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M J Klein

Publications and source records attributed to M J Klein.

At least 19 recordsLinked to original sources
PubMed2001

Cathepsin k is a critical protease in synovial fibroblast-mediated collagen degradation.

Synovial fibroblasts (SFs) play a critical role in the pathogenesis of rheumatoid arthritis (RA) and are directly involved in joint destruction. Both SF-resident matrix metalloproteases and cathepsins have been implicated in cartilage degradation although their identities and individual contributions remain unclear. The aims of this study were to investigate the expression of cathepsin K in SFs, the correlation between cathepsin K expression and disease severity, and the contribution of cathepsin K to fibroblast-mediated collagen degradation. Immunostaining of joint specimens of 21 patients revealed high expression of cathepsin K in SFs in the synovial lining and the stroma of synovial villi, and to a lesser extent in CD68-positive cells of the synovial lining. Cathepsin K-positive SFs were consistently observed at sites of cartilage and bone degradation. Expression levels of cathepsin K in the sublining and vascularized areas of inflamed synovia showed a highly significant negative correlation with results derived from the Hannover Functional Capacity Questionnaire (r = 0.78, P = 0.003; and r = 0.70, P = 0.012, respectively) as a measure of the severity of RA in individual patients. For comparison, there was no correlation between Hannover Functional Capacity Questionnaire and cathepsin S whose expression is limited to CD-68-positive macrophage-like synoviocytes. The expression of cathepsin K was also demonstrated in primary cell cultures of RA-SFs. Co-cultures of SFs on cartilage disks revealed the ability of fibroblast-like cells to phagocytose collagen fibrils whose intralysosomal hydrolysis was prevented in the presence of a potent cathepsin K inhibitor but not by an inhibitor effective against cathepsins L, B, and S. The selective and critical role of cathepsin K in articular cartilage and subchondral bone erosion was further corroborated by the finding that cathepsin K has a potent aggrecan-degrading activity and that cathepsin K-generated aggrecan cleavage products specifically potentiate the collagenolytic activity of cathepsin K toward type I and II collagens. This study demonstrates for the first time a critical role of cathepsin K in cartilage degradation by SFs in RA that is comparable to its well-known activity in osteoclasts.

Adult↗
PubMed2001

Detection of c-fos expression in benign and malignant musculoskeletal lesions.

The proto-oncogene c-fos has been implicated in the development of both benign and malignant lesions of bone. Although c-fos expression in such lesions has been well studied in transgenic mouse models, less is known about its role in human musculoskeletal pathology. To clarify this relationship, we used in situ hybridization to localize c-fos m-RNA transcripts in 26 fibrous lesions (eight cases of extra-abdominal fibromatosis and six cases each of fibrous dysplasia, fibrosarcoma, and malignant fibrous histiocytoma of bone) as well as six chondrosarcomas and eight conventional high grade osteosarcomas. We found detectable levels of c-fos expression in tissues from each type of lesion tested. Moreover, all fibrous lesions consistently demonstrated high levels of expression in a majority of cells in each lesion. Chondrosarcomas and osteosarcomas exhibited more heterogeneity in c-fos expression than fibrous tissues. Three of six chondrosarcomas showed moderate expression of c-fos while only one of six was considered high. Similarly, only three of eight osteosarcomas had high expression of c-fos. These findings indicate that the expression of c-fos may be important in the development of a broad range of fibrous lesions as well as in bone and cartilaginous tumors. Additionally, this is the first report, to our knowledge, of detectable c-fos m-RNA in human chondrosarcoma.

Adolescent↗
PubMed2001

Severe osteopenia in a young boy with Kostmann's congenital neutropenia treated with granulocyte colony-stimulating factor: suggested therapeutic approach.

