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Biomedical subjects

G Bryant

Publications and source records attributed to G Bryant.

At least 55 records · Page 3Linked to original sources
PubMed1992

Phase I and II study of high-dose ifosfamide, carboplatin, and etoposide with autologous bone marrow rescue in lymphomas and solid tumors.

PURPOSE: High-dose chemotherapy produces durable disease-free remissions in a minority of patients with resistant lymphomas and solid tumors. In an attempt to improve on the available regimens, ifosfamide, carboplatin, and etoposide (ICE) were selected for a new high-dose regimen because of their favorable spectrum of nonhematopoietic toxicity and evidence of synergy in in vitro systems. PATIENTS AND METHODS: Forty-one patients with drug-resistant Hodgkin's and non-Hodgkin's lymphomas, and breast and testicular cancers were entered onto a phase I and II trial of a single course of ICE with autologous bone marrow rescue. Before transplantation, all patients received combination chemotherapy until maximal tumor response was achieved. RESULTS: Patients received total doses of ifosfamide from 10 to 18 g/m2, carboplatin from 0.9 to 1.98 g/m2, and etoposide from 0.6 to 1.5 g/m2 administered during a 4-day period, with a maximum-tolerated dose (MTD) of ifosfamide 16 g/m2, carboplatin 1.8 g/m2, and etoposide 1.5 g/m2. The dose-limiting toxicities included irreversible renal, cardiac, and CNS dysfunction. There were three toxic deaths (7%), and all occurred above the MTD. Thirteen patients who were treated at the MTD tolerated the regimen well; reversible renal dysfunction and grade 2 mucositis commonly were observed. Of 23 heavily pretreated patients with persistent disease at the time of transplant, 10 (43%) achieved complete remissions (CRs) and 11 (48%) achieved partial remissions (PRs). Hodgkin's and non-Hodgkin's lymphoma patients who were treated at or below the MTD had a median potential follow-up of 11.9 months, and 12-month progression-free survivals of 62% and 48%, respectively. CONCLUSION: High-dose ICE with bone marrow rescue was well tolerated with a high response rate, and should be considered for further testing.

Adult↗
PubMed1990

Acetylcholine, carbachol, and GABA induce no detectable change in the length of isolated outer hair cells.

The mechanical and electrical properties of cochlear outer hair cells (OHCs) are suggested to modulate transduction by inner hair cells. These properties of OHCs are presumably regulated by efferent neurons which use several transmitters including acetylcholine (Ach) and gamma aminobutyric acid (GABA). Since it had been suggested that Ach causes isolated OHCs to shorten visibly, this study was designed to investigate whether GABA also alters the length of OHCs. OHCs were isolated from the guinea pig cochlea by mechanical dispersion after collagenase treatment. Cells were initially selected by strict morphological criteria. In addition they were only included in further studies if they attained a constant length during 10 min of superfusion with buffer solution. Neither GABA (20 microM: 100 microM), Ach (5 mM; 10 microM with 10 microM eserine) or carbachol (10 microM; 100 microM) altered OHC length when applied in iso-osmotic Hank's balanced salt solution (total number of cells tested, 72). If a change in length occurred it must have been smaller than 0.3 microns, our detection ability. In contrast, high potassium and variations in osmolarity changed hair cell length by 3-10% in agreement with other reports.

Acetylcholine↗
PubMed1990

Evaluation of amino-oxyacetic acid as a palliative in tinnitus.

Amino-oxyacetic acid (AOAA) was evaluated as a palliative in tinnitus. Sixty-six patients with tinnitus presumed to be of cochlear origin were given either a placebo or 75 mg of AOAA four times a day for 1 week. Response was evaluated by both audiometric measurement of tinnitus loudness and subjective rating by patients of change or no change in tinnitus severity. Because loudness measurements and self-rating have not been shown to be independent, and since the aim of clinical treatment of tinnitus is the alleviation of subjective distress, greater weight was given to the patient's self-rating. A total of 21% of all patients reported a subjective decrease in tinnitus severity, usually within 3 to 4 days after the start of AOAA use. Patients with tinnitus caused by presbycusis or Meniere's disease were the most likely to respond to AOAA treatment with a reduction in tinnitus severity, whereas those with drug-induced tinnitus were the least likely to respond. Nausea and dysequilibrium were the most common side effects of AOAA use. Of the 21% of patients who responded to AOAA, 71% developed some type of side effect. Amino-oxyacetic acid produces a reduction in the severity of tinnitus in about 20% of patients; however, the incidence of side effects makes the drug unacceptable for clinical use.

