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P S Thorner

Publications and source records attributed to P S Thorner.

At least 37 records · Page 2Linked to original sources
PubMed1994

An assessment of postnatal growth after in utero long bone osteotomy with fixation.

Researchers have recently suggested that rigid fixation of the immature bony skeleton may restrict growth and development. This study assesses the effect on postnatal growth of an in utero tibial osteotomy fixed with a miniplate in fetal sheep. A midshaft osteotomy was performed on fetal sheep tibia (n = 5) at 95 days' gestation (term 145 days). One tibia was reduced and fixed with a titanium miniplate and screws, while the contralateral hindlimb served as a control. The newborns were vaginally delivered and sacrificed at 2 months of age. The hindlimbs, control and fractured, were harvested, stripped of soft tissue, and the tibia, femur, and distal metatarsal were each measured and weighed. Each tibia also underwent radiographic analysis and histologic examination (after decalcification) using hematoxylin and eosin, Sirius red, and Alcian blue stains. No prenatal, postnatal, or perioperative medical complications occurred. Apart from a slight angulation in one operated tibia, no gross morphologic differences, either visible or palpable, were found between the operated and control limbs. This was confirmed radiographically where no remnant of the osteotomy site was visible. Measurements of the operated and control tibias, femurs, and metatarsal bones were not statistically different. Histologic analysis showed a total incorporation of bone at the osteotomy site with appositional growth present. All bone was lamellar with longitudinal orientation. In the area of the screw sites, the surrounding bone shaft was the same width as its neighboring bone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Multidrug resistance. Clinical opportunities in diagnosis and circumvention.

Increased P-glycoprotein expression has been shown to be the molecular cause of multidrug resistance in tumor cell lines. Sensitive immunohistochemical and molecular biologic techniques have been developed to detect P-glycoprotein/mdr1 mRNA expression in clinical samples of tumors. We have reviewed the tools now available for assessment of P-glycoprotein expression in the clinic, the current evidence for a relevant role of the protein in mediation of resistance to chemotherapy, and one strategy used to overcome therapeutic failures due to multidrug resistance. It is now recognized that low levels of increased P-glycoprotein/mdr1 mRNA can occur at diagnosis and during the course of treatment in some cases of acute myelogenous leukemia, non-Hodgkin's lymphoma, multiple myeloma, breast carcinoma, rhabdomyosarcoma and undifferentiated sarcoma of children, neuroblastoma, and retinoblastoma, and these relatively low levels of mdr1 overexpression appear to be associated with poor prognosis. In contrast, it has not been established whether a multidrug resistance mechanism is the rate-limiting factor in response to chemotherapy in carcinomas that arise from tissues normally expressing increased P-glycoprotein. Clinical trials have been initiated to determine whether pharmacologic chemosensitization improves the outcome of chemotherapy-treated malignancies. Preliminary results suggest that chemosensitizers can modulate the effects of increased P-glycoprotein in low-expressing tumors for which effective multiagent chemotherapy is available. Further research is needed for more potent chemosensitizers or combinations of agents that can be used more effectively. The successful circumvention of chemotherapy failure by chemosensitizers will ultimately establish the clinical relevance of the P-glycoprotein efflux mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

A sensitive multilayer immunoalkaline phosphatase method for detection of P-glycoprotein in leukemic and tumor cells in the bone marrow.

