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T Holmström

Publications and source records attributed to T Holmström.

At least 19 recordsLinked to original sources
PubMed2003

Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders.

From 1990 to 1997, 113 eligible patients with classical osteosarcoma received neo-adjuvant chemotherapy consisting of high-dose methotrexate, cisplatin and doxorubicin. Good histological responders continued to receive the same therapy postoperatively, while poor responders received salvage therapy with an etoposide/ifosfamide combination. With a median follow-up of 83 months, the projected metastasis-free and overall survival rates at 5 years are 63 and 74%, respectively. Independent favourable prognostic factors for outcome were tumour volume < 190 ml, 24-h serum methotrexate > 4.5 microM and female gender. The etoposide/ifosfamide replacement combination did not improve outcome in the poor histological responders. In conclusion, this intensive multi-agent chemotherapy results in > 70% of patients with classical osteosarcoma surviving for 5 years. The data obtained from this non-randomised study do not support discontinuation and exchange of all drugs used preoperatively in histological poor responders. As observed in previous Scandinavian osteosarcoma studies, female gender appears to be a strong predictor of a favourable outcome.

Adolescent↗
PubMed1999

Modulation of peripheral blood mononuclear cell activation status during Salmonella-triggered reactive arthritis.

OBJECTIVE: To determine the activation status of mononuclear cells in the peripheral circulation during the acute phase and the recovery phase of Salmonella-triggered reactive arthritis (ReA). METHODS: Peripheral blood mononuclear cells (PBMC) were obtained from 8 patients with Salmonella infection (4 with ReA and 4 without) and were studied by reverse transcription-polymerase chain reaction for messenger RNA (mRNA) of proinflammatory and antiinflammatory cytokines, by flow cytometry (FC) for cell surface activation and adhesion molecules, by immunofluorescence (IF) microscopy for bacterial antigens, and by FC, IF, and DNA fragmentation on gel for signs of apoptosis. RESULTS: During the acute phase of the infection, PBMC were activated in all patients, as characterized by high levels of expression of CD14, CD11b, and CD11c on monocytes. In the patients with ReA, PBMC also had the capacity to produce interleukin-1beta (IL-1beta), IL-6, IL-8, IL-10, and tumor necrosis factor alpha. During the amelioration of disease, monocyte activation was decreased in all patients. A complete down-regulation of CD14 was detected only in the patients with ReA, whereas the expression of CD14 in the patients without ReA was positive and was similar to that in healthy controls. In addition, cytokine mRNA levels decreased regardless of the presence of Salmonella antigens in blood cells in all 4 patients with ReA. CONCLUSION: High levels of expression of some activation and adhesion molecules and elevated levels of mRNA for certain cytokines that are predominantly produced by monocytes were found in PBMC from patients with acute Salmonella-triggered ReA, which suggests that these cells are activated. On the other hand, complete down-regulation of CD14 and a marked decrease in the cytokine production capacity during amelioration of the disease suggest that suppression of PBMC activity might be involved in recovery from ReA.

Acute-Phase Reaction↗
PubMed1999

Diagnosis and tumor response in osteosarcoma and Ewing's sarcoma, according to treatment protocols SSG II, SSG VIII, ISG/SSG I, SSG IV and SSG IX.

114 patients with osteosarcoma in the extremities had been reported to the SSG II trial, 132 to the SSG VIII trial and, until October 1998, 99 to the ISG/SSG I trial. The SSG IV trial included 53 patients and the SSG IX trial 104 patients until October 1998. In the SSG II trial, 19% were good responders (grades III and IV) as compared to 51% in the SSG VIII trial. On reevaluation was the response changed in one forth of the cases in both the SSG II and SSG VIII trials. In 9 and 10 cases (8%), respectively, the reevaluation resulted in a change from "good responder" to "bad responder". In the ISG/SSG I trial, the preliminary results showed a good response in 22% of the cases. In the SSG IV trial, 44% were good responders (grades III and IV), as compared to 54% in the SSG IX trial.