Acetates↗
PubMed1989

Can hydration forces induce lateral phase separations in lamellar phases?

Large repulsive forces measured between membranes of lamellar lipid phases at low hydration are attributed to hydration interactions which vary widely among lipid species. We include this interaction in a model of lamellar phases of two membrane components (two lipids or lipid and protein). The surface polarization of a mixture is taken as a linear combination of those of the components. The model predicts phase separation at low hydration. This may have important consequences for living cells which are dehydrated either by the osmotic effects of tissue freezing, or by desiccation in unsaturated atmospheres.

Lipid Bilayers↗
PubMed1988

Peritoneal carcinomatosis: imaging with intraperitoneal injection of I-131-labeled B72.3 monoclonal antibody.

Monoclonal antibody (MoAb) B72.3 is reactive with a variety of carcinomas such as colorectal and ovarian carcinoma and not reactive with a range of normal tissues in adults. Twelve patients, ranging in age from 16 to 63 years, with metastatic colorectal or appendiceal carcinoma were studied by means of radioimmunoscintigraphy after injection of 5-10 mCi (185-370 MBq) of iodine-131-labeled B72.3 immunoglobulin G (IgG). Eight of the 12 patients had positive scans. In three of these patients the MoAb scan depicted tumors that were not found by other means. Positive scans had excellent correlation with surgical findings in seven patients and caused underestimation of the extent of disease in one patient. In one patient the scan was technically inadequate and could not be evaluated. In three patients the scan was negative. No adverse reactions were associated with the infusions.

Adenocarcinoma↗
PubMed1988

Diagnostic value of the history and examination in giant cell arteritis: a clinical pathological study of 81 temporal artery biopsies.

To determine the value of the history and examination in predicting a temporal artery biopsy result, 81 temporal artery biopsies between 1974-1980 were studied. Each biopsy was scored blindly and independently by 2 pathologists and correlated with clinical data and the indications for biopsy at the time of the biopsy. Thirteen biopsies had giant cells and were considered positive, 8 had mononuclear inflammatory cells in the wall (7 cases) or healed arteritis (1 case) and were considered probable, and 60 were negative. In patients with an elevated sedimentation rate, the presence of a sign (tenderness or abnormal temporal artery), or a symptom (visual change or headache) predicted 18 of 21 (86%) positive-probable biopsies, but misclassified 32 of 60 negative biopsies. Attempts to derive a clinical decision rule with improved specificity resulted in unacceptably low sensitivity (missing 5 of 21 positive-probable biopsies). A minimum 5-year followup showed that those patients treated with steroids had a 6-fold increase in fractures and a 4-fold increase in cataracts.

Aged↗
PubMed1988

Radioimmunoscintigraphy of colon cancer with iodine-131-labeled B72.3 monoclonal antibody.

The monoclonal antibody B72.3 is a murine IgG1 that is reactive with a wide range of carcinomas while demonstrating little or no reactivity to normal adult tissues. We have shown (27) quantitative analyses demonstrating selective targeting of [131I]B72.3 IgG to metastatic colorectal cancer. We have also shown (28) that (a) B72.3 localization in metastases correlated with the percentage of tumor cells in the biopsy specimen; (b) B72.3 could localize in carcinomas of various degrees of differentiation with best localization in well-differentiated tumors and (c) [131I]B72.3 could penetrate tumor masses, as determined by autoradiographic studies. We report here the various parameters effecting radioimmunoscintigraphy with [131I]B72.3 IgG. Sixteen of 35 patients with colorectal carcinoma had positive scans (without blood-pool subtraction). High circulating TAG-72 antigen levels correlated with positive scans. No dose dependent differences were seen in biodistribution or tumor imaging. The plasma clearance and urinary excretion of [131I]B72.3 and [125I]BL-3 (nonspecific control) were not significantly different. No toxicity was noted. Approximately one-half of patients developed human anti-mouse immune response.

Adolescent↗
PubMed1987

Complementation of intracavitary and intravenous administration of a monoclonal antibody (B72.3) in patients with carcinoma.