BACKGROUND: Relatively low levels of the multidrug resistance P-glycoprotein have correlated with poor prognosis in rhabdomyosarcoma, neuroblastoma, acute myelogenous leukemia, lymphoma, myeloma and breast carcinoma. A sensitive, nonradioactive method, less costly and time-consuming than the present molecular biologic techniques, is desirable for direct measurement of P-glycoprotein in tumor cells versus normal cells. EXPERIMENTAL DESIGN: We have devised an immunoalkaline phosphatase method using four antibody layers to amplify the primary signal considerably and refined staining conditions to optimize the 'signal-to-noise' ratio. Immunoalkaline phosphatase is preferred to immunoperoxidase for testing leukemic and tumor cells in bone marrow, because it avoids myeloperoxidase staining in myeloblasts and myeloid progenitors that interferes with P-glycoprotein interpretation. RESULTS: Multilayer immunoalkaline phosphatase detected low levels of P-glycoprotein overexpression, that could not be identified by conventional immunoperoxidase or immunoblot, in a low-resistance (8-fold) cell line with a barely detectable transcript. Our technique also detected increased P-glycoprotein in malignant cells in bone marrow of relapsed acute lymphoblastic leukemia (10/11), acute myelogenous leukemia (2/2), lymphoma (1/1), neuroblastoma (7/7), and rhabdomyosarcoma (2/2). Increased P-glycoprotein was not identified at diagnosis in 6 patients with acute lymphoblastic leukemia, and two with stage IV and three with stage IVS neuroblastoma that remained relapse-free in the long-term, but was detected in 4 patients with stage IV neuroblastoma and three with rhabdomyosarcoma who ultimately relapsed. CONCLUSIONS: Our new technique is more sensitive than conventional immunoperoxidase and immunoblot for assaying P-glycoprotein in low-resistance cell lines. It may be potentially applicable for detecting low levels of P-glycoprotein overexpression in leukemic and tumor cells in bone marrow. Early identification of low levels of multidrug resistance may be clinically relevant by allowing poor-prognostic patients to receive alternative therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1993

Fetal bone gap healing in utero.

The healing of fetal tibial bone after osteotomy with and without stable fixation has been reported previously. The present study was designed to evaluate fetal bone gap healing using a tibial ostectomy model in fetal sheep. Eighteen time-dated pregnant ewes (20 fetuses, 34 experimental hind limbs) underwent intrauterine surgery at 95 days gestation (term, 145 days). A titanium miniplate was applied to the anterior aspect of the tibia and a longitudinal length of bone approximately 1.5 times its diameter was removed and the incision closed. The pregnancies were then allowed to progress until the ewe was killed at postoperative weeks 1, 2, 4, or 7. Assessments at that time included evaluation of gross morphology, histologic and radiologic appearance, and collagen analysis and hydroxyproline determination of the tissue within and at the borders of the gap. At 7 weeks, seven of nine bone gap specimens exhibited radiographic and histologic evidence of union with woven and lamellar bone. Hydroxyproline concentrations gradually increased within the bone gap over the period of the study. At all intervals, type I collagen composed over 90% of the collagen within the healing bony gap. Histologically and biochemically, the process appears to be similar to postnatal bone healing, albeit occurring at an accelerated rate.

Animals↗
PubMed1993

Extremity osteosarcoma in childhood: prognostic value of radiologic imaging.

PURPOSE: To evaluate previously described radiologic prognostic factors in extremity osteosarcoma. MATERIALS AND METHODS: In 47 pediatric patients, available images were evaluated for seven prognostic factors at diagnosis and seven additional factors after preoperative chemotherapy. These factors were correlated with histopathologic response and clinical outcome. The association of histopathologic response and outcome was also evaluated. RESULTS: Metastases at presentation and a > 20-cm-diameter soft-tissue mass were predictive of a poor outcome but occurred in few patients. Factors most predictive of < 90% tumor necrosis after chemotherapy included an increase or no change in soft-tissue mass size and increased bone destruction. Although a significant relationship (P < .05) was found between histopathologic response and outcome, no factors predictive of histopathologic response were also predictive of outcome. The accuracy of pathologic response in predicting outcome was 66%. CONCLUSION: Radiologic studies are of only limited use in predicting which patients with extremity osteosarcoma will have a poor response to chemotherapy or a poor outcome, and are not useful in predicting a good response or outcome.

Adolescent↗
PubMed1993

Fetal tibial bone healing in utero: the effects of miniplate fixation.