Antineoplastic Agents↗
PubMed1998

Enhancement of fibroblast collagenase-1 (MMP-1) gene expression by tumor promoter okadaic acid is mediated by stress-activated protein kinases Jun N-terminal kinase and p38.

Collagenase-1 (matrix metalloproteinase-1, MMP-1) is expressed by several types of cells, including fibroblasts, and apparently plays an important role in the remodeling of collagenous extracellular matrix in various physiologic and pathologic situations. Here, we have examined the molecular mechanisms of the activation of fibroblast MMP-1 gene expression by a naturally occurring non-phorbol ester type tumor promoter okadaic acid (OA), a potent inhibitor of serine/threonine protein phosphatase 2A. We show that in fibroblasts OA activates three distinct subgroups of mitogen activated protein kinases (MAPKs): extracellular signal-regulated kinase1,2 (ERK1,2), c-Jun N-terminal-kinase/stress-activated protein kinase (JNK/SAPK) and p38. Activation of MMP-1 promoter by OA is entirely blocked by overexpression of dual-specificity MAPK phosphatase CL100. In addition, expression of kinase-deficient forms of ERK1,2, SAPKbeta, p38, or JNK/SAPK kinase SEK1 strongly inhibited OA-elicited activation of MMP-1 promoter. OA-elicited enhancement of MMP-1 mRNA abundance was also strongly prevented by two chemical MAPK inhibitors: PD 98059, a specific inhibitor of the activation of ERK1,2 kinases MEK1,2; and SB 203580, a selective inhibitor of p38 activity. Results of this study show that MMP-1 gene expression in fibroblasts is coordinately regulated by ERK1,2, JNK/SAPK, and p38 MAPKs and suggest an important role for the stress-activated MAPKs JNK/SAPK and p38 in the activation of MMP-1 gene expression. Based on these observations, it is conceivable that specific inhibition of stress-activated MAPK pathways may serve as a novel therapeutic target for inhibiting degradation of collagenous extracellular matrix.

3T3 Cells↗
PubMed1998

Liquid ionization chambers for absorbed dose measurements in water at low dose rates and intermediate photon energies.

Two new liquid ionization chamber (LIC) designs, consisting of cylindrical and plane-parallel configurations, are presented. They are designed to be suitable for high-precision measurements of absorbed dose-to-water at dose rates and photon energies typical for LDR intermediate photon energy brachytherapy sources. The chambers have a sensitive liquid layer thickness of 1 mm and sensitive volumes of 7 mm3 (plane-parallel) and 20 mm3 (cylindrical). The liquids used as sensitive media in the chambers are either isooctane (C8H18), tetramethylsilane (Si(CH3)4) or mixtures of these two liquids in the approximate proportions 2 to 1. A chamber filled with such a liquid mixture and with a polarizing voltage of 300 V, provides a volume sensitivity of about 10(-9)C Gy(-1) mm(-3) for absorbed dose measurements in water in an x-ray radiation field with an effective photon energy of 120 keV. In the interval 30 to 140 keV, the relative change in sensitivity is less than +/- 2.5%. The leakage current of the chambers is low and stable, which implies that absorbed dose measurements can be done with good reproducibility at dose-rates as low as 50 microGy min-1 (sigma < 3%). The long-term calibration stability was tested for a set of five chambers over a period of more than 1 year. No systematic change in their sensitivity could be observed. The general recombination at a polarizing voltage of 300 V is less than 2% for dose-rates up to about 100 mGy min-1. The temperature dependence at room temperature is 0.5% per degree C. The response is almost independent of the direction of the radiation for the plane-parallel LIC.

Biophysical Phenomena↗
PubMed1997

Three-year follow-up of the use of a levonorgestrel-releasing intrauterine system in hormone replacement therapy.