Monoclonal antibody (MAb) B72.3 has been shown to have selective reactivity for a wide range of carcinomas (colorectal, ovarian, breast, lung, gastric, and endometrial) versus normal adult tissues. 131I-Labeled B72.3 IgG has recently been shown to selectively bind carcinoma lesions when administered i.v. in patients with metastatic colorectal cancer. We report here the first direct comparison of i.p. administered [131I]B72.3 IgG to specifically localize metastatic carcinoma. Three of 10 patients studied were negative for tumor detection by both CAT scan and X-ray but were positive for tumor localization via gamma scanning i.p. administered 131I-labeled MAb B72.3 IgG. Direct analyses of biopsy specimens of carcinoma and normal tissues demonstrated ratios of greater than 70:1 (based on percentage of injected dose/mg) for tumor MAb localization versus normal tissues. Specificity of [131I]B72.3 tumor targeting was demonstrated by the concomitant administration of an equal dose of an 125I-labeled isotype identical (IgG1) control MAb. Simultaneous i.p. administration of [131I]B72.3, and i.v. administration of [125I]B72.3 in individual patients demonstrated: peritoneal implants are targeted more efficiently via i.p. MAb administration, and hematogenously spread and lymph node metastases as well as local recurrences are targeted more efficiently by i.v. administered MAb. No antibody toxicity was observed in any patients. Pharmacokinetics of MAb clearance demonstrated that only 10 to 30% of the i.p. administered MAb was found in plasma. These studies thus demonstrate the efficacy of intracavitary MAb administration as well as the advantage of the concomitant use of intracavitary and i.v. administered MAbs for tumor targeting and for potential MAb guided therapy of metastatic carcinoma.

Adolescent↗
PubMed1987

Quantitative analyses of selective radiolabeled monoclonal antibody localization in metastatic lesions of colorectal cancer patients.

We have previously demonstrated, using in vitro assays, a high degree of selective binding of monoclonal antibody (MAb) B72.3 for carcinomas of the colon, ovary, and breast versus normal adult tissues using in vitro assays. We report here a demonstration of selective tumor localization in colorectal cancer patients of i.v. administered 131I-labeled MAb B72.3 immunoglobulin G prior to surgery. Radiolocalization indices (RI) were obtained by direct analyses of biopsy materials (i.e., cpm of 131I-labeled MAb per g of tumor versus cpm per g of normal tissues). Using as a "positive" localization, RI of 3 times greater than normal tissue (i.e., RI greater than 3.0), tumor lesions in various sites from 17 of 20 patients scored positive. In eight of these patients, all tumor lesions demonstrated RIs of greater than 3, while in five patients RIs of some lesions were greater than 10 and as high as 30 to 46. Seventy % (99 of 142) of tumor lesions showed RIs of greater than 3, while only 12 of 210 histologically confirmed normal tissues examined showed RIs of greater than 3. These tissues, moreover, were either adjacent to tumor or draining tumor masses, or, as in the case of two patients, apparently due to high levels of circulating immune complexes that were deposited in the spleen. Positive gamma scans (confirmed at surgery) were observed in 14 of 27 patients. An isotype-identical control immunoglobulin G was coinjected and showed RIs considerably lower than that of B72.3. No toxicity or adverse reaction was observed with either MAb. These studies are among the most comprehensive to date concerning the definition of the actual delivery of radiolabeled MAb to carcinoma lesions versus a wide range of adjacent and distal normal tissues and lead the way for other diagnostic and potential therapeutic applications of this antibody either alone, or in combinations with other monoclonal antibodies.

Antibodies, Monoclonal↗
PubMed1987

Quantitative and qualitative aspects of radiolocalization in colon cancer patients of intravenously administered MAb B72.3.