Although clinical and experimental findings have demonstrated that fetal soft-tissue wounds heal without scarring, very little is known about the process of fetal bone healing. This study examined fetal long bone healing in utero, both histologically and biochemically, with and without fracture fixation in a fetal sheep model. Our study group consisted of 25 live fetuses (from 16 ewes). There were 50 fetal tibias in this group; 12 were control, 17 were fixed (miniplate fixation), and 21 were nonfixed. A midshaft osteotomy of the tibia, either fixed or non-fixed, was performed on fetal sheep at 95 days' gestation (term = 145 days) in utero. The sheep were then killed at one of five postoperative time intervals (weeks 1, 2, 3, 4, and 7), and fetal bone healing was examined. The variables reviewed included gross morphology, histology, radiology, and collagen analysis (proportions of types II to I and III to I collagen). Fetal bone healing without fixation was accompanied by a large callus with rapid and abundant cartilage and collagen deposition. Bone healing was characterized by malunion or nonunion at 7 weeks. However, with miniplate and screw fixation, callus formation was minimal; primary bone healing occurred by 3 weeks and did not adversely affect long bone growth. Analysis of callus samples revealed a minimal amount of type III collagen, whereas the proportion of type II collagen was variable and proportional to the content of callus cartilage.

Animals↗
PubMed1992

Molecular genetic, cytogenetic, and immunohistochemical characterization of alveolar soft-part sarcoma. Implications for cell of origin.

BACKGROUND: Alveolar soft-part sarcoma is a rare tumor of uncertain histogenesis. METHODS: The authors report a patient who was studied using immunohistochemistry, cytogenetic analysis, and molecular probes for MyoD1 and MYCN (N-myc proto-oncogene). RESULTS: By immunoperoxidase, the tumor was focally positive for vimentin, neuron-specific enolase, and S-100 protein but negative for muscle-specific actin, desmin, and low-molecular-weight keratin. Direct chromosome analysis of primary tumor cells using G-banded preparations yielded two clonally abnormal lines: one demonstrated trisomy 47,XX+5; the other demonstrated 46,XX,1p-,17q+. Expression of the MYCN RNA was detectable at a low level, and MYCN was single copy at the DNA level. Expression of the myogenic molecular marker MyoD1 was not detected by Northern blotting analysis. CONCLUSIONS: This is the first detailed study to address the molecular biology and tumor cytogenetics of alveolar soft-part sarcoma. The results of this study indicate a neurogenic origin for this unusual tumor and fail to provide support for the notion of a myogenic origin.

Adolescent↗
PubMed1992

Iris sector heterochromia as a marker for neural crest disease.

A 6-month-old female infant with biopsy-proved Hirschsprung's disease had associated sector heterochromia of the irides. The association between sector heterochromia and Hirschsprung's disease has been previously reported and both conditions have been ascribed to neural crest defects. Histologic characteristics of the ocular involvement have not previously been reported, to our knowledge. Histopathologic examination of the globes revealed decreased iris stroma, decreased pigmentation in the anterior stroma, and reduced numbers of pigment-producing cells in the affected areas. Both the ocular and gastrointestinal findings reflect abnormalities in tissues of neural crest origin.

Female↗
PubMed1992

Production of anti-NC1 antibody by affected male dogs with X-linked hereditary nephritis: a probe for assessing the NC1 domain of collagen type IV in dogs and humans with hereditary nephritis.

