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Biomedical subjects

T Boyle

Publications and source records attributed to T Boyle.

18 recordsLinked to original sources
PubMed2001

Clinically evident fat necrosis in women treated with high-dose-rate brachytherapy alone for early-stage breast cancer.

PURPOSE: To investigate the incidence of and variables associated with clinically evident fat necrosis in women treated on a protocol of high-dose-rate (HDR) brachytherapy alone without external-beam whole-breast irradiation for early-stage breast carcinoma. METHODS AND MATERIALS: From 6/1997 until 8/1999, 30 women diagnosed with Stage I or II breast carcinoma underwent surgical excision and postoperative irradiation via HDR brachytherapy implant as part of a multi-institutional clinical Phase I/II protocol. Patients eligible included those with T1, T2, N0, N1 (< or = 3 nodes positive), M0 tumors of nonlobular histology with negative surgical margins, no extracapsular lymph-node extension, and a negative postexcision mammogram. Brachytherapy catheters were placed at the initial excision, re-excision, or at the time of axillary sampling. Direct visualization, surgical clips, ultrasound, or CT scans assisted in delineating the target volume defined as the excision cavity plus 2-cm margin. High activity (192)Ir (3-10 Ci) was used to deliver 340 cGy per fraction, 2 fractions per day, for 5 consecutive days to a total dose of 34 Gy to the target volume. Source position and dwell times were calculated using standard volume optimization techniques. Dosimetric analyses were performed with three-dimensional postimplant dose and volume reconstructions. The median follow-up of all patients was 24 months (range, 12-36 months). RESULTS: Eight patients (crude incidence of 27%) developed clinically evident fat necrosis postimplant in the treated breast. Fat necrosis was determined by clinical presentation including pain and swelling in the treated volume, computed tomography, and/or biopsy. All symptomatic patients (7 of 8 cases) were successfully treated with 3 to 12 months of conservative management. Continuous variables that were found to be associated significantly with fat necrosis included the number of source dwell positions (p = 0.04), and the volume of tissue which received fractional doses of 340 cGy, 510 cGy, and 680 cGy (p = 0.03, p = 0.01, and p = 0.01, respectively). Other continuous variables including patient age, total excised tissue volume, tumor size, number of catheters, number of days the catheters were in place, planar separation, dose homogeneity index (DHI), and uniformity index (UI) were not significant. Discrete variables including the presence/absence of DCIS, sentinel versus full axillary nodal assessment, receptor status, presence/absence of diabetes, and the use of chemotherapy or hormone therapy were not found to have a significant association with the risk of fat necrosis. CONCLUSIONS: In this study of HDR brachytherapy of the breast tumor excision cavity plus margin, treatment was planned and delivered in accordance with the dosimetric parameters of the protocol resulting in a high degree of target volume dose homogeneity. Nonetheless, at a median follow-up of 24 months, a high rate of clinically definable fat necrosis occurred. The overall implant volume as reflected in the number of source dwell positions and the volume of breast tissue receiving fractional doses of 340, 510, and 680 cGy were significantly associated with fat necrosis. Future dosimetric optimization algorithms for HDR breast brachytherapy will need to include these factors to minimize the risk of fat necrosis.

Adult↗
PubMed2000

Six year survey of screening for Down's syndrome by maternal age and mid-trimester ultrasound scans.

OBJECTIVE: To assess the effectiveness of antenatal screening for Down's syndrome by maternal age and routine mid-pregnancy ultrasound scanning. DESIGN: Retrospective six year survey. SETTING: Maternity units of a district general hospital. SUBJECTS: Pregnant women booked for delivery in hospital between 1 January 1993 and 31 December 1998. MAIN OUTCOME MEASURES: All cases of Down's syndrome occurring in district identified from regional congenital anomaly register and cytogenetic laboratory records. Women's case notes were examined to identify indication for karyotyping, gestation at diagnosis, and outcome of pregnancy. RESULTS: 31 259 deliveries occurred during study period, and 57 cases of Down's syndrome were identified, four in failed pregnancies and 53 in ongoing pregnancies or in neonates. The analysis was confined to ongoing pregnancies or liveborn children. Invasive antenatal tests were performed in 6.6% (2053/31 259), and 68% (95% confidence interval 56% to 80%) of cases of Down's syndrome were detected antenatally, giving a positive predictive value of 1.8%. There were 17 undetected cases, and in seven of these the women had declined an offer of invasive testing. In women aged less than 35 years the detection rate was 53% (30% to 76%). Most of the cases detected in younger women followed identification of ultrasound anomalies. CONCLUSIONS: The overall detection rate was considerably higher than assumed in demonstration projects for serum screening. As a result, the benefits of serum screening are much less than supposed. Before any new methods to identify Down's syndrome are introduced, such as nuchal translucency or first trimester serum screening, the techniques should be tested in properly controlled trials.

