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S M Kumta

Publications and source records attributed to S M Kumta.

At least 19 recordsLinked to original sources
PubMed2004

Alendronate regulates cell invasion and MMP-2 secretion in human osteosarcoma cell lines.

BACKGROUND: Osteosarcoma is the most common malignant bone tumor of childhood. Significant proportions of these patients eventually develop pulmonary metastases and succumb to their disease even after conventional multi-agent chemotherapy and surgical excision. Matrix metalloproteinase (MMP)-2 induced degradation of blood vessel basement membranes is an important pre-requisite for tumor invasion and metastasis. Bisphosphonates (BPs) have been known to inhibit tumor growth and metastasis in some tumors such as breast cancer, renal cell carcinoma, and prostate cancer, and may do so through inhibition of MMP secretion. We, therefore, tested the effect of BPs on tumor cell invasion, MMP-2 secretion, and apoptosis of osteosarcoma cell lines. PROCEDURE: Two osteosarcoma cell lines (SaOS-2, U(2)OS) were treated with alendronate (50, 100, and 150 microM) for 24 and 48 hr. Matrigel invasion assay was used to investigate the invasive potential of osteosarcoma cell lines before and after alendronate treatment. Real-time quantitative RT-PCR was used to determine the mRNA level of MMP-2 with and without alendronate treatment. Enzyme-linked immunosorbent assay (ELISA) was used to quantify the cytokine level of MMP-2 secreted in the condition medium. BP-induced cell apoptosis was evaluated by fluorescent flow cytometric analysis. RESULTS AND CONCLUSIONS: The results showed that alendronate inhibited cell invasion of both osteosarcoma cell lines in a dose-dependent manner. Alendronate reduced the mRNA level and cellular level of MMP-2 in both cell lines in a time and dose-dependent manner. Alendronate also induced significant apoptosis in both cell lines. Our finding suggests that alendronate downregulates MMP-2 secretion and induces apoptosis in osteosarcoma cells, which may both contribute to the reduction of invasive potential of the tumor cells.

Alendronate↗
PubMed2004

Bisphosphonates induce apoptosis of stromal tumor cells in giant cell tumor of bone.

Giant cell tumour of bone (GCT) is an aggressive primary neoplasm that results in the production of osteolytic lesions. Stromal cells, which form the main neoplastic component of this tumor, regulate the formation of osleoclast-like giant cells that are ultimately responsible for bone destruction. Bisphosphonates prevent bone resorption by inhibiting osteoclast activity and promoting osteoclast apoptosis, and they have been known to induce apoptosis of primary neoplastic cells such as those in breast and prostate cancers. We hypothesized that in bisphosphonates may induce apoptosis not only in osteoclast-like giant cells but also in neoplastic stromal cells of GCT both in vitro and in vivo. Twelve patients with GCT were treated with weekly injections of pamidronate for a period of 6 weeks prior to surgery. GCT specimens were collected at the time of biopsy and during definitive surgery. TUNEL assay was used to evaluate apoptotic DNA fragmentation in cells. In addition, twelve GCT primary cultures from these patients were treated with zoledronate, pamidronate, or alendronate for 48 hours at different doses (3, 30, or 150 microM) and subjected to apoptosis assay by flow cytometry following fluorescent Annexin-V labeling. The results showed that pamidronate significantly induced apoptosis in both osteoclast-like giant cells and stromal tumor cells, in vivo. All three bisphosphonates caused substantial apoptosis of stromal tumor cells in cultures. Zoledronate was the most potent reagent, resulting in an average cell death of 27.41% at 150 microM, followed by pamidronate (22.23%) and alendronate (15.3%). Our observations suggest that these drugs may be considered as potential adjuvants in the treatment of GCT.

Alendronate↗
PubMed2004

Expression of preosteoblast markers and Cbfa-1 and Osterix gene transcripts in stromal tumour cells of giant cell tumour of bone.