Some patients with hereditary nephritis (HN) who have received a renal transplant have been shown to form antibody with specificity for the NC1 domain of collagen type IV, a major constituent of glomerular basement membranes (GBM). We attempted to duplicate this phenomenon in a family of dogs with X-linked HN, a model for human X-linked HN, by immunizing affected male dogs with normal dog NC1 domain. A collagenase digest was prepared from normal dog GBM, the NC1 domain was separated into dimer (approximately 50 kDa) and monomer (24 kDa and 26 kDa) components by SDS-PAGE, and injected into two affected male dogs. Antisera obtained from both dogs contained antibody which reacted with the NC1 domain of dog and human GBM by a plate-binding radioimmunoassay, bound to the dimer and 26 kDa monomer bands by Western blotting, and staining dog and human GBM by immunofluorescence (IF). The affected male dog antiserum reacted equally by radioimmunoassay with the NC1 domain isolated from GBM of unaffected, affected male, and carrier female dogs in the family with X-linked HN, and bound by Western blotting to dimers and the 26 kDa monomer band of the NC1 domain of GBM in each group of dogs. However, the affected male dog antiserum differentiated these dogs by IF; it produced global staining of GBM of unaffected dogs, failed to stain GBM of affected male dogs, and produced segmental staining of GBM of carrier female dogs. Absorption of the affected male dog antiserum with normal dog NC1 domain eliminated the staining of dog GBM by IF, whereas staining persisted after absorption with affected male dog NC1 domain. The abnormal staining patterns of GBM seen by IF in the affected male and carrier female dogs and the results of the absorption studies imply an abnormality of one or more determinants in the 26 kDa monomer band of the NC1 domain of their GBM. Amino acid sequencing of this band identified the alpha 1(IV) chain of collagen type IV, a finding that has implications for the pathogenesis of canine X-linked HN. Absent and segmental staining respectively were also seen by IF in GBM of a male and female patient with HN, using the affected male dog antiserum. Thus, the results obtained in affected male and carrier female dogs with X-linked HN may also be relevant to patients with this disease.

Amino Acid Sequence↗
PubMed1992

The contribution of antibody-mediated cytotoxicity and immune-complex formation to tubulointerstitial disease in passive Heymann nephritis.

Passive Heymann nephritis (PHN), an experimental model of membranous nephropathy, is produced by Fx1A antiserum, which also reacts with antigens on the brush border (gp 330) and basolateral membrane (gp 90) of proximal tubules. We examined tubulointerstitial disease in PHN, identifying two distinct processes occurring on the luminal and basolateral membranes, respectively. Injected antibody bound diffusely to the tubular brush border from Day 1 to Day 7, followed by sloughing of microvilli and tubular-cell regeneration. Fine granular deposits of Fx1A antibody were present along the basolateral cell membrane by Day 1. These deposits rearranged in situ, enlarged, and became more focally distributed along tubular basement membranes (TBM). Interstitial inflammation, dominated by macrophages (Ia+, ED-1+) in association with a smaller number of T-cytotoxic cells (OX19+, OX8+) began by Day 3, reached peak intensity and persisted throughout the autologous phase (to Day 21). The distribution of focal clusters of interstitial macrophages predominately in association with TBM-immune deposits was demonstrated. Complement depletion prevented proteinuria but TBM deposits developed and the interstitial inflammation was unchanged. All aspects of the tubulointerstitial disease were amplified by a second injection of Fx1A antiserum. In vitro, Fx1A antibody bound to the surface of isolated proximal tubular epithelial cells and redistributed to form clusters of immune aggregates. Anti-Fx1A-induced cytotoxicity of tubular cells was demonstrated by prelabeling cells with 2'-7'-bis(carboxyethyl)-5(6)-carboxyfluorescein. The degree of cytotoxicity was dependent on complement concentration and the duration of incubation at 37 degrees C. PHN induced by Fx1A antiserum causes tubular-cell injury following interactions with brush-border antigens and TBM immune-complex disease associated with interstitial inflammation. These findings may be relevant to the acute and chronic interstitial disease of human membranous nephropathy.

Albuminuria↗
PubMed1991

P-glycoprotein expression as a predictor of the outcome of therapy for neuroblastoma.