Adult↗
PubMed2000

The contemporary use of radiation therapy in the management of lymphoma.

In this article the classification and the treatment regimens for malignant lymphomas are discussed in a stage-oriented approach. The clinical trials that have redefined the role of staging laparotomy are reviewed. Intensity-modulated radiation therapy allows for highly conformal target definition. This novel delivery system is discussed through a case presentation.

Chemotherapy, Adjuvant↗
PubMed1999

The influence of age and extensive intraductal component histology upon breast lumpectomy margin assessment as a predictor of residual tumor.

PURPOSE: Young age and extensive intraductal component (EIC) histology have been shown to be associated with increased local recurrence in women treated with breast conservation therapy. This study was conducted to determine if the status of the lumpectomy specimen margin consistently predicted for residual tumor burden risk irrespective of these variables. METHODS AND MATERIALS: As part of an institutional prospective approach for breast conservation therapy (BCT), 265 cases with AJCC Stage I/II carcinoma with an initial excision margin that was < or =2 mm or indeterminate were subjected to reexcision. The probability of residual tumor (+RE) was evaluated with respect to tumor size, histopathologic subtype (invasive ductal carcinoma, invasive ductal carcinoma with an EIC, and invasive lobular carcinoma), relative closeness of the measured margin, and the extent of margin positivity graded as focal, minimal, moderate, or extensive. The amount of residual tumor was graded as microscopic, small, medium, or large. All variables were analyzed for patient age < or =45 or >45 years. RESULTS: There was no significant difference in the incidence of a +RE according to age < or =45 versus >45 years when the margin was >0 < or =2 mm. Of the patients aged < or =45 years, the incidence of a +RE with a margin that was positive as compared to >0 < or =2 mm was 71% vs. 23%, respectively (p = 0.002). For women >45 years old, the difference in the incidence of +RE comparing margins that were positive or >0 < or =2 mm was not significant at 50% vs. 40%, respectively (p = 0.23). For all cases in aggregate, age < or =45 years was associated with a greater incidence of +RE as compared to patients aged >45 years with the discrepant incidence of a +RE by age strata most pronounced for focally positive margins (60% vs. 18%;p< or =0.05). In a logistic regression analysis, age (per year, as a continuous variable) and an EIC histology were significantly associated with the probability of a +RE (odds ratio [OR] = 0.80, p = 0.05 and OR = 1.9, p = 0.01, respectively). Tumor size was not significant (p = 0.23). In patients with an EIC histology, margin status is generally less predictive for differences in the incidence of a +RE. Further, the overall magnitude of difference in the incidence of a +RE related to age appears to be minimized when an EIC histology is present. In contrast, for cases classified as having non-EIC histology, there is a near-linear relationship for both age strata with respect to margin status and the incidence of a +RE. When histology is classified as non-EIC, age < or =45 years is consistently associated with a greater risk of residual tumor for all margin status categories. When the extent of margin positivity was graded as focal or minimal, residual tumor was semiquantitatively estimated as a medium/large amount in 33% versus 26% of cases aged < or =45 or >45 years, respectively (p = 0.62). CONCLUSION: For positive lumpectomy specimen margins, younger age is associated with an increased residual tumor risk. An EIC histology appears to be associated with an elevated risk of residual tumor irrespective of age and may undermine the predictive utility of margin status. Therefore, age and an EIC histology should be factored into risk assessments for residual tumor that rely upon margin assessment.

Adult↗
PubMed1999

Role of splenic irradiation in patients with chronic myeloid leukemia undergoing allogeneic bone marrow transplantation.