BACKGROUND: The efficacy of a levonorgestrel-releasing intrauterine system in opposing endometrial proliferation and in preventing bleeding was studied in peri- and postmenopausal women receiving estrogen replacement therapy. METHODS: This was an open, non-controlled follow-up study of the use of a levonorgestrel-releasing intrauterine system during continuous estrogen replacement therapy carried out by using oral, transdermal or subdermal estradiol. The efficacy of the progestin therapy was evaluated by transvaginal ultrasonography and by examination of endometrial biopsy samples taken 20 months (mean, range 17 - 22; first evaluation) and 34 months (mean, range 31 - 38 months; second evaluation) after insertion of the levonorgestrel-releasing intrauterine system, and by studying patterns of bleeding. Twenty-five women participated in the first evaluation, and 29 in the second. RESULTS: Seventy-six percent of the women were amenorrheic at the first evaluation, and 79% at the second evaluation. Others had spotting for 1-2 days monthly or less often. The mean time until amenorrhea was reached was 6 months (range 2-13 months) after insertion of the levonorgestrel-releasing intrauterine system. The median endometrial thickness assessed by ultrasound was 2 mm at both evaluations. No signs of proliferation were observed in any of the endometrial samples. CONCLUSIONS: Local progestin delivery via a levonorgestrel-releasing intrauterine system was effective in suppressing the endometrium and in eliminating bleeding in women receiving estrogen replacement therapy, and the intrauterine progestin therapy was also well accepted.

Aged↗
PubMed1996

Lamin and beta-tubulin fragmentation precede chromatin degradation in glutamate-induced neuronal apoptosis.

During ischaemic brain injury, glutamate accumulation with overstimulation of postsynaptic glutamate receptors and intracellular Ca2+ overload lead to neuronal death. We have shown previously that delayed neuronal death in cultures of cerebellar granule cells (CGCs) exposed to glutamate occurs by apoptosis. Here, we report that lamin cleavage and dissolution of the microtubule network precede chromatin fragmentation in glutamate-induced CGC apoptosis. Like other events that characterize excitotoxic cell death, degradation of lamins, beta-tubulin and disruption of microtubule architecture is inhibited by the NMDA-receptor antagonist MK-801. Our findings suggest that cleavage of key cytoskeletal elements is an important step in glutamate-induced neuronal apoptosis.

Animals↗
PubMed1996

Endometrial response to hormone replacement therapy as assessed by expression of insulin-like growth factor-binding protein-1 in the endometrium.

OBJECTIVE: To assess endometrial response to parenteral levonorgestrel in hormone replacement therapy by means of morphological criteria and immunohistochemical staining of insulin-like growth factor-binding protein-1 (IGFBP-1). DESIGN: Endometrial samples were collected from 35 postmenopausal women after 12 to 22 months of continuous combined estrogen-progestin therapy. All subjects were treated with parenteral progestin. A group of 8 women was treated with a subdermal levonorgestrel-releasing implant, and 27 women had a levonorgestrel-releasing intrauterine device (IUD). Sections of formalin-fixed paraffin-embedded biopsies were used for immunohistochemistry and after hematoxylin-eosin staining for routine histologic examination. RESULTS: Atrophic epithelium with pronounced decidual reaction in the stroma was detected by histologic examination in all endometrial samples obtained from 27 women treated with the levonorgestrel-releasing IUD. In contrast, the endometrium was proliferative in seven of eight (87.5 percent) biopsies obtained from women treated with the levonorgestrel-releasing implant. Immunoreactive IGFBP-1 was detected in decidualized stromal cells in all endometrial samples obtained during intrauterine levonorgestrel therapy, whereas only one of eight samples obtained from women treated with subdermal levonorgestrel exhibited weak staining for IGFBP-1. CONCLUSIONS: Our data show that both the morphological and biochemical response of post- menopausal endometrium to parenteral levonorgestrel was strikingly different, depending on the route of progestin administration, and that the decidual reaction and epithelial atrophy induced by intrauterine levonorgestrel were associated with expression IGFBP-1 in decidualized stromal cells.

Atrophy↗
PubMed1995

Intrauterine and subdermal progestin administration in postmenopausal hormone replacement therapy.