BACKGROUND AND METHODS: Multidrug resistance in chemotherapy for cancer is characterized by increased genetic expression of P-glycoprotein, which acts as an ATP-dependent drug-efflux pump. To determine whether P-glycoprotein levels are of prognostic value in such cases, we measured these levels immunohistochemically in a retrospective study of sequential tumor samples from 67 children with neuroblastoma. RESULTS: P-glycoprotein was not detected in pretreatment samples from either of the 2 patients with Stage I disease, any of the 21 with Stage II disease, or any of the 8 with Stage IVS disease, but it was detected in the samples from 1 of the 17 patients with Stage III disease (6 percent) and 12 of the 19 with Stage IV disease (63 percent). Of the 44 patients with nonlocalized neuroblastoma (Stage III, IVS, or IV), 26 of the 31 who were negative for P-glycoprotein had a complete response to primary treatment, as compared with 6 of the 13 who were positive for P-glycoprotein (84 percent vs. 46 percent, P = 0.0232 by Fisher's exact test). Log-rank analysis of outcome, with simultaneous stratification according to tumor stage and age, showed that the group that was negative for P-glycoprotein had significantly longer relapse-free survival (P = 0.0011) and overall survival (P = 0.0373) than the group that was positive. CONCLUSIONS: Expression of P-glycoprotein before treatment may predict the success or failure of therapy for nonlocalized neuroblastoma. Neuroblastoma may be a promising tumor to treat with anticancer drug therapy combined with a chemosensitizing agent capable of reversing P-glycoprotein-mediated multidrug resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Multidrug-resistant phenotype in retinoblastoma correlates with P-glycoprotein expression.

Chemotherapy plays an important role in therapy for patients with extraocular and metastatic retinoblastoma. The authors used chemotherapy for management of selected patients with uncontrolled intraocular tumors or tumors larger and more posteriorly located than those conventionally treated with local cryotherapy or photocoagulation. Rapid regrowth of some tumors after an initial excellent chemotherapy response led us to investigate the hypothesis that failure of treatment is caused by P-glycoprotein-related multidrug resistance. By using a sensitive immunoperoxidase method, increased P-glycoprotein was detected in five multidrug-resistant and two selectively plant alkaloid-resistant retinoblastoma cell lines and in the intraocular and metastatic tumors from which they were derived. In four chemotherapy-treated cases, increased P-glycoprotein in the tumor samples correlated with clinically relevant drug resistance. None of the four chemosensitive tumor cell lines had increased P-glycoprotein expression. Continuous surveillance of P-glycoprotein levels in metastatic retinoblastoma may be a useful guide to drug therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1991

Hairy polyp of the eustachian tube.

The hairy polyp of the nasopharynx is a rare but potential cause of airway obstruction in the newborn. A case of hairy polyp arising off the Eustachian tube is reported. Only eight prior cases of Eustachian tube origin have been described in the literature. The terminology and embryology of these tumors are included in the discussion. The site of the tumor and histopathology of this case supports the embryologic origin of a congenital inclusion cyst.

Dermoid Cyst↗
PubMed1990

Pulmonary syndrome in patients with thalassemia major receiving intravenous deferoxamine infusions.

Eight patients with transfusion-dependent thalassemia major were given continuous intravenous infusions of the chelator, deferoxamine mesylate, to reduce iron overload. Within 5 to 9 days of starting the infusions, four patients developed a pulmonary syndrome of moderate to life-threatening severity characterized by tachypnea, hypoxemia, and a diffuse interstitial pattern on chest roentgenogram. Pulmonary function studies showed restrictive dysfunction. Lung biopsy showed diffuse abnormalities with alveolar damage, interstitial fibrosis, and inflammation. The inflammatory infiltrate comprised lymphocytes, eosinophils, and mast cells. Exposure of the biopsy specimen to fluorescein-conjugated anti-IgE antibody showed fixation of IgE to the mast cell surface, suggesting a hypersensitivity reaction. Detailed studies failed to identify an infectious agent. The temporal relationship between drug administration and lung disease, and the clinical similarities in the four affected patients, strongly suggested a cause and effect relationship. We recommend that therapy with continuous intravenous infusions of deferoxamine be monitored carefully with respect to pulmonary status.

Adolescent↗
PubMed1990

A study by immunofluorescence microscopy of the NC1 domain of collagen type IV in glomerular basement membranes of two patients with hereditary nephritis.