Allogeneic bone marrow transplantation (BMT) has become the treatment of choice for patients of appropriate age with chronic myeloid leukemia (CML). In an attempt to enhance tumor cytoreduction, splenic radiation therapy (RT) has been done before the allogeneic transplant, but the role of splenic RT in this setting remains controversial. The purpose of this study is to evaluate the role of splenic RT before allogeneic BMT in patients with CML. Thirty-seven patients with chronic (n=33) or accelerated (n=4) phase CML underwent BMT from April 1990 to January 1998. All patients received splenic RT consisting of 500 cGy in five daily fractions (n=36) or 250 cGy in five daily fractions (n=1) completed within 10 days before BMT. The conditioning regimen included total-body irradiation and cyclophosphamide; etoposide was added to the regimen of patients in the accelerated phase. Continuous-infusion cyclosporine and pulse methotrexate were administered to all patients for prophylaxis of graft-vs.-host disease (GVHD). All patients achieved hematologic and cytogenetic remission. At a median follow-up of 37 months, the freedom from progression (FFP) and overall survival (OS) were 90 and 82%, respectively. None of the patients in accelerated phase have relapsed. Five patients have died of late transplant-related complications while in complete remission. Acute GVHD of grade > or = II was observed in 20% (14% grade II, 6% grade III). Fifty-one percent of patients developed limited chronic GVHD. The median posttransplant creatinine level was 1.2 mg/dL (range 0.6-4.2). Renal dysfunction, manifested as a persistent elevation in serum creatinine level (> 1.2 mg/dL), was observed in 40% of the patients. Only 8.5% had a creatinine level > 2.0 mg/dL, and no patient required dialysis as a result of renal dysfunction. Seven patients (18.9%) developed pulmonary complications, which included idiopathic interstitial pneumonitis (two), biopsy-proven interstitial fibrosis (four), and alveolar hemorrhage (one). The low relapse rate observed in this study may reflect the use of splenic RT as a part of the cytoreductive regimen before BMT. The fractionation schedule of 500 cGy in five daily fractions was well tolerated and did not appear to increase the toxicity of the preparative regimen. These favorable results indicate that splenic RT deserves further investigation and may be of benefit as a part of the conditioning regimen for patients receiving allogeneic BMT for CML.

Adult↗
PubMed1996

Growth control of lung cancer by interruption of 5-lipoxygenase-mediated growth factor signaling.

Signal transduction pathways shared by different autocrine growth factors may provide an efficient approach to accomplish clinically significant control of lung cancer growth. In this study, we demonstrate that two autocrine growth factors activate 5-lipoxygenase action of the arachidonic acid metabolic pathway in lung cancer cell lines. Both growth factors increased the production of 5(S)-hydrooxyeicosa-6E,8Z,11Z,14Z-tetraeno ic acid (5-HETE), a major early 5-lipoxygenase metabolic product. Exogenously added 5-HETE stimulated lung cancer cell growth in vitro. Inhibition of 5-lipoxygenase metabolism by selective antagonists resulted in significant growth reduction for a number of lung cancer cell lines. Primary clinical specimens and lung cancer cell lines express the message for the 5-lipoxygenase enzymes responsible for the generation of active metabolites. In vivo evaluation demonstrated that interruption of 5-lipoxygenase signaling resulted in enhanced levels of programmed cell death. These findings demonstrate that 5-lipoxygenase activation is involved with growth factor-mediated growth stimulation for lung cancer cell lines. Pharmacological intervention with lipoxygenase inhibitors may be an important new clinical strategy to regulate growth factor-dependent stages of lung carcinogenesis.

5-Lipoxygenase-Activating Proteins↗
PubMed1996

Toward antibody-directed "abzyme" prodrug therapy, ADAPT: carbamate prodrug activation by a catalytic antibody and its in vitro application to human tumor cell killing.

Antibody-directed enzyme prodrug therapy, ADEPT, is a recent approach to targeted cancer chemotherapy intended to diminish the nonspecific toxicity associated with many commonly used chemotherapeutic agents. Most ADEPT systems incorporate a bacterial enzyme, and thus their potential is reduced because of the immunogenicity of that component of the conjugate. This limitation can be circumvented by the use of a catalytic antibody, which can be "humanized," in place of the bacterial enzyme catalyst. We have explored the scope of such antibody-directed "abzyme" prodrug therapy, ADAPT, to evaluate the potential for a repeatable targeted cancer chemotherapy. We report the production of a catalytic antibody that can hydrolyze the carbamate prodrug 4-[N,N-bis(2-chloroethyl)]aminophenyl-N-[(1S)-(1,3- dicarboxy)propyl]carbamate (1) to generate the corresponding cytotoxic nitrogen mustard (Km = 201 microM, kcat = 1.88 min-1). In vitro studies with this abzyme, EA11-D7, and prodrug 1 lead to a marked reduction in viability of cultured human colonic carcinoma (LoVo) cells relative to appropriate controls. In addition, we have found a good correlation between antibody catalysis as determined by this cytotoxicity assay in vitro and competitive binding studies of candidate abzymes to the truncated transition-state analogue ethyl 4-nitrophenylmethylphosphonate. This cell-kill assay heralds a general approach to direct and rapid screening of antibody libraries for catalysts.