Kostmann's syndrome is a congenital disorder that causes an impairment of myeloid differentiation in the bone marrow characterized by severe neutropenia, which can be treated with recombinant human granulocyte colony-stimulating factor (G-CSF). We present the case of a 13-year-old boy with Kostmann's syndrome who was treated with recombinant human G-CSF from age 3.5 years. His growth and development was normal, although complicated by intermittent infections. Bone mineral density (BMD) measurement revealed severe osteopenia at the spine and hips (lumbar spine BMD 0.486 g/cm(2); Z score -3.6), and he was referred to the Endocrine Service. Relevant laboratory evaluation showed a pretreatment ionized calcium level at the upper limit of normal (1.28 mmol/L; range: 1.13-1.32 mmol/L), suppressed intact parathyroid hormone (iPTH) level (12 pg/mL; range: 10-65 pg/mL), and a low 1,25-dihydroxy vitamin D level (21 pg/mL; range: 24-65 pg/mL). He had evidence of increased bone turnover evidenced by elevated urinary deoxypyridinoline (DPD) cross-links (46.9 nmol/mmol creatinine; range: 2-34 nmol/mmol creatinine) and a simultaneous increase in markers of bone formation with elevated osteocalcin level (200 ng/mL; normal: 20-80 ng/mL) and alkaline phosphatase level (236 IU/mL; normal: 38-126 IU/mL). Because of clinical concern for his skeletal health, bisphosphonate therapy with intravenous pamidronate was initiated. One month after treatment, the iPTH and DPD cross-links were in the normal range (54 pg/mL and 17.7 nmol/mmol creatinine, respectively) and the 1,25-dihydroxy vitamin D level was elevated (111 pg/mL). Four months after treatment, there was a striking increase in BMD at the lumbar spine (+30.86%), femoral necks (left, +20.02%; right, +17.98%), and total hips (left, +18.40%; right, +15.94%). Seven months after bisphosphonate therapy, his biochemical parameters showed a return toward pretreatment levels with increasing urinary DPD cross-links (28.7 nmol/mmol creatinine) and decreasing iPTH (26 pg/mL). However, the BMD continued to increase (8 months posttreatment), but the magnitude of the increment was attenuated (lumbar-spine, +4.8%; left total hip, +1.2% and right total hip +2.4%), relative to BMD at 4 months. Eight months after the initial treatment, his iPTH was suppressed at 14 pg/mL and he again received pamidronate (at a lower dose); 3 months later, he had an additional increase in BMD (lumbar spine +7.4%, left total hip +3.9%, right total hip +2.7%), relative to the previous study. We hypothesize that prolonged administration of G-CSF as treatment for Kostmann's syndrome is associated with increased bone resorption, mediated by osteoclast activation and leading to bone loss. In children, the resulting osteopenia can be successfully managed with antisreorptive bisphosphonate therapy with significant improvement in bone density. Measurements of biochemical parameters of bone turnover can be used to monitor the magnitude and duration of the therapeutic response and the need for BMD reassessment and, perhaps, retreatment.

Adolescent↗
PubMed2000

Late effects of therapy in 94 patients with localized rhabdomyosarcoma of the orbit: Report from the Intergroup Rhabdomyosarcoma Study (IRS)-III, 1984-1991.

BACKGROUND: We reviewed the late complications of therapy in 94 patients with localized, primary rhabdomyosarcoma of the orbit treated on the Intergroup Rhabdomyosarcoma Study (IRS)-III protocol (1984-1991). PROCEDURE: A questionnaire was sent to the institutions that had registered 106 patients with orbital RMS on the IRS-III protocol, seeking information about vision, periocular structures, and growth and development of the 102 survivors. RESULTS: Ninety-four questionnaires were returned. The median follow-up interval was 7.6 years. The affected eye was removed from 13 patients because of local recurrence (N = 10) or other causes (N = 3). Seventy-nine of the eighty-one remaining patients had received radiation therapy. Sixty-five of these seventy-nine patients (82%) developed a cataract, and 43 of them (66%) underwent cataract surgery. Fifty-five patients (70%) had decreased visual acuity. Twenty-four patients had a dry eye, and 22 had chronic keratitis, conjunctivitis, or corneal changes. Strabismus, diplopia, retinopathy, and uveitis were uncommon. The orbit was hypoplastic in 48 of 82 patients assessed (59%). Ptosis and enophthalmos were reported in 22 patients. Decreased statural growth was noted in 13 of the 53 irradiated patients aged 3-14 years at diagnosis with sufficient data (24%). CONCLUSIONS: The overall survival rate was 96% (102/106). The eye was preserved in 86% of the patients, but vision was impaired in 70% of them. Other frequent complications were cataract, orbital hypoplasia, keratoconjunctivitis, and ptosis/enophthalmos. The current IRS-V study recommends decreasing the dose of irradiation and using conformal techniques in an attempt to minimize these complications.

Adolescent↗
PubMed2000

Amelioration of collagen-induced arthritis in DBA/1J mice by recombinant TSG-6, a tumor necrosis factor/interleukin-1-inducible protein.