The NC1 domain of the collagen type IV molecule, the major component of glomerular basement membranes (GBM), consists of dimers and 24 kilodalton (K), 26 K and 28 K monomers in man, and contains the Goodpasture antigen. Serum obtained from patients with Goodpasture's syndrome has been reported not to stain GBM of most male and some female patients with hereditary nephritis (HN) by immunofluorescence (IF) microscopy. In the present study, GBM seen on the renal biopsies of 2 patients (one male and one female) with HN were examined by IF to ascertain whether NC1 monomers were detectable. Three reagents were used: a plasmapheresis fluid (PPF) obtained from a patient who was treated for anti-GBM nephritis (human anti-GBM PPF); a commercial rabbit antibody against human NC1; and a rabbit antibody raised by us against dog NC1, which cross-reacted with human NC1. All 3 reagents detected NC1 determinants in GBM of normal human kidney by IF and reacted with human NC1 by a plate-binding radioimmunoassay (RIA). The human anti-GBM PPF bound to 28 K and 26 K monomer components of NC1 by Western blotting, the rabbit anti-human NC1 antibody bound to 26 K and 24 K monomers, while the rabbit anti-dog NC1 antibody bound only to the 26 K monomer. By IF, the human anti-GBM PPF did not stain GBM of the male patient with HN, but produced segmental staining of GBM (i.e., some GBM stained, while others did not) of the female patient. In contrast, the rabbit anti-NC1 antibodies produced global staining by IF of GBM of both patients. The absence of staining (i.e., global or segmental) seen with the human anti-GBM PPF implied that the 26 K and 28 K monomers of NC1 were either absent from GBM, or were present but altered structurally, leading to a diminution in their immunological reactivity. However, the positive staining observed with the rabbit anti-NC1 antibodies implied that the 26 K monomer was actually present in GBM. Hence, we postulate that the 26 K monomer of NC1 in GBM was structurally altered, and that the 28 K monomer was either absent, or present but altered. These findings suggest that there is an abnormality of more than one monomer of NC1 in GBM of patients with HN.

Basement Membrane↗
PubMed1990

Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood.

Increased expression of P-glycoprotein is associated with multidrug resistance (MDR) in many cell lines. Significant levels of P-glycoprotein have been detected in a number of human tumors. The purpose of this study was to determine whether P-glycoprotein expression correlates with both response to chemotherapy and prognosis in soft tissue sarcoma of childhood. In a retrospective study, biopsy samples from 30 cases of rhabdomyosarcoma (RMS) and undifferentiated sarcoma (US) treated at The Hospital for Sick Children in Toronto were analyzed using a semiquantitative immunohistochemical procedure. P-glycoprotein was detected in nine patients, four at diagnosis, and five at subsequent biopsy. All nine patients relapsed after a clinical response (complete [CR] 55%, partial [PR] 45%) to chemotherapy. Twenty of 21 patients with consistently P-glycoprotein-negative tumors received chemotherapy and they all responded clinically (CR 80%, PR 20%). Only one of these 20 patients has relapsed. The probability of relapse-free survival was significantly different (P less than .000000012) in chemotherapy-treated patients whose tumors contained detectable levels of P-glycoprotein (n = 9), compared with those whose tumors contained no detectable P-glycoprotein (n = 20). The overall probability of survival was also significantly different in these two groups (P less than .0000267). Both relapse-free and overall survivals remained statistically different in the two groups of patients when analyzed by the log-rank method, after adjustment for differences in stages and sites. The incidence of other adverse prognostic factors in the two groups, for example, younger and older ages, low pretreatment lymphocyte counts, large tumors, and unfavorable histology were not significantly different. Thus, detectable P-glycoprotein appears to be an important adverse prognostic factor in children with soft tissue sarcoma, and consistent absence of the protein is associated with a favorable prognosis.

ATP Binding Cassette Transporter, Subfamily B, Mem↗