Aniline Mustard↗
PubMed1996

The preclinical pharmacology of "Arimidex" (anastrozole; ZD1033)--a potent, selective aromatase inhibitor.

Anastrozole is a comparatively simple, achiral benzyltriazole derivative, 2,2'-[5-(1H-1,2,4-triazol-1-ylmethyl)-1,3-phenylene]bis(2-++ +methylpropiononitrile), that inhibits human placental aromatase with an IC50 of 15 nM and elicits maximal activity in vivo in rats (inhibition of ovulation and androstenedione-induced uterine hypertrophy) and monkeys (lowering of plasma oestradiol) at 0.1 mg/kg p.o. At 30 times this dose, anastrozole does not elevate plasma 11-deoxycorticosterone in monkeys, and at 100 times this dose, does not affect plasma aldosterone levels or Na+/K+ excretion in rats, plasma K+ concentrations in dogs, or cause adrenal hypertrophy in rats or dogs. It therefore has no discernible effect on adrenocorticoid hormone synthesis in vivo at very large multiples of its maximally effective aromatase-inhibiting dose. At similar large multiples in rats it displays no oestrogenic, anti-oestrogenic, androgenic, anti-androgenic, progestogenic, glucocorticoid, antiglucocorticoid or mineralocorticoid activity. Anastrozole is thus a potent and highly selective aromatase inhibitor, with no intrinsic hormonal activities--a pharmacological profile particularly suitable for the treatment of breast cancer.

Adrenal Glands↗
PubMed1994

Method for simultaneous isolation and quantitation of platelet activating factor and multiple arachidonate metabolites from small samples: analysis of effects of Staphylococcus aureus enterotoxin B in mice.

A novel method has been developed for the extraction and simultaneous separation and quantitation of key arachidonate metabolites and platelet activating factor (PAF) from plasma samples of limited size. Aqueous solutions of these metabolites were added onto a solid phase C-18 cartridge and arachidonate metabolites and PAF were eluted, successively, with acetonitrile-methanol (85:15, v/v), followed by 100% methanol. Arachidonate metabolites (first eluate) were fractionated by C-18 reverse-phase high-performance liquid chromatography using a program designed for the resolution of 31 arachidonate metabolites (3-min separation). The fractions were collected and assayed by radioimmunoassay or radiography, if radioactively labeled. Two internal standards were added to each sample, 15-hydroxyeicosadienoic acid (detected at 235 nm) to determine gradient shifts and [1-14C]eicosatrienoic acid to estimate the recoveries of arachidonate metabolites at any stage of the process. This method was developed to answer specific questions concerning the mode of action of Staphylococcus aureus enterotoxin B (SEB). Plasma samples from mice challenged with SEB were analyzed and major differences were seen in 5-lipoxygenase metabolites. Low doses of SEB vs saline stimulated 5-hydroxyeicosatetraenoic acid production, while high doses of SEB stimulated leukotriene D4 production.

Animals↗
PubMed1994

Identification of staphylococcal enterotoxin B sequences important for induction of lymphocyte proliferation by using synthetic peptide fragments of the toxin.

A series of 13 synthetic peptides, approximately 30 amino acids each, which spanned the entire sequence of staphylococcal enterotoxin B (SEB) were tested to evaluate their effects on T-cell proliferation in a culture system containing elutriated human peripheral blood lymphocytes incubated with a specific ratio of mononuclear cells. Four peptide regions were found to inhibit SEB-induced proliferation; they included sequences 1 to 30 (previously thought to be involved in major histocompatibility complex class II binding), 61 to 92 (sequences which relate to the T-cell receptor site), 93 to 112 (a linear sequence corresponding to the cysteine loop), and 130 to 160 (containing a highly conserved sequence, KKKVTAQEL). Antisera raised to this last peptide were capable of neutralizing SEB-induced proliferation. Antisera raised against the peptides which overlapped this sequence also were somewhat inhibitory. Neutralizing antisera were not produced from any other peptide sequence tested. To determine if any of these effects were nonspecific with regard to SEB-induced proliferation, the peptides were tested for inhibition of phorbol dibutyryl ester-induced proliferation, and only the sequence 93 to 112 (corresponding to the cysteinyl loop region) was consistently inhibitory (40%). Of the regions which displayed inhibition of SEB-induced proliferation, the peptide 130 to 160 inhibited binding of 125I-SEB to lymphocytes. These data suggest that the residues containing and surrounding the sequence KKKVTAQEL may be critical in the SEB-induced proliferation and may be useful for developing neutralizing antisera to SEB.