OBJECTIVE: To compare the effects of intrauterine and subdermal administration of levonorgestrel on control of bleeding and on the endometrium in postmenopausal hormone replacement therapy. INTERVENTIONS: Nineteen women started continuous oral E2 valerate therapy (2 mg daily) together with continuous parenteral progestin therapy. The subjects randomly received either a subdermal levonorgestrel-releasing implant (n = 9) or an intrauterine device (IUD) releasing levonorgestrel (n = 10). MAIN OUTCOME MEASURES: Serum concentrations of estrone, E2, FSH, sex hormone-binding globulin (SHBG) and levonorgestrel were followed. Endometrial biopsies and transvaginal ultrasonography were used to evaluate the endometrium. The subjects kept daily records of bleeding. The observation time was 1 year. RESULTS: Serum concentrations of the hormones mentioned above and SHBG were similar in both groups during the observation time, but the patterns of bleeding differed. In the IUD group there were 0.9 days (mean, range 0 to 4 days) of spotting and no days of bleeding during the last month of the follow-up year. In the implant group there were 8 days (mean, range 0 to 25 days) of spotting and 3.4 days (mean, range 0 to 14 days) of bleeding. In histological examination there was uniform atrophy in the endometrial samples from the IUD group, and a weak or absent progestin effect in the implant group. CONCLUSIONS: In spite of similar serum levonorgestrel concentrations, local intrauterine administration of levonorgestrel resulted in better control of bleeding and in more effective endometrial suppression than subdermal administration.

Administration, Cutaneous↗
PubMed1995

Properties of liquid ionization chambers at LDR brachytherapy dose rates.

Properties such as sensitivity, general recombination and reproducibility of liquid-filled parallel-plate ionization chambers for dosimetry in low-dose-rate brachytherapy radiation fields have been evaluated. Two different dielectric liquids, isooctane (C8H(1)8) and tetramethylsilane (Si(CH3)4), have been used as sensitive media in chambers having a coin-shaped sensitive volume of 3 mm in diameter and 1 mm thickness. An electric field strength of 300 kV m-1 was found to be optimal with respect to sensitivity, leakage current and general recombination. At absorbed dose rates from 0.1-100 mGy min-1 the ionization charge measurements at an irradiation time of 1 min showed a reproducibility better than 1%, and a general recombination not exceeding 0.5%. The calibration--absorbed dose to water against ionization charge at a 60Co reference source--did not show any significant change over an observation time of one year for any of the chambers.

Brachytherapy↗
PubMed1993

Different healing patterns of experimental osteotomies treated by intramedullary nailing.

The healing of 52 diaphyseal osteotomies in rabbit tibiae was followed up histologically from 3 to 24 weeks after rigid intramedullary nailing. The histological evaluation was made from longitudinal sections through the osteotomy area. Particular attention was paid to the fracture healing pattern. A bulky periosteal response was visible in every specimen. At 24 weeks, the external callus was always well remodeled. The osteotomy line rapidly filled with bone from 6 weeks onwards. At 24 weeks, the site of osteotomy was detectable only on the basis of slight irregularity in the cortex. The secondary gap healing seen in 19 specimens was the most common type of bone union from 6 weeks onwards. In 13 specimens, the exact type of osteonal healing was not definable, since a solid union with good cortical reconstruction was always the final outcome. Altogether, four nonunions were detected throughout the study, none of these, however, in the specimens at 24 weeks. Considerable endosteal resorption was detected at 24 weeks, at which time at least one third of the original cortex had disappeared in all specimens. The rigid nail seems to ensure a relatively uneventful healing of the experimental osteotomies. Vast endosteal resorption and some nonunions make the use of medullary reaming in this connection doubtful.

Animals↗
PubMed1993

Biologic anchorage of cruciate ligament prosthesis. Bone ingrowth and fixation of the Gore-Tex ligament in sheep.

The biologic fixation and strength of fixation of the polytetrafluoroethylene (PTFE) Gore-Tex ligament prosthesis was investigated in sheep knees. The device was inserted to replace the anterior cruciate ligament according to the recommended technique. Histological bone tunnel evaluation together with mechanical tensile studies were done at 6, 12, and 18 months. Already at 6 months the pull-out load of the prosthesis exceeded that of the normal ligament, and this finding persisted up to 18 months postoperatively. At 6 months there was marked fibrous tissue ingrowth into the prosthesis, and at 12 months trabecular bone had replaced the fibrous tissue between the interstices of the filaments; at 18 months bone even penetrated into the individual porous fibers of the prosthesis. The intra-articular part of the prosthesis was surrounded and partly invaded by undifferentiated connective tissue, with no recognizable macrophages or other inflammatory cells. In this experiment, the biocompatibility and porosity of the Gore-Tex prosthesis seemed optimal to permit ingrowth from surrounding fibrous and osseous tissues and firm anchorage into the bone tunnels.