OBJECTIVE: To examine the effect of recombinant TSG-6 on collagen-induced arthritis (CIA) in DBA/1J mice. TSG-6 is a tumor necrosis factor (TNF)/ interleukin-1 (IL-1)-inducible hyaluronan-binding protein produced by synovial cells and chondrocytes that is present in synovial fluids of patients with rheumatoid arthritis. METHODS: To determine the effect of TSG-6 on chronic inflammatory joint disease, we induced CIA in DBA/1J mice by immunization with bovine type II collagen. Animals were treated with 12 intraperitoneal doses of 200 microg of recombinant TSG-6, beginning 3 days before the expected onset of disease symptoms. Progression of arthritis was monitored by determining the disease incidence, arthritis index, and footpad swelling. Levels of IgG1, IgG2a, and IgG2b antibodies against bovine and murine type II collagen and serum concentrations of IL-6 were determined at various time points. Histologic examination of affected joints was performed approximately 20 days after the onset of arthritis. RESULTS: Treatment with recombinant TSG-6 protein had a potent ameliorative effect, manifested by decreases in the disease incidence, arthritis index, and footpad swelling. Histologic examination of affected joints in TSG-6-treated animals revealed little pannus formation and cartilage erosion, features which were conspicuous in control mice. Animals treated with recombinant TSG-6 developed significantly reduced levels of IgG1, IgG2a, and IgG2b antibodies against bovine and murine type II collagen. CONCLUSION: The antiinflammatory effect of the TNF/IL-1-inducible TSG-6 protein in murine CIA suggests a role for this protein as an endogenous regulator of the inflammatory process.

Animals↗
PubMed2000

Growth hormone deficiency in children with neurofibromatosis type 1 without suprasellar lesions.

Risk factors for shortness of stature in children with neurofibromatosis type 1 (NF-1) include suprasellar lesions, which can lead to growth hormone deficiency (GHD), skeletal deformities, nutritional insufficiency, and methylphenidate use. At our Neurofibromatosis Clinic, we have observed short children growing poorly without these risk factors. This study investigated whether GHD occurs in children with NF-1 in the absence of suprasellar lesions. Of 251 children with NF-1, 112 were at or below the 25th percentile for height (68 were at or below the 10th). Of these, 51 children, 5-16 years of age were short, growing poorly, and without medical or radiologic findings to explain the poor growth. In 19 of 51, we evaluated GH secretion; 15 of 19 had GHD (peak GH level less than 5 ng/mL in most cases). These findings suggest that GHD may be relatively common in short children with NF-1 without suprasellar abnormalities, suggesting an association with NF-1 independent of organic, pituitary damage. Larger cohorts of NF-1 children should be evaluated to clarify whether NF-1 represents a novel etiology of GHD. Also, a careful assessment of GH secretion in children with NF-1 who are growing poorly in the absence of another clinical explanation is warranted.

Adolescent↗
PubMed2000

Fine-needle aspiration diagnosis of synovial chondromatosis of the tibiofibular joint.

We report a case of synovial chondromatosis of the tibiofibular joint in a 25-year-old woman that was diagnosed by fine-needle aspiration (FNA). The patient presented with pain in the left knee and a mass in the popliteal fossa. Synovial chondromatosis usually presents with joint symptoms and is often associated with intra-articular loose bodies, whereas presentation as a soft tissue mass is unusual and may raise the clinical suspicion of malignant neoplasm. The diagnosis is commonly confirmed by histopathologic examination of biopsy or excision of the specimen. To the best of our knowledge, this is the first case of synovial chondromatosis of a large joint successfully diagnosed by FNA. Two cases of synovial chondromatosis of the temporomandibular joint have been reported in which the diagnosis was suspected on the basis of FNA. In both these cases, the final diagnosis was established by histopathology of the excised specimens.

Adult↗
PubMed1999

Osteopenia in young adult survivors of childhood cancer.

