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Biomedical subjects

J E Wright

Publications and source records attributed to J E Wright.

At least 19 recordsLinked to original sources
PubMed1992

Defective transport as a mechanism of acquired resistance to methotrexate in patients with acute lymphocytic leukemia.

Although the mechanisms of resistance to methotrexate (MTX) are known in experimental tumors made resistant to this drug, little information is available regarding acquired resistance to MTX in patients. A competitive displacement assay using the fluorescent lysine analogue of MTX, N-(4-amino-4-deoxy-N10-methylpteroyl)-N epsilon-(4'-fluorescein-thiocarbamyl)-L-lysine (PT430), was developed as a sensitive method of detection of transport resistance to MTX in cell lines, as well as in blast cells from patients with leukemia. Rapid uptake of PT430 at high concentrations (20 mumol/L) in leukemic blasts resulted in achievement of steady-state levels within 2 hours. Subsequent incubation with the folate antagonists, MTX and trimetrexate (TMTX), which differ in the mode of carrier transport, produced characteristic patterns of PT430 displacement. Flow cytometric analysis of the mean fluorescence intensity in the human CCRF-CEM T-cell lymphoblastic leukemia cell line and its MTX-resistant subline clearly identified the presence of transport deficiency in the resistant subline. Analysis of blasts from 17 patients with leukemia, nine with no prior chemotherapy and eight previously treated with chemotherapy, found evidence of MTX transport resistance in two of the four patients who were treated with MTX and considered to be clinically resistant to the drug. The finding that blast cells of some patients with leukemia considered clinically resistant to MTX is due to decreased MTX transport has important implications for clinical use of this drug and for new drug development.

Adolescent↗
PubMed1992

Characterization of the coexisting multiple mechanisms of methotrexate resistance in mouse 3T6 R50 fibroblasts.

We have studied the discrepancy in the degree of methotrexate (MTX) resistance that exists between two clonal cell lines, mouse 3T6 R50 cells and Chinese hamster ovary B11 0.5 cells that overexpress comparable levels of dihydrofolate reductase, yet exhibit a 100-fold difference in MTX resistance while maintaining similar sensitivity to the lipophilic antifolates trimetrexate and piritrexim. These data suggested that R50 cells may possess additional mechanism(s) of antifolate resistance, such as MTX transport alteration. Flow cytometric analysis using fluorescein methotrexate revealed comparable levels of fluorescein MTX displacement with lipophilic antifolates in viable R50 and B11 0.5 cells, but marked insensitivity of R50 cells to MTX competition, thus suggesting a poor uptake of MTX into R50 cells. Analysis of the kinetic parameters of dihydrofolate reductase from R50 cells neither showed alterations in enzyme affinities for various antifolates nor in the Michaelis constant for folic acid and NADPH nor a change in the pH activity optimum. R50 cell-free extracts contained wild-type levels of folylpoly-gamma-glutamyl synthetase activity. However, following metabolic labeling with [3H]MTX, no MTX polyglutamates could be detected in R50 cells. We conclude that the high level of MTX resistance in R50 cells is multifactorial, including overexpression of dihydrofolate reductase, reduced MTX transport, and possibly altered formation of MTX polyglutamates. The potential interactions between the different modalities of MTX resistance in R50 cells are being discussed.

Animals↗
PubMed1992

Haemangiopericytoma of the orbit.

Orbital haemangiopericytomas are ideally managed by complete surgical excision in the first instance. This is frequently not achieved, because difficulty in making the diagnosis preoperatively results in incisional biopsy and the highly vascular nature of the tumour makes complete excision difficult. A series of 12 patients with orbital haemangiopericytoma seen over a 23-year period is presented. The following combination of clinical and radiological features is suggestive of haemangiopericytoma. 1. Painless non-axial proptosis with downward displacement of the globe. 2. Intermittent upper lid swelling. 3. A soft, superiorly located mass with poorly defined borders, especially with a blue hue. 4. A superiorly located, rounded or elongated extraconal mass on CT, isodense with brain, with smooth, well-defined borders and moderate to marked enhancement with the injection of intravenous contrast medium. 5. Significant blush in all three phases of carotid angiography, without prominent arteriovenous shunting. Once haemangiopericytoma is suspected, complete surgical excision is recommended.

Adult↗
PubMed1992

Dedifferentiated chondrosarcoma arising in the orbit.

Orbital chondrosarcomas are extremely rare and are usually an extension of tumours involving the paranasal sinuses. A unique case of dedifferentiated chondrosarcoma arising solely within the orbit is presented.

Adult↗
PubMed1992

Pleomorphic adenoma of the lacrimal gland.