Amino Acid Sequence↗
PubMed1993

Effects of nasal airflow on breathing during sleep in normal humans.

The nasal airway is a common route for oxygen delivery to hypoxemic patients, and it has been advocated as a suitable route for intermittent positive pressure ventilation to patients in respiratory failure. There is, however, conflicting evidence on the question of whether nasal airflow has a stimulant or a depressant effect on ventilation. We therefore studied the effects on ventilation of increasing and decreasing nasal airflow during sleep, thereby avoiding the voluntary and behavioral influences on breathing seen during wakefulness. After an acclimatization night, each of nine normal male volunteers (20 to 28 yr of age) underwent overnight sleep studies using standard techniques. Each sleep study had three phases of at least 2-h durations: (1) control nasal breathing (CNB); (2) added nasal flow of 4 L of compressed air via nasal prongs (ANF); (3) predominant mouth breathing (PMB). Significant differences were found by ANOVA for the three experimental periods for both minute ventilation (Vl) and mean inspiratory flow rate (VT/Tl) during Stage 2 sleep, with the highest values occurring during ANF. Vl was 5.40 +/- 0.58 L/min (mean +/- SD) during ANF, 5.35 +/- 0.82 during CNB, and 4.92 +/- 0.71 during PMB (p < 0.05 by ANOVA). VT/Tl was 266 +/- 23 ml/s during ANF, 248 +/- 39 during CNB, and 241 +/- 30 during PMB (p < 0.02 by ANOVA). VT also tended to be higher during ANF (p < 0.1 by ANOVA). Respiratory frequency did not differ significantly during the three study periods. There was insufficient slow-wave and REM sleep to allow ventilatory comparisons in these sleep stages.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1992

Cytokines and arachidonic metabolites produced during human immunodeficiency virus (HIV)-infected macrophage-astroglia interactions: implications for the neuropathogenesis of HIV disease.

Human immunodeficiency virus (HIV) infection of brain macrophages and astroglial proliferation are central features of HIV-induced central nervous system (CNS) disorders. These observations suggest that glial cellular interactions participate in disease. In an experimental system to examine this process, we found that cocultures of HIV-infected monocytes and astroglia release high levels of cytokines and arachidonate metabolites leading to neuronotoxicity. HIV-1ADA-infected monocytes cocultured with human glia (astrocytoma, neuroglia, and primary human astrocytes) synthesized tumor necrosis factor (TNF-alpha) and interleukin 1 beta (IL-1 beta) as assayed by coupled reverse transcription-polymerase chain reaction, enzyme-linked immunosorbent assay, and biological activity. The cytokine induction was selective, cell specific, and associated with induction of arachidonic acid metabolites. TNF-beta, IL-1 alpha, IL-6, interferon alpha (IFN-alpha), and IFN-gamma were not produced. Leukotriene B4, leukotriene D4, lipoxin A4, and platelet-activating factor were detected in large amounts after high-performance liquid chromatography separation and correlated with cytokine activity. Specific inhibitors of the arachidonic cascade markedly diminished the cytokine response suggesting regulatory relationships between these factors. Cocultures of HIV-infected monocytes and neuroblastoma or endothelial cells, or HIV-infected monocyte fluids, sucrose gradient-concentrated viral particles, and paraformaldehyde-fixed or freeze-thawed HIV-infected monocytes placed onto astroglia failed to induce cytokines and neuronotoxins. This demonstrated that viable monocyte-astroglia interactions were required for the cell reactions. The addition of actinomycin D or cycloheximide to the HIV-infected monocytes before coculture reduced, > 2.5-fold, the levels of TNF-alpha. These results, taken together, suggest that the neuronotoxicity associated with HIV central nervous system disorders is mediated, in part, through cytokines and arachidonic acid metabolites, produced during cell-to-cell interactions between HIV-infected brain macrophages and astrocytes.

Animals↗