BACKGROUND: Improved survival of children with malignant diseases is in part due to the application of intensive, multimodality therapies, including radiotherapy, surgery, glucocorticoids, and cytotoxic agents. Such interventions have the potential to induce complex hormonal, metabolic and nutritional effects that may interfere with skeletal mass acquisition during childhood and adolescence: it is possible that such childhood cancer survivors may therefore reach adulthood with diminished peak bone mass and be at increased risk for clinically significant osteoporosis later in their life. PROCEDURE: A bone mineral density (BMD) was measured in 26 unselected former cancer patients attending the Pediatric Long-Term Clinic at M.D. Anderson Cancer Center. BMD was measured at the lumbar spine and the hip using dual X-ray absorptiometry (Hologic QDR-4500W). In addition, the patients' complete medical records were reviewed with particular attention to disease type, age modalities of treatment, and hormonal residual deficiencies. RESULTS: The median age of patients at the time of cancer diagnosis was 8 years (range, 0.3 to 16 years). Median age at BMD determination was 23 years (range, 18 to 41 years), and the median interval since cancer diagnosis and BMD was 18 years (range, 5 to 29). Overall, their BMD was decreased relative to peak bone mass at all sites: osteopenia was especially pronounced in patients with a history of cranial irradiation who had developed evidence of pituitary insufficiency during childhood or adolescence. Overall, the median BMD T-score was -1.41 at the lumbar spine, -1.04 at the femoral neck, and -1.06 for total hip. For patients with prior cranial irradiation, T-score at the lumbar spine was -2.18 (range, -4.06 to -0.98), at the femoral neck -1.92 (range, -4.11 to +1.10), and for total hip -1.67 (range, -4.79 to +0.56); BMD for irradiated patients was significantly lower than BMD of patients without cranial irradiation. We could not discern an independent impact of other disease characteristics or treatment modalities in this small group of patients. CONCLUSIONS: Osteopenia is a prominent finding in young adults who are survivors of childhood cancers; it is likely that antineoplastic treatments during childhood and adolescence impede peak bone mass acquisition. We suggest that systematic attention to this potential complication is needed in order to identify what subgroups of children may require regular surveillance and what interventions are required for its prevention or treatment.

Adolescent↗
PubMed1999

Late complications of therapy in 213 children with localized, nonorbital soft-tissue sarcoma of the head and neck: A descriptive report from the Intergroup Rhabdomyosarcoma Studies (IRS)-II and - III. IRS Group of the Children's Cancer Group and the Pediatric Oncology Group.

BACKGROUND: This review of children and adolescents with nonorbital soft-tissue sarcoma of the head and neck was undertaken to describe late sequelae of treatment, as manifested primarily by problems with statural growth, facial and nuchal symmetry, dentition, vision and hearing, and school performance. PROCEDURE: Four hundred sixty-nine patients entered the IRS-II and -III protocols with localized, nonorbital soft-tissue sarcomas of the head and neck from 1978 through 1987. Their overall survival rate was 53% (250/469) at 5 years. Two hundred thirteen patients were surviving relapse-free 5 or more years after diagnosis, for whom there were serial height measurements at 2 or more years after initiation of therapy. Their median age at diagnosis was 5 years; the median length of follow-up was 7 years. All received multiple-agent chemotherapy, and all but 3 received irradiation to the primary tumor volume. Sixty-eight percent of the tumors arose in cranial parameningeal sites, 22% in nonparameningeal sites, and 10% in the neck. We reviewed flow sheets submitted to the IRS Group Statistical Office to ascertain which late sequelae were recorded. RESULTS: One hundred sixty-four patients (77%) had one or more problems recorded. One hundred ninety of the two hundred thirteen patients (89%) were under 15 years of age at study entry, and at follow-up 92 (48%) had failed to maintain their initial height velocity, which had decreased by more than 25 percentile points from the original value. Thirty-six of the one hundred ninety patients (19%) were receiving growth hormone injections. Hypoplasia or asymmetry of tissues in the primary tumor site was reported in 74 patients, and 13 underwent reconstructive surgery. Poor dentition or malformed teeth were noted in 61 patients. Impaired vision developed in 37 patients, owing primarily to cataracts, corneal changes, and optic atrophy. Thirty-six patients had decreased hearing acuity, and 9 were fitted with hearing aids; 5 of these 9 had received cisplatin. Thirty-five patients were noted to have problems learning in school. Four patients developed a second malignancy (two sarcomas, one carcinoma, one leukemia). CONCLUSIONS: Late sequelae affected the majority of these patients treated for soft-tissue sarcoma of the head and neck on IRS-II and -III. The potential impact of certain sequelae could be reduced by specific measures, such as surgical reconstruction and hormonal therapy. Late sequelae must be taken into account in designing future curative treatments.

Adolescent↗
PubMed1999

Primary non-Hodgkin lymphoma of bone: unusual manifestation of lymphoproliferative disease following liver transplantation.

We present the case of a 66-year-old man with primary non-Hodgkin lymphoma of the right femur that developed following orthotopic liver transplant, while on immunosuppressive therapy. The diagnosis was suggested on the basis of the MRI findings and confirmed by open biopsy. He was treated successfully with local radiotherapy and has remained disease free for 14 months after the onset of the disease.