To reduce the risk of recurrence and malignant transformation, pleomorphic adenomas of the lacrimal gland should be removed intact, without prior biopsy. Seventy one of the 78 patients in this series were referred without previous surgery, and, on clinical or radiological evidence, 63 (89%) tumours were correctly diagnosed and totally excised, with preservation of a margin of the surrounding normal tissue. Sixty three patients had tumour within the body of the gland and 55 (84%) had radiological signs or satisfied clinical criteria for pleomorphic adenoma that we suggested previously; that is, over 1 year of symptoms and absence of pain. Eight (16%) orbital lobe tumours were misdiagnosed preoperatively and biopsied; in all these patients symptoms had been present for less than 1 year, and four patients had pain. Eight patients with tumours arising in the palpebral lobe had a short history of an upper lid mass, and their tumours were excised without biopsy. With the surgical techniques described in this paper, there has been no recurrence of tumour in patients with follow-up as long as 21 years. A modification of surgical technique, with preservation of the palpebral lobe of the gland, has reduced the incidence of postoperative dry eye and distortion of the upper eyelid.

Adolescent↗
PubMed1992

Primary malignant neoplasms of the lacrimal gland.

The clinical characteristics and outcome of 50 primary malignant neoplasms of the lacrimal gland are reviewed: 38 (76%) adenoid cystic carcinomas, six (12%) carcinomas arising in pleomorphic adenoma, and six (12%) adenocarcinomas or other types of carcinoma. Most patients presented with a short history and pain, though pain tended to occur less often and later with adenocarcinoma than with adenoid cystic carcinoma. Pain was unrelated to the duration of symptoms, invasion of bone, loss of trigeminal nerve function, or the frequency and time of tumour recurrence. The estimated disease-free survival for patients with adenoid cystic carcinoma was significantly (p less than 0.01) reduced where half or more of the biopsy specimen showed basaloid differentiation. Eleven patients underwent extended cranio-orbital resection, and the others received a combination of total dacryoadenectomy adenectomy and/or radiotherapy. Survival after adenoid cystic carcinomas appears to be significantly (p less than 0.05) greater when tumour resection is combined with radiotherapy than after radiotherapy alone. At present, however, the rate of disease-free survival after treatment of adenoid cystic carcinoma appears unaltered by cranio-orbital resection, though these latter patients form a relatively greater proportion of those surviving for more than 10 years. Further long-term follow-up is needed to see if this technique does influence survival.

Adenocarcinoma↗
PubMed1992

Actinomycosis of the orbit.

Actinomycosis is a very rare cause of orbital abscess usually attributable to direct spread from adjacent structures. A case of actinomycosis of the orbit is presented, which was treated as orbital pseudotumour for 3 months before progression of signs and symptoms, despite high dose steroids, led to the diagnosis being reconsidered.

Actinomycosis↗
PubMed1992

Cyclophosphamide pharmacokinetics: correlation with cardiac toxicity and tumor response.

BACKGROUND: Cyclophosphamide, which forms the nucleus for virtually all preparative regimens for autologous bone marrow transplantation (ABMT), is an alkylating agent of which cytotoxicity is not directly caused by the parent compound but by its biologically active metabolites. Its nonmyelosuppressive toxicity in the ABMT setting is cardiomyopathy. We attempted to determine any correlation between plasma levels of total cyclophosphamide and the subsequent development of cardiac dysfunction. PATIENTS AND METHODS: Analyses of plasma levels and the derivation of plasma concentration-time curves (area under the curve [AUC]) were performed in 19 women with metastatic breast carcinoma, who received a continuous 96-hour infusion of cyclophosphamide, thiotepa, and carboplatin (CTCb) with ABMT. The assay for total cyclophosphamide measures the inactive parent compound; reliable assays of the active metabolites of cyclophosphamide are not yet available. RESULTS: Six of 19 women developed moderate, but transient, congestive heart failure (CHF) as assessed by clinical and radiologic criteria. These patients had a significantly lower AUC of total cyclophosphamide (median, 2,888 mumol/L/h) than patients who did not develop CHF (median, 6,121 mumol/L/h) (P less than .002). Median duration of tumor response in these patients was also more durable; at least 22 months in patients with lower AUCs versus a median of 5.25 months in those with higher AUCs (P = .008). CONCLUSION: These pharmacokinetic data support the premise that enhancement of cyclophosphamide activation may lead to both greater tumor cytotoxicity and increased but reversible end-organ toxicity. Early analysis of pharmacokinetic data may allow modulation of cyclophosphamide administration in an attempt to enhance therapeutic efficacy.

Adult↗
PubMed1992

[Anabolic steroids in athletes].

The use of anabolic-androgenic steroids (AS) to enhance appearance as well as physical/physiological capacities has increased dramatically over the past four decades in all age groups from early adolescence to adulthood. Although higher AS use rates are reported by elite and competitive athletes, a significant number of recreational athletes appear to be using AS. The scientific literature is inconsistent and at times at odds with the conventional wisdom and empirical experiences of the athletic community regarding the ergogenic effects of AS. However, individuals experienced in weight training, with an adequate diet, and who continue training during AS administration seem to consistently increase their strength and lean mass over what would have been expected from training alone. Previous research documenting deleterious but transient and mostly asymptomatic acute changes in physiology, risk factors and behavior has been inconclusive regarding the long term health impact. The abuse of AS constitutes a special challenge to society. AS are not euphorigenic or mood altering immediately following administration, as are other illicit drugs; the appetite for AS has been created predominantly by our societal fixations on winning and physical appearance. Consequently any successful intervention in this area must go beyond education, law enforcement and drug testing, and attempt to change a social environment which currently encourages the use of AS.