In giant cell tumour of bone (GCT), mononuclear stromal cells, which represent the neoplastic component of this lesion, regulate the formation of multinucleated osteoclast-like giant cells which are the characteristic hallmark of this tumour. However, the origin of stromal tumour cells has not yet been clearly defined. In this study, we evaluated several osteoblast markers including collagen type I, bone sialoprotein (BSP), osteonectin and osteocalcin in GCT using immunohistochemical techniques. Amongst the 13 GCT specimens and 7 GCT stromal cell (GCTSC) cultures studied, majority of the GCTSC synthesized type I collagen, BSP and osteonectin proteins but did not produce the differentiated osteoblast marker, osteocalcin. We further examined the regulation of several important osteogenic genes such as Cbfa-1, osterix and osteocalcin, and regulation of ALP activity in GCTSC in culture by bone morphogenetic protein 2 (BMP-2). Real-time PCR analysis indicated that Cbfa-1, osterix and osteocalcin mRNA were present in primary cultures of GCTSC. The addition of BMP-2 upregulated Cbfa-1 and osterix gene expression within 12 h and the enhancement was still observed at 24 h. ALP activity was minimal in untreated GCTSC in cultures. The number of ALP-positive GCTSC was significantly increased following treatment with BMP-2 or combinations with beta-glycerophosphate and ascorbic acid. In contrast, BMP enhancement of osterix mRNA level and ALP activity was also seen in SaOS2 osteoblast-like cells, but not in the primary culture of normal human skin fibroblasts. In summary, our data suggest that GCT stromal tumour cells may have an osteoblastic lineage and retain the ability to differentiate into osteoblasts.

Analysis of Variance↗
PubMed2004

Does Doppler analysis of musculoskeletal soft-tissue tumours help predict tumour malignancy?

AIM: To investigate whether analysing vascularity of soft-tissue tumours on ultrasound assists differentiating benign from malignant tumours. MATERIALS AND METHODS: One hundred and forty-eight vascular soft-tissue tumours in 148 patients (88 males, mean age 45.6 years) were studied. Final diagnosis was established histologically in 95 (64%) of cases. For each tumour, three-colour Doppler imaging features (vascularity, vascular density, vascular organization) and 13 pulsed Doppler (spectral analysis) parameters were assessed. Data analysis was performed to isolate optimal discriminatory criteria for differentiating benign from malignant tumours. RESULTS: Significantly more benign soft-tissue tumours had an organized vascular pattern on colour Doppler imaging. If the vascular pattern is organized, this is a good indicator of tumour benignity. However, this pattern was apparent in less then one-third of the soft-tissue tumours. Benign tumours also had significantly higher minimum end diastolic velocity (EDVmin) and lower mean ratio of resistive index (RImean) than malignant soft-tissue tumours, though considerable overlap existed between the two groups. CONCLUSION: Colour Doppler imaging analysis of soft-tissue tumours is of limited value when differentiating benign from malignant tumours. If an organized vascular pattern is present, the tumour is more likely to be benign. Flow characteristics were not specific enough to be applicable in clinical practice.

Adolescent↗
PubMed2004

Primary osteochondrorhabdomyosarcoma (malignant mesenchymoma) of the fibula: a rare tumour in an unusual site -- case report and review of the literature.

Malignant mesenchymoma, defined by Stout as sarcomas comprising two or more unrelated differentiated tissue elements other than a fibrosarcoma component, is rare. We report a case of primary malignant mesenchymoma of the proximal fibula in a 10-year-old female student who presented with pain and swelling of the right knee for 2 months. Initial biopsy showed features of rhabdomyosarcoma only, but the resected specimen revealed additional osteosarcomatous and chondrosarcomatous elements. The patient remained well more than 5 years after initial presentation. Including our present patient, 16 cases of primary malignant mesenchymoma of bone are found in the English literature, affecting mainly adolescents and young adults, with a slight male predominance and predilection for the metaphysis of long bones, especially around the knee. More than 60% of the patients develop metastasis, almost invariably to the lung, but occasionally to the brain. About 60% of the patients, all with metastasis, died mostly within one year of diagnosis. The clinical features of primary malignant mesenchymoma of bone thus resemble those of conventional osteosarcoma. Moreover, our case illustrates that, with combination chemotherapy targeted for individual elements, the prognosis of this rare tumour might be much improved, as in osteosarcoma.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed2004

Primary sclerosing epithelioid fibrosarcoma of the sacrum: a case report and review of the literature.

Sclerosing epithelioid fibrosarcoma is a rare tumour characterised histologically by a predominant population of epithelioid cells arranged in strands and nests, embedded in a fibrotic and hyalinised stroma. It is a low grade tumour with an indolent course. A 48 year old woman presented with a painful swelling over her back for six months. Investigation and biopsy revealed features of sclerosing epithelioid fibrosarcoma involving the left half of the sacrum, left sacro-iliac joint, and posterior part of the left ilium. Preoperative radiotherapy and wide location excision of the tumour were followed by metastatic recurrence of the tumour in the lung and scalp six years after initial presentation. The tumour showed typical histology of sclerosing epithelioid fibrosarcoma. The radiological features confirmed its primary location in the sacrum. The patient declined chemotherapy and died of disseminated disease eight years after initial presentation. Review of the literature confirms the fact that sclerosing epithelioid fibrosarcoma, despite its low grade, is a clinicopathologically distinct tumour with full malignant potential, the recurrence, metastasis, and mortality rate being 48%, 60%, and 35%, respectively. Sclerosing epithelioid fibrosarcoma can occur as a primary bone tumour, the clinical behaviour of which is probably similar to its soft tissue counterpart.