Monoclonal antibody (MAb) B72.3 has been previously shown, by in vitro assays, to have a high degree of specificity for carcinomas of the colon, ovary and breast versus normal adult tissues. B72.3 IgG was labelled with 131I and injected i.v. into 20 patients with known or suspected colorectal cancer. All patients subsequently underwent surgical exploration, with tumor and selected normal tissues removed for staging purposes. The selective localization of 131I-MAb B72.3 IgG was demonstrated in biodistribution studies in which the % ID/g of each tumor was compared with that of the normal tissues, thus providing a relative RI for each lesion. Of the tumor lesions, 70% (99/142) had an RI of at least 3 (i.e., 3 times greater uptake per gram than normal tissues), and 31% of the tumor lesions had RIs of over 10. Only 12 of 210 (6%) histologically normal tissues had RIs of greater than 3; either these tissues were adjacent to or draining tumor masses or, as in the case of 2 patients, the high RI values were apparently due to deposition of immune complexes in the splenic tissues. Several parameters were studied to determine factors that might influence MAb localization. Whereas tumors of all histologic types localized the MAb, 31% of the well-differentiated mucinous carcinomas displayed tumor-to-normal ratios greater than 10, while less than 5% of the lesions of other tumor types demonstrated similar localization. The expression of the antigen (TAG-72) detected by MAb B72.3 in these tumors, as studied by immunohistochemical techniques using tissue sections, did not always correlate with the outcome of the MAb distribution. No differences in MAb uptake were observed among the carcinoma lesions from numerous anatomic locations, demonstrating the ability of i.v. administered B72.3 to reach all the tumor sites. Furthermore, autoradiographic studies of tumors showed good penetration of the MAb into the medial areas of the tumors, regardless of their size.

Adolescent↗
PubMed1987

A role for the laminin receptor in leukocyte chemotaxis.

Previous studies on the mechanism of leukocyte traversal of basement membranes showed that rabbit peritoneal exudate polymorphonuclear cells (PMN) preferentially used laminin, a major constituent of basement membrane, to attach to another component, type IV collagen. PMN also responded chemotactically to nanomolar levels of laminin. We have now determined that PMN possess a receptor for laminin. Scatchard analysis using 125I laminin indicates a single class of saturable high affinity binding sites (kd = 6.15 nM/L) on PMN and 3.6 X 10(4) sites per cell. A chymotryptically derived fragment of laminin, C1, which lacks both the long arm and the globular end regions of the short arm (i.e., matrix binding sites) but retains the laminin receptor binding region, gave similar results. Immunoperoxidase studies using monoclonal antibodies to the laminin receptor (mAbLR) indicated the presence of the receptor on the surface of PMN. These cells responded chemotactically to nanomolar levels of C1 and laminin, a result consonant with binding data. PMN chemotaxis to a formyl peptide was markedly inhibited by mAbLR, suggesting that the laminin receptor may be required for PMN chemotaxis in general. Our results suggest that PMN extravasation across basement membranes is aided both by reversible attachment of the cells to laminin in the matrix and by chemotaxis to a gradient of soluble intact and possibly degraded laminin. These characteristics have much in common with those of highly metastatic tumor cells.

Animals↗
PubMed1987

Electromechanical stresses produced in the plasma membranes of suspended cells by applied electric fields.

We analyze the electrical and mechanical stress in the bounding membrane of a cell (or vesicle) in suspension which is deformed by an external applied field. The membrane is treated as a thin, elastic, initially spherical, dielectric shell and the analysis is valid for frequencies less than the reciprocal of the charging time (i.e. less than MHz), or for constant fields. A complete analytic solution is obtained, and expressions are given which relate the deformation, the surface tension and the transmembrane potential difference to the applied field. We show that mechanical tensions in the range which lyse membranes are induced at values of the external field which are of the same order as those which are reported to lyse the plasma membranes of cells in suspension.

Animals↗
PubMed1987

Radiolabeled monoclonal antibody B72.3 localization in metastatic lesions of colorectal cancer patients.