Anabolic Agents↗
PubMed1991

Isolated peripheral nerve sheath tumours of the orbit.

Fifty-four cases of peripheral nerve sheath tumours within the orbit are reviewed. Benign neurilemmomas or neurofibromas occurred in 93% of patients and had an equal incidence. There was a family history or other signs of systemic neurofibromatosis in one-quarter of those with solitary neurofibromas, but in none of the patients with neurilemmoma. Symptoms and signs were generally those of an orbital mass lesion and pain or sensory loss was unusual, occurring more frequently with malignancy. Within the orbit, most peripheral nerve sheath tumours affect the first division of the trigeminal nerve and extension of some tumours through the superior orbital fissure limits their surgical resection. Despite incomplete resection of some tumours, with up to 23 years follow-up there have been no recurrences requiring further surgery. A postoperative sensory deficit occurred in only 32% of patients with benign neurilemmomas and 72% with neurofibromas.

Adolescent↗
PubMed1991

Direct inguinal hernias in the newborn.

Direct inguinal hernias occur in newborn babies, both term and premature. Five cases are reported to illustrate three types of direct hernia. The first is a direct weakness without associated significant indirect hernial sac; the second, a sliding direct hernia. The third might be called a 'secondary' direct weakness resulting from a primarily indirect hernia which assumes such large size and develops such a wide neck at the internal ring that the posterior wall of the inguinal canal is stretched and weakened. This is most likely to occur in very low birthweight babies, who develop giant inguinoscrotal hernias. Full exploration and repair of the posterior wall of the inguinal canal should be performed in such babies with huge indirect hernial sacs and in all babies where the size of the processus vaginalis identified at the internal ring is not consistent with the hernial swelling identified clinically. Repair should be performed in conventional manner with non-absorbable sutures reinforcing the transversalis fascia. Overlying Bassini repair with or without Tanner's slide can be performed. The repair should be carried out before the baby leaves a high dependency area.

Hernia, Inguinal↗
PubMed1991

Intussusception in Newcastle in a 25 year period.

The history of intussusception in Newcastle in a quarter of a century is presented by analysis of patient presentation and the results of management. The figures for the early years are incomplete, retrieved from one hospital in the area. For the years 1976-1988, all cases were managed by two paediatric surgeons who kept individual disease indices. One hundred and sixty-five episodes of intussusception in 153 patients were reviewed in this study. There was one death in the series, whereas there had been several in the years preceding it. There has been an improvement in the success of hydrostatic and later pneumatic reduction. These changes are attributed to the development of appropriate skills resulting from concentration of the management of this problem in the hands of paediatric surgeons and radiologists with special training and interest in paediatrics. Enema reduction has been used more aggressively in recent years and has widened criteria. In the series there were 8 patients with causal lead points, none associated with recurrence. The overall recurrence rate within the series was estimated at 8%. There seems to be a high incidence of intussusception in doctors' families.

Abdomen↗
PubMed1991

Orbital xanthogranuloma in adults.

The onset of periorbital xanthogranuloma in adults is rare and may be accompanied by haematological abnormalities and malignancy. The appearance of the eyelid lesions is virtually diagnostic, producing readily recognisable diffuse, yellow plaques, and affected patients should be investigated and reviewed regularly for systemic disease. Three cases are described, in which periorbital cutaneous plaques were associated with abnormal tissues in the superior part of the orbit; these abnormal tissues caused displacement or restricted movement of the globe or upper eyelid. The possibility that two cases represent a necrobiotic type of xanthogranuloma is presented. Nine years after the onset of xanthogranuloma one patient developed non-Hodgkin's lymphoma. A multiple-drug regimen of systemic chemotherapy, given for lymphoma, caused a marked clinical reduction in the periorbital xanthogranuloma.

Adult↗
PubMed1991

Orbital lymphoma versus reactive lymphoid hyperplasia: an analysis of the use of computed tomography in differential diagnosis.

Computed x ray tomography (CT) studies of 40 patients with proptosis or periorbital swelling, in whom biopsy showed lymphoma in 23 and reactive lymphoid hyperplasia in 17, were analysed in an attempt to identify radiological differences between the two conditions. The results indicate that homogeneity of an orbital mass is a sensitive but non-specific indication of lymphoma, 75% of lymphomatous masses and only 23% of reactive lesions being homogeneous. Bone destruction was seen only in cases of lymphoma, but was rare. Other radiological features of the mass or the affected orbital structures did not allow discrimination of tumour from a reactive lesion.

Diagnosis, Differential↗