Animals↗
PubMed1993

Clodronate reduces plate osteopenia in the rabbit.

An osteosynthesis with a four-hole AO/ASIF-DCP plate was performed on the right tibia of 40 rabbits. Clodronate (50 mg/kg s.c.) was given once a week, resulting in a mean bone concentration of 509 micrograms/g in 2 hours. Plate fixation caused a decrease in mean net cross-sectional area of compact cortical bone of 17 percent at 9 weeks and 46 percent at 18 weeks. This resulted from bone resorption in bone under the plate, from pronounced cavitation in the plated bone (about 5 percent of cortical bone area at 9 weeks and 15 percent at 18 weeks), and from the fact that the medullary space was increased by 15 percent at 18 weeks. The total cross-sectional area of the diaphysis was increased by 31 percent at 9 weeks and by 17 percent at 18 weeks. Clodronate treatment reduced cortical porosity to about half of the mean values in the placebo group. Clodronate increased both the calcium content in the retained bone and the cross-sectional area of compact cortical bone, but induced only an insignificant increase in the area of periosteal new bone. Clodronate treatment seems not to be contraindicated in conjunction with rigid osteosynthesis, and may even slow down the osteopenic response occurring under the rigid plate.

Animals↗
PubMed1993

Intramedullary nailing and cortical bone mineral content. Photon absorptiometry measurements in vitro.

A transverse diaphyseal osteotomy of the tibia was stabilized using rigid intramedullary nailing in rabbits. In a 2nd group, nailing was performed without osteotomy. The rabbits were sacrificed 3 to 24 weeks postoperatively, and the nails were removed. The mineral content (BMC) was measured by dual photon absorptiometry and the mineral density (BMD) was calculated. At 24 weeks the osteotomized bones had significantly lower BMC values than did the respective nonosteotomized bones or the intact bones. The BMC of the nonosteotomized bones remained above the control level throughout the experiment. The minimum BMD values of the osteotomized bones were detected at 3 weeks, whereafter they gradually approached the control level over time. The results suggest that rigid intramedullary nailing in connection with osteotomy causes a significant decrease in cortical bone mineral mass, seen at 24 weeks postoperatively. The photon absorption method used seemed sensitive enough to detect changes in cortical bone mineral quantity in these experimental conditions.

Absorptiometry, Photon↗
PubMed1992

Endometrial effect of transdermal estradiol and progestin ST-1435 in postmenopausal women.

OBJECTIVE: To study the endometrial effect of the transdermal synthetic progestin ST-1435. DESIGN: Prospective. SETTING: City Maternity Hospital, Helsinki, Finland. PATIENTS: Eleven postmenopausal women used transdermal estradiol (E2) patches for 6 weeks immediately before a vaginal operation for prolapse. For the last 10 days, 1 mg of ST-1435 transdermally in a gel was combined to the treatment. MAIN OUTCOME MEASURES: Blood samples were taken to follow serum concentrations of E2, follicle-stimulating hormone, and ST-1435. Endometrial samples for histologic examination were collected during the operation to evaluate the effect of the progestin. RESULTS: Transdermal absorption of ST-1435 resulted in reasonably constant serum concentrations of ST-1435 in each subject. A progestin effect on the endometrium was seen in 9 of 10 samples obtained. One sample did not show any progestin effect in spite of adequate ST-1435 levels, but this patient's E2 concentrations were low. CONCLUSIONS: When the estrogen stimulation was adequate, the transdermal ST-1435 induced a progestin effect on the endometrium, i.e., it had an end-organ effect.

Administration, Cutaneous↗
PubMed1991

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.

Adolescent↗