We have previously demonstrated a high degree of selective binding of monoclonal antibody (MAb) B72.3 to carcinomas of the colon, ovary, and breast in contrast to normal adult tissues using in vitro assays. In this report we demonstrate selective tumor localization in colorectal cancer patients after intravenously administering 131I-labeled MAb B72.3 IgG. Radiolocalization Indices (RI) (i.e. cpm 131I-labeled MAb per gram of tumor vs cpm per gram of normal tissues), were obtained by direct analyses of biopsy materials. Using an RI of greater than or equal to 3 as a positive localization, tumor lesions in various sites from 17/20 patients scored positive. In eight of these patients, all tumor lesions demonstrated RIs of greater than 3, while in five patients RIs of some lesions were greater than 10 and as high as 30-46. Seventy percent (99/142) of the tumor lesions showed RIs of greater than 3, while only 12 of 210 histologically confirmed normal tissues examined showed RIs of greater than 3. These tissues were either adjacent to the tumor or the draining tumor masses or, as in the case of two patients, was caused by high levels of circulating immune complexes that deposited in the spleen. Positive scintigraphic images (confirmed at surgery) were observed in 14/27 patients. No toxicity or adverse reactions were observed with either MAb. These studies provide absolute quantitative analyses of the actual delivery of radiolabeled MAb to carcinoma lesions vs a wide range of adjacent and distal normal tissues and establishes the means for other diagnostic and potential therapeutic applications of this antibody alone, or in combinations with other monoclonal antibodies.

Antibodies, Monoclonal↗
PubMed1987

125I-iodinated benzazepines bind to melanin: implications for the noninvasive localization of pigmented melanomas.

Both the 5-R and the 5-S enantiomers of [125I]2,3,4,5-tetrahydro-8-iodo-3-methyl-5-phenyl-1H-3-benzazepin- 7-ol bind to melanin. The interaction between the 5-R enantiomer and melanin permits visualization of melanomas in mice with a noninvasive imaging procedure. Two lines of evidence suggest that the interaction between iodinated ligands and melanin is not related to the D-1 dopamine receptor, a known target for the 5-R enantiomer: first, melanin binds both enantiomers of the 125I-iodinated benzazepine while the D-1 receptor binds only the 5-R enantiomer; second, the melanin binding site displays only a 5-fold difference in affinity towards the R- and S-enantiomers of SCH 23390 while the D-1 receptor displays a 100-fold difference in affinity towards these two molecules. Because both enantiomers of the iodinated benzazepine bind to a human pigmented melanoma, we propose that such compounds may be of use in the diagnosis of pigmented melanoma: in addition, we discuss the possible application of these molecules as a supplement to existing technology for the localization of pigmented melanomas.

Animals↗
PubMed1986

Butyrate induced reduction of tumor cell laminin receptors.

Laminin, a glycoprotein of basement membranes, binds to the surface of cultured human pancreatic carcinoma cells (PANC-1). The binding is saturable, with a high proportion of specific binding, as determined by competition of labeled ligand with 80-fold excess unlabeled ligand. Pretreatment of the carcinoma cells with butyrate markedly reduces the amount of specific laminin binding. The butyrate effect on laminin binding is dose dependent and is observed at a concentration of butyrate which does not significantly reduce cellular protein synthesis or increase laminin production. Scatchard analysis indicates that butyrate reduces the total number of laminin binding sites without affecting the binding coefficient (Kd = 2 nm). The laminin receptor protein isolated from the PANC-1 cell extract has a molecular weight of approximately 70,000. After butyrate treatment the total amount of extractable laminin receptor protein is significantly reduced. Thus butyrate reduces laminin binding to PANC-1 carcinoma cells by a mechanism which involves decreased expression of laminin receptor proteins in the plasma membrane.

Adenocarcinoma↗
PubMed1985

Monoclonal antibodies to the human laminin receptor recognize structurally distinct sites.

Laminin, a glycoprotein of basement membranes, binds to a specific receptor on the surface of neoplastic and non-neoplastic cells. The laminin receptor purified from human breast carcinoma plasma membranes was used as an antigen to generate two types of monoclonal antibodies (mAbs). Both types of mAbs bind to (a) the purified receptor coated on a solid phase; (b) isolated breast carcinoma plasma membranes; and (c) the surface of cultured MCF-7 human breast carcinoma cells by immunohistology. Using immunoblotting, both types of mAbs recognize a single 67 000 Dalton protein among all the proteins extracted from breast carcinoma plasma membranes. The mAbs differed in their ability to block binding of laminin to the plasma membrane receptor. Antibody LR1 inhibited virtually 100% of the specific binding of laminin to both the isolated human breast carcinoma plasma membranes or the living MCF-7 cells. In contrast, antibody LR2 had no effect on laminin binding under identical conditions. Thus, the two types of mAbs may recognize structurally distinct sites on the laminin receptor. These mAbs should be useful to dissect the biology and the molecular genetics of the laminin receptor.

Antibodies, Monoclonal↗