Fatal Outcome↗
PubMed2003

The effect of hyaluronan on osteoblast proliferation and differentiation in rat calvarial-derived cell cultures.

Hyaluronan (or hyaluronic acid, HA) is an essential component of extracellular matrices. It interacts with other macromolecules and plays a predominant role in tissue morphogenesis, cell migration, differentiation, and adhesion. The cell signaling functions of HA are mediated through the CD-44 receptor and are dependent upon the molecular weight of the polymer. We hypothesized that an HA of appropriate molecular weight alone in optimal concentration may induce osteoblast differentiation and bone formation. Enzyme-digested calvarial-derived mesenchymal cells from 2-day-old newborn rats were cultured with the addition of HA of three different molecular weights (2300, 900, and 60 kDa). We added, 0.5, 1.0, and 2.0 mg/mL HA for each molecular weight to the medium at the first plating of cells. After 7 to 20 days in culture, cell proliferation and differentiation were evaluated by measuring thymidine incorporation, alkaline phosphatase activity, and osteocalcin gene expression. The effects of HA on bone formation were examined by using Alizarin red staining for mineralization. The results showed that low molecular weight HA (60 kDa) significantly stimulated cell growth, increased osteocalcin mRNA expression in a dose-dependent manner, but showed no apparent effects on alkaline phosphatase activity and bone mineralization. On the other hand, high-weight HA (900 and 2,300 kDa) significantly increased all the parameters examined, particularly alkaline phosphatase activity, in a dose-dependent manner and stimulated cell mineralization to 126% and 119% of the controls, respectively, in the 1.0 mg/mL dose. Our findings suggest that HA has a molecular weight-specific and dose-specific mode of action that may enhance the osteogenic and osteoinductive properties of bone graft materials and substitutes due to its stimulatory effects on osteoblasts.

Alkaline Phosphatase↗
PubMed2003

Expression of VEGF and MMP-9 in giant cell tumor of bone and other osteolytic lesions.

This study aims to investigate the expression of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-9 (MMP-9) in giant cell tumor of bone (GCT) and other osteolytic lesions in bone. By using semi-quantitative RT-PCR, we showed that three major isoforms of VEGF (121, 165 and 189) were expressed in GCTs, with isoform 121 being the most abundant. The expression levels of VEGF and MMP-9 mRNA were significantly higher in advanced GCTs (stage II/III) than in stage I GCTs. We further elucidated the cellular localization of VEGF and MMP-9 gene transcripts in GCT and other osteolytic lesions using an in situ hybridization assay. The results showed that stromal tumor cells and osteoclast-like giant cells of GCT, fibrous stromal cells in anuerysmal bone cysts and fibrous dysplasia, and Langerhans-type giant cells as well as histocytes in eosinophillic granuloma, were all strongly positive for VEGF and MMP-9 mRNA expression. In a prospective study, we performed VEGF and MMP-9 immuno-staining on paraffin sections of pathological tissues harvested from 48 patients (14 GCT, 10 anuerysmal bone cysts, 10 eosinophillic granuloma, 4 fibrous dysplasia, 2 simple bone cyst, 2 osteomyelitis and 6 patients with fractured femoral head as control). The results showed that the differences in VEGF and MMP-9 expression between Stage I and other advanced Stages (II, III and recurrent) were highly significant (p<0.001), with advanced stages showing a higher mean expression. The difference between recurrent and Stage II and III lesions, was also statistically significant (p=0.03 for VEGF, and p=0.01 for MMP-9 expression), with recurrent lesions showing a higher mean expression of both VEGF and MMP-9. In conclusion, VEGF and MMP-9 expression in osteolytic lesions of bone co-relates well with the extent of bone destruction and local recurrence. Their expression may therefore provide some prognostic indication of the possible aggressive behavior of the underlying pathology.

Bone Cysts↗
PubMed2003

Massive intestinal hemorrhage resulting from a polypoid tumor in the sigmoid colon: an unusual complication of a giant cell tumor of the fifth lumbar vertebra.

