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Biomedical subjects

J P Duffy

Publications and source records attributed to J P Duffy.

At least 19 recordsLinked to original sources
PubMed2004

Pathological determinants of survival in node-negative oesophageal cancer.

BACKGROUND: Many studies have analysed prognostic factors following oesophagectomy, but few have examined survival determinants in node-negative (N0) oesophageal cancer. The prognostic significance of a number of histological variables following surgical resection of N0 oesophageal cancer was studied. METHODS: The case notes of 219 patients undergoing potentially curative oesophagectomy for N0 squamous cell carcinoma or adenocarcinoma of the oesophagus were reviewed. Details of the patient's sex, age at operation, histological type, longitudinal tumour length, tumour (T) stage, circumferential resection margin involvement, tumour grade, presence of vascular invasion, perineural invasion, Barrett's metaplasia, and survival were noted. Univariate and multivariate analyses were performed to identify prognostic factors. RESULTS: Univariate analysis revealed three factors that correlated with poor prognosis: T stage (P = 0.024), adenocarcinoma (P = 0.033) and degree of differentiation (P = 0.001). Multivariate analysis revealed that all three were significant independent adverse prognostic indicators. CONCLUSION: Surgical resection of node-negative oesophageal cancer is associated with diverse long-term outcomes. This diversity of outcome is not reflected in the tumour node metastasis (TNM)-based staging system. The utility of the TNM system in predicting prognosis after surgical resection is open to question.

Adenocarcinoma↗
PubMed2003

Prognostic significance of circumferential resection margin involvement following oesophagectomy for cancer.

The factors affecting long-term survival following oesophagectomy for oesophageal cancer are poorly understood. We examined the significance of microscopic tumour involvement at the circumferential resection margin (CRM) on postoperative survival following oesophagectomy. The case notes of 329 patients who underwent a potentially curative oesophagectomy for squamous or adenocarcinoma were reviewed retrospectively. As part of the procedure, all patients underwent an en-bloc resection of their periesophageal tissue. The presence of tumour either at, or within, 1 mm of the CRM was recorded and correlated with their TNM and survival data. A total of 67 patients (20%) were noted to have a positive CRM, of which 40 cases (12%) had tumour at the resection margin and the remainder had tumour within 1 mm of the margin. Univariate analysis showed no statistically significant association between survival and either category of CRM involvement. Multivariate analysis showed that only T-stage, nodal status and tumour grade were prognostic markers. In conclusion, the presence of microscopic tumour at the CRM following an en-bloc oesophagectomy is not a significant prognostic marker.

Adenocarcinoma↗
PubMed2002

Preliminary findings in the neurophysiological assessment of intercostal nerve injury during thoracotomy.

OBJECTIVE: Previous work has suggested that intercostal nerve injury is a major factor in the aetiology of chronic post-thoracotomy pain. The aim of this study was to establish if there was identifiable intercostal nerve injury during thoracotomy. METHODS: Intercostal nerves were stimulated and motor evoked potentials were recorded from intercostal muscles in 13 patients undergoing thoracotomy. Measurements were taken before and after entering the pleural space, after removal of the rib retractor and after intercostal space closure. RESULTS: Intercostal nerves functioned normally before and after entering the pleural space. After the rib retractor was removed, there was a total conduction block in the nerve immediately above the incision in every patient. In the nerves above this, six had a total block, one a partial block and three had normal conduction. There was a total conduction block in the nerve immediately below the incision in all but one patient. Of the nerves below this, four had a total block, two a partial block and three had normal conduction. In the cases of total conduction block, there was either a discrete block at the level of the distal end of the rib retractor or impairment throughout the whole nerve. Intercostal space closure did not injure any previously uninjured nerve. In a solitary patient where rib retraction was not employed, there was no impairment of the intercostal nerves throughout the operation. CONCLUSIONS: This study demonstrates for the first time that intercostal nerve injury occurs routinely due to rib retraction during thoracotomy. We believe that it may be an important step toward understanding the cause of post-thoracotomy neuralgia.

Evoked Potentials, Motor↗
PubMed2001

Surgical treatment of para-oesophageal hiatal hernia.

The development of laparoscopic antireflux surgery has stimulated interest in laparoscopic para-oesophageal hiatal hernia repair. This review of our practice over 10 years using a standard transthoracic technique was undertaken to establish the safety and effectiveness of the open technique to allow comparison. Sixty patients with para-oesophageal hiatal hernia were operated on between 1989 and 1999. There were 38 women and 22 men with a median age of 69.5 years. There were 47 elective and 13 emergency presentations. Operation consisted of a left thoracotomy, hernia reduction and crural repair. An antireflux procedure was added in selected patients. There were no deaths among the elective cases and one among the emergency cases. Median follow-up time was 19 months. There was one recurrence (1.5%). Seven patients (12%) required a single oesophagoscopy and dilatation up to 2 years postoperatively but have been asymptomatic since. Two patients (3%) developed symptomatic reflux which has been well controlled on proton-pump inhibitors. Transthoracic para-oesophageal hernia repair can be safely performed with minimal recurrence.

