc treatment resulted in a reduction in tumor progression in bony sites. OPG-Fc treatment also caused a dose-dependent reduction in tumor-induced osteolysis, supporting the essential role of RANKL in this process. In combination, RANKL inhibition increased the anti-tumor efficacy of an anti-EGFR antibody, and completely blocked tumor-induced bone breakdown, demonstrating that addition of the indirect anti-tumor effect of RANKL inhibition increases the anti-tumor efficacy of panitumumab, a targeted anti-EGFR antibody.

Decreased Bone Density in Splenectomized Gaucher Patients Receiving Enzyme Replacement Therapy

ABSTRACTLittle is known about the effect of enzyme replacement therapy (ERT) on the bone abnormalities in Gaucher disease. Splenectomized Gaucher patients tend to suffer the most severe skeletal complications. We hypothesized that vitamin D supplementation would act synergistically with glucocerebrosidase infusions to increase bone density in splenectomized Gaucher patients. In a 24-month study, 29 splenectomized Gaucher patients were randomized to three groups: Group 1, calcitriol (1,25-dihydroxyvitamin D3; 0.25–3.0 μg/day) alone for the first 6 months with the addition of ceredase/cerezyme at 60 IU/kg every 2 weeks during months 7–12; Group 2, calcitriol together with ceredase/cerezyme at 60 IU/kg every 2 weeks during months 1–6; and Group 3, enzyme only at 60 IU/kg body wt every 2 weeks. In all three groups, enzyme dose was halved after the first 6 months of therapy. The primary outcome measure was bone mineral density of the lumbar spine measured by single-energy quantitative CT. Bone density by single-energy CT (P = 0.001) and by dual-energy CT (P = 0.06) declined overall, but there was no significant difference between the groups. Calcitriol had no significant effect on bone density. Fat fraction in lumbar spine increased (P = 0.000) and skeletal MRI scores improved. Bone-specific alkaline phosphatase (P = 0.002) and serum osteocalcin increased (P = 0.008), while blood cyclic AMP and urinary deoxypyridinoline did not change appreciably. Hemoglobin, platelet counts, and liver volume significantly improved. We conclude that ERT alone, or in combination with calcitriol, cannot repair the bone composition in splenectomized adult Gaucher patients. Alternatively, measuring trabecular bone density may be an inadequate marker of clinical efficacy for treating skeletal involvement in Gaucher disease.

Mechanism of increased parathyroid hormone mRNA in experimental uremia: roles of protein RNA binding and RNA degradation.

Patients with chronic renal failure develop secondary hyperparathyroidism with increased synthesis and secretion of parathyroid hormone (PTH) resulting in severe skeletal complications. In rats with secondary hyperparathyroidism due to 5/6 nephrectomy, there are increased PTH mRNA levels, and this mechanism was studied. Parathyroid glands were microdissected from control and 5/6 nephrectomy rats and analyzed for PTH mRNA and control genes, and the nuclei were used for nuclear run-on experiments. The cytosolic proteins of the parathyroids were used to study PTH mRNA protein binding by ultraviolet cross-linking and the degradation of the PTH transcript in vitro. Nuclear run-ons showed that the increase in PTH mRNA levels was posttranscriptional. Protein binding to the PTH mRNA 3'-UTR determines PTH mRNA stability and levels. Parathyroid proteins from uremic rats bound PTH mRNA similar to control rats by ultraviolet cross-linking. To determine the effect of uremia on PTH mRNA stability, an in vitro RNA degradation assay was performed with parathyroid proteins from uremic rats. When parathyroid proteins from control rats were incubated with PTH mRNA, there was transcript degradation already at 30 min, reaching 50% at 60 min and 90% at 180 min. With uremic parathyroid proteins, the PTH mRNA was not degraded at all at 120 min and was moderately decreased at 180 min. This decrease in degradation by uremic parathyroid proteins suggests a decrease in parathyroid cytosolic endonuclease activity in uremia resulting in a more stable PTH transcript. The increased PTH mRNA levels would translate into increased PTH synthesis and serum PTH levels, which would lead to metabolic bone disease in many patients with chronic renal failure.

Severe skeletal complications in Japanese patients with type 1 Gaucher disease.

To better characterize skeletal complications in Japanese patients with type 1 Gaucher disease (GD), we performed genotyping and clinical and radiological analysis of 35 patients, the vast majority of this population, Skeletal complications tend to be very common, severe and rapidly progressive in Japanese patients with type 1 GD. Twenty (57%) of these patients manifested end points of severe bone disease including avascular necrosis, pathological fracture and/or bone crisis. Mean time from presentation/diagnosis of GD until presentation of this involvement was 3 years 6 months +/- 4 years 1 month. Prevalence of severe bone disease is significantly higher in splenectomized than in non-splenectomized patients--81% (17/21) versus 21% (3/14) (p = 0.0007, Fisher's exact test). Four (29%) of 14 patients receiving enzyme replacement therapy (ERT) or bone marrow transplantation (BMT) manifested severe bone involvement for the first time during or after treatment. All cases occurred in children in whom ERT doses had been lowered after only brief administration of higher starting doses (n = 3) or partial donor marrow engraftment resulted in low glucocerebrosidase (GCR) activity (n = 1). These observations suggest that splenectomy may correlate with accelerated skeletal deterioration with severe skeletal disease, at least in patients with severe phenotypic expression. They also suggest that it is important that sufficient GCR is available in paediatric patients with severe phenotypic expression. Hence ERT dosages should be based on disease severity and on age, with sustained administration of full doses in patients at greater risk of important skeletal complications.

Radiologic Findings of Korean Gaucher Disease

Purpose : To document the radiologic characteristics of Korean Gaucher disease. Materials and Methods :Fifteen bone marrow biopsy and laboratory data confirmed Gaucher disease patients (age 1 -21, mean 10.9 yr) were undertaken plain X ray and MRI. Number of type I were 10, type II, 2, type III, 3. Seven were splenectomized oninitial evaluation or during follow up. Five enzyme treated patient were undertaken follow-up MR examination during 6 -40 month with 6 month interval. Conventional T1 and T2WI of spine and femur was performed and FMPSPGR inand out of phase image was also done. Volume of liver and spleen were measured, and bone marrow infiltration and presence of infarction were scored according to 6 scale scoring system. Clinical data were also reviewed and correlated with the MR findings. Results : Marrow infiltration was noted in 71.4% of all patients in MRI, while itwas in 45.7% with plain radiography. Type I group showed marrow infiltration in all but one cases, which was parallel with ages, SGPT, and presence of osteopenia, reversely correlated with spleen size. Severe bone complications (infarction or fracture) were noted in 7 of 10 type I group, and 6 patients showed severe growth retardation (below 3rd percentile). Follow up MR examination of 5 patient showed decrease in liver and spleen size first without bone change until 6 months. There showed bone regeneration in 2 patient 1 year after, and increased fat signal in one patient 3.5 years after. In and out of phase images couldn’t help in quantifying fat composition in bone marrow. Conclusion : Korean Gaucher patients revealed as more severe skeletal complications than others reported from Western groups. MR examination is a effective modality to evaluate and monitor of Gaucher patients.