STUDY DESIGN: Clinicopathologic study of a case of giant cell tumor of the spine. SUMMARY OF BACKGROUND DATA: Giant cell tumors of the spine are uncommon, accounting for 1.3-6.5% of all cases in various series. Because of their location, they may cause neurologic deficits. The treatment consists of excision or curettage and has been claimed to give good results. METHODS: A 33-year-old woman presented with low back pain in 1995; radiologic investigation and biopsy showed features of giant cell tumor involving the fifth lumbar and first sacral vertebrae. Wide excision was performed, but the tumor recurred in 1996 and was curetted. She developed massive intestinal bleeding in 1997 resulting from infiltration of the sigmoid colon by giant cell tumor in the form of a polypoid intraluminal mass. The involved segment of colon was resected, and the patient remained alive, although debilitated, 7 years after initial presentation. RESULTS: Examination of the tumor in the spine and the colon showed typical histology of giant cell tumor with no evidence of malignant transformation. The involved colon was freely mobile and away from the tumor of the spine. CONCLUSION: Giant cell tumor of the spine can result in unusual complication, massive intestinal hemorrhage in our case, which causes considerable morbidity.

Adult↗
PubMed2003

Receptor activator of NF-kappaB ligand (RANKL) is expressed in chondroblastoma: possible involvement in osteoclastic giant cell recruitment.

AIMS: Chondroblastoma is a rare, locally aggressive bone tumour that causes osteolytic destruction at the epiphyseal end of the affected bone. It is possible that tumour cells may stimulate osteoclastogenesis and osteolytic destruction through the production of receptor activator of NF-kappaB ligand (RANKL), which is a key molecule essential for regulating osteoclast formation and activity. Therefore, the expression of RANKL at both the mRNA and the protein level was investigated in chondroblastoma tumour tissue obtained from patients. METHODS: The expression of RANKL gene transcripts was analysed by the reverse transcription-polymerase chain reaction (RT-PCR), and the cellular localisation of RANKL mRNA and protein was demonstrated by means of in situ hybridisation and immunohistochemistry. RESULTS: RT-PCR analysis indicated that RANKL mRNA was present in all chondroblastoma specimens and normal cancellous bone samples, but not in normal articular cartilage and chondrosarcoma tissues. In contrast, gene transcripts of osteoprotegerin (OPG), the decoy receptor of RANKL, were detected in all types of tissues. The chondroid origin of neoplastic mononuclear cells in chondroblastoma was confirmed by positive S-100 immunohistochemical staining. Both RANKL mRNA and protein were exclusively expressed in these neoplastic mononuclear cells. CONCLUSIONS: These findings suggest that RANKL may be involved in the tumour cell induced recruitment of osteoclast-like cells and consequent osteolytic bone destruction in chondroblastoma.

Adolescent↗
PubMed2003

Local flap coverage for soft tissue defects following open repair of Achilles tendon rupture.

The authors assessed the long term clinical and functional results following local flap coverage (medial plantar flap, peroneal reverse flow island flap, posterior tibial reverse flow flap) in 11 patients who developed wound complications after open repair of a ruptured Achilles tendon. At the latest follow-up, seven patients had achieved a good result, having returned to their pre-injury activities. All patients were able to stand on tiptoes unaided, and were able to walk without aid. In our hands, local flaps are a reliable means of treating skin defects following open repair of subcutaneous ruptures of the Achilles tendon.

Achilles Tendon↗
PubMed2002

Closed retrograde nailing of pathological humeral fractures.

We treated 19 patients with 21 pathological humeral fractures secondary to metastatic disease. All patients were stabilized using retrograde Ender's nails. Open reduction was required in one patient and mean operative time was 40 min (range 30-65 min). All patients retained satisfactory elbow and shoulder function while 16 patients reported good pain relief. Functional recovery was rated as good in 15 patients, fair in three, and poor in one. In our experience the retrograde technique using Ender's nails provides secure stabilization with minimal morbidity, minimal blood loss, and short operative time, and is well suited for this category of patients.

Adult↗
PubMed2002

Pseudoaneurysm complicating osteochondromas: symptom relief with embolization.

Pseudoaneurysm is a recognized vascular complication of osteochondromas. The diagnosis is confirmed by various imaging techniques including ultrasound, magnetic resonance imaging, and conventional angiography. Surgical repair and excision of the adjacent osteochondroma is considered the treatment of choice. The authors report a case of successful transarterial embolization using helical microcoils in the treatment of osteochondroma-related pseudoaneurysm of the superficial femoral artery. It resulted in complete obliteration of blood flow to the pseudoaneurysm and good symptomatic relief before subsequent semielective surgery. No complication was encountered during the procedure. Transarterial embolization is a safe mode of treatment in experienced hands. In patients with contraindications to surgery, embolization may be considered a definitive treatment.