Aged↗
PubMed1999

Estrogen replacement therapy after localized breast cancer: clinical outcome of 319 women followed prospectively.

PURPOSE: To determine whether estrogen replacement therapy (ERT) alters the development of new or recurrent breast cancer in women previously treated for localized breast cancer. PATIENTS AND METHODS: Potential participants (n = 319) in a trial of ERT after breast cancer were observed prospectively for at least 2 years whether they enrolled onto the randomized trial or not. Of 319 women, 39 were given estrogen and 280 were not given hormones. Tumor size, number of lymph nodes, estrogen receptors, menopausal status at diagnosis, and disease-free interval at the initiation of the observation period were comparable for the trial participants (n = 62) versus nonparticipants (n = 257) and for women on ERT (n = 39) versus controls (n = 280). Cancer events were ascertained for both groups. RESULTS: Patient and disease characteristics were comparable for the trial participants versus nonparticipants, as well as for the women on ERT versus the controls. One patient in the ERT group developed a new lobular estrogen receptor-positive breast cancer 72 months after the diagnosis of a ductal estrogen receptor-negative breast cancer and 27 months after initiation of ERT. In the control group, there were 20 cancer events: 14 patients developed new or recurrent breast cancer at a median time of 139.5 months after diagnosis and six patients developed other cancers at a median time of 122 months. CONCLUSION: ERT does not seem to increase breast cancer events in this subset of patients previously treated for localized breast cancer. Results of randomized trials are needed before any changes in current standards of care can be proposed.

Adult↗
PubMed1999

Osteoid osteoma of a cervical vertebral body.

An osteoid osteoma in the anterior part of the body of the fourth cervical vertebra occurred in a 22-year-old female. The patient's main complaint was neck pain and occasional numbness of the extremities. The pain was relieved by analgesics. Plain radiography and a 99Tcm MDP bone scan showed a non-specific abnormality. CT suggested the pathological diagnosis with reasonable certainty. The unusual location of the lesion and the role of various diagnostic modalities are discussed and the literature reviewed.

Adult↗
PubMed1998

Malignant fibrous histiocytoma associated with a bone infarct in a patient with hereditary bone dysplasia.

Hereditary bone dysplasia (HBD) is an extremely rare clinicopathological entity manifested by diaphyseal medullary stenosis and cortical bone thickening associated with a propensity for fractures affecting the long tubular bone. Malignant transformation has been reported to occur at an alarming frequency. The hereditary pattern appears to be autosomal dominant. In this paper we present the case of a 19-year-old man with hereditary bone dysplasia who was unaware of his underlying condition until he presented with malignant transformation arising in an area of bone infarct of the left tibia.

Adult↗
PubMed1998

Angiosarcomas associated with bone infarcts.

OBJECTIVE: A bone infarct may occasionally dedifferentiate to osteogenic sarcoma, fibrosarcoma or malignant fibrous histiocytoma. However, the association of an angiosarcoma with a bone infarct is extremely rare. Such an association is presented in three patients. Their clinical course is compared with that of patients with bone infarcts associated with other sarcomas. DESIGN AND PATIENTS: The three patients were men with a mean age of 43 years. Cases 1 and 3 presented with a pathological fracture at the site of the angiosarcoma. Plain radiography was done in the three patients, computed tomography (CT) was performed in cases 1 and 3 and magnetic resonance imaging (MRI) in case 3. The femur was the site of the three tumors: midshaft in cases 1 and 3 and distal shaft in case 2. On the basis of the radiographic findings, and clinical examination, an open biopsy was performed for the three men, which confirmed the diagnosis of a high-grade angiosarcoma associated with a bone infarct. RESULTS: Case 1 was treated with high-above knee amputation and is still alive after 18 months from the time of operation. Segmental resection of the distal femur with adjuvant chemotherapy and local irradiation was the treatment for case 2, who is still alive with no tumor recurrence on metastatic disease 3 years from the operation. Intramedullary rodding was done for case 3 who died 6 months later. CONCLUSION: The association of an angiosarcoma with a bone infarct has been established in only five cases. Although the number of such associations is small, it seems that such an association may be prognostically more or less the same as in those cases in which a bone infarct is associated with either osteosarcoma, fibrosarcoma or malignant fibrous histiocytoma, where the survival rate is unfavorable. A cause-and-effect relationship may exist between a bone infarct and subsequent development of a bone sarcoma.

Adult↗