Adolescent↗
PubMed2001

Gene expression of glucocorticoid receptor alpha and beta in giant cell tumour of bone: evidence of glucocorticoid-stimulated osteoclastogenesis by stromal-like tumour cells.

Glucocorticoids have been shown to increase bone resorption in vitro and in vivo, however, the mechanism(s) of this action are not fully understood. Given that human giant cell tumour of bone (GCT) is considered to arise from mesenchymal stromal cells and has the capacity to recruit and harbour macrophages and multinucleated osteoclasts, we have used GCT as a model for studying the effect of glucocorticoids on osteoclast formation. We have demonstrated, by RT-PCR and fluorescence in-situ hybridisation, that both glucocorticoid receptor alpha and beta (GRalpha and GRbeta) gene transcripts were present in the stromal-like tumour cells, macrophage-like cells (putative osteoclast precursors) and multinucleated osteoclast-like cells. Moreover, in the presence of 1,25(OH)(2)D(3), dexamethasone dose-dependently stimulated the formation of osteoclast-like cells from GCT-derived co-culture system of stromal-like tumour cells and macrophage-like cells. The stimulation of osteoclastogenesis by dexamethasone was coincident with the up-regulation of receptor activator of NF-kappaB ligand (RANKL) but down-regulation of osteoprotegerin (OPG) gene expression in stromal-like tumour cells. These data are consistent with the hypothesis that glucocorticoids increase bone resorption by promoting osteoclastogenesis which is at least in part due to the stimulation of RANKL and inhibition of OPG production in bone stromal cells.

Cells, Cultured↗
PubMed2001

Alveolar soft-part sarcoma: a rare soft-tissue malignancy with distinctive clinical and radiological features.

Alveolar soft-part sarcoma (ASPS) is a rare tumour. Certain distinctive clinical and radiological features suggest the correct diagnosis. There is moderate predilection for young women. ASPS almost always arises in skeletal muscle and occurs most frequently in the lower limbs. There is often a long clinical history and a large mass at presentation. Two young females with ASPS presented with very vascular tumours in the thigh, with prominent intra- and extra-tumoural blood vessels. The imaging findings and the existing literature are reviewed.

Adolescent↗
PubMed2001

Clinical significance of P-glycoprotein immunohistochemistry and doxorubicin binding assay in patients with osteosarcoma.

In 45 osteosarcoma patients, mean age 18 (4-61) years and followed for 14 (5-48) months, we studied the sensitivity to doxorubicin as well as P-glycoprotein expression, and compared these with the extent of tumour necrosis following chemotherapy. Doxorubicin assay was positive in 37 patients in whom necrosis induced by chemotherapy was good in 20 and poor in 17. Metastases developed in nine patients. In eight patients in whom doxorubicin assay indicated tumour resistance, chemonecrosis was poor and all developed pulmonary metastases. P-glycoprotein was studied in pre-treatment biopsies and post-treatment resection specimens. Its expression was positive in 16 patients in whom the necrosis induced by chemotherapy was good in four and poor in 12. In 29 patients with negative P-glycoprotein expression, necrosis was good in 16 and poor in 13. The doxorubicin sensitivity had a high correlation with chemonecrosis (P=0.006) and the incidence of metastases (P<0.001). However, P-glycoprotein expression at the time of diagnosis did not correlate statistically with chemonecrosis (P=0.066). Doxorubicin sensitivity prior to treatment is a better determinant of the response to chemotherapy and clinical outcome than is the P-glycoprotein expression.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Kaposiform hemangioendothelioma: five patients with cutaneous lesion and long follow-up.

Kaposiform hemangioendothelioma is a rare locally aggressive vascular tumor of the skin, deep soft tissue, and bone in children, characterized by infiltrating nodules and sheets of spindle cells, and unmistakable resemblance to Kaposi's sarcoma. More than 60 patients with such tumor have been reported so far, and while many have died as a result of extensive disease and severe coagulopathy, the long-term biologic behavior of this tumor remains undetermined. We describe five patients with kaposiform hemangioendothelioma and a mean follow-up of 19 years, ranging from 8 to 35 years. This report emphasizes on the importance of cutaneous lesions being the most commonly affected site, but also for its clinical diversity. Early diagnosis is possible even for a small skin lesion, which may be critical for the treatment of a potentially fatal deep-seated extensive tumor. All five patients are well, and three of them with persistent vascular tumor, which has carried two patients from childhood to adult. Although the behavior of this tumor might have been modified by radiation or interferon in three patients, this series indicates that kaposiform hemangioendothelioma is incapable of metastasis, despite a protracted course of many decades with no tendency for spontaneous regression.

Adult↗