Adult↗
PubMed2000

Surgical aspects of chronic post-thoracotomy pain.

Chronic post-thoracotomy pain is a continuous dysaesthetic burning and aching in the general area of the incision that persists at least 2 months after thoracotomy. It occurs in approximately 50% of patients after thoracotomy and is usually mild or moderate. However, in 5% the pain is severe and disabling. No one technique of thoracotomy has been shown to reduce the incidence of chronic postthoracotomy pain. The most likely cause is intercostal nerve damage, although the precise mechanism for this is not known. Future work needs to examine surgical technique in detail. Until then, patients need to be adequately warned of this sequela of thoracotomy.

Chronic Disease↗
PubMed1997

Cellular and biochemical characterization of VX-710 as a chemosensitizer: reversal of P-glycoprotein-mediated multidrug resistance in vitro.

VX-710 or (S)-N[2-Oxo-2-(3,4,5-trimethoxyphenyl)acetyl]-piperidine-2-carboxylic acid 1,7-bis(3-pyridyl)-4-heptyl ester, a novel non-macrocyclic ligand of the FK506-binding protein FKBP12, was evaluated for its ability to reverse P-glycoprotein-mediated multidrug resistance in vitro. VX-710 at 0.5-5 microM restored sensitivity of a variety of multidrug resistant cells to the cytotoxic action of doxorubicin, vincristine, etoposide or paclitaxel, including drug-selected human myeloma and epithelial carcinoma cells, and human MDR1 cDNA-transfected mouse leukemia and fibroblast cells. Uptake experiments showed that VX-710 at 0.5-2.5 microM fully restored intracellular accumulation of [14C]doxorubicin in multidrug resistant cells, suggesting that VX-710 inhibits the drug efflux activity of P-glycoprotein. VX-710 effectively inhibited photoaffinity labeling of P-glycoprotein by [3H]azidopine or [125I]iodoaryl azidoprazosin with EC50 values of 0.75 and 0.55 microM. Moreover, P-glycoprotein was specifically labeled by a tritiated photoaffinity analog of VX-710 and unlabeled VX-710 inhibited analog binding with an EC50 of 0.75 microM. VX-710 also stimulated the vanadate-inhibitable P-glycoprotein ATPase activity 2- to 3-fold in a concentration-dependent manner with an apparent k(a) of 0.1 microM. These data indicate that a direct, high-affinity interaction of VX-710 with P-glycoprotein prevents efflux of cytotoxic drugs by the MDR1 gene product in multidrug resistant tumor cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Phase II study of mitomycin, ifosfamide and cisplatin in adenocarcinoma of the oesophagus.

We evaluated the effect of brief neoadjuvant chemotherapy in patients with apparently operable adenocarcinoma of the oesophagus. Two courses of mitomycin (6 mg/m2), ifosfamide (3 g/m2) and cisplatin (50 mg/m2;MIC) were given followed by evaluation of response by barium swallow and computed tomography scan. Of 20 patients, 17 completed both courses and 4 (20%) showed a partial response. Toxicity was generally mild and consisted principally of nausea and vomiting. Altogether, 15 patients were surgically explored; resection was completed in 12 patients, 3 of whom died in hospital (25%). Neoadjuvant therapy with MIC offers no advantage over surgery alone.

Adenocarcinoma↗
PubMed1995

Design, synthesis and structure of non-macrocyclic inhibitors of FKBP12, the major binding protein for the immunosuppressant FK506.

We have synthesized a series of non-macrocyclic ligands to FKBP12 that are comparable in binding potency and peptidyl prolyl isomerase (PPIase) inhibition to FK506 itself. We have also solved the structure of one of these ligands in complex with FKBP12, and have compared that structure to the FK506-FKBP12 complex. Consistent with the observed inhibitory equipotency of these compounds, we observe a strong similarity in the conformation of the two ligands in the region of the protein that mediates PPIase activity. Our compounds, however, are not immunosuppressive. In the FKBP12-FK506 complex, a significant portion of the FK506 ligand, its 'effector domain', projects beyond the envelope of the binding protein in a manner that is suggestive of a potential interaction with a second protein, the calcium-dependent phosphatase, calcineurin, whose inhibition by the FKBP 12-FK506 complex interrupts the T-cell activation events leading to immunosuppression. In contrast, our compounds bind within the surface envelope of FKBP12, and induce significant changes in the structure of the FKBP12 protein which may also affect calcineurin binding indirectly.

Journal Article↗
PubMed1994

A phase II study of mitomycin, ifosfamide and cisplatin in operable and inoperable squamous cell carcinoma of the oesophagus.

We have evaluated the effect of mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2 (MIC) in two groups of patients with squamous or undifferentiated carcinoma of the oesophagus, as either preoperative or primary treatment. Response was assessed by barium swallow, CT scan, and measurement of metastases where present. Toxicity was acceptable and there were no chemotherapy related deaths. In the operated group, five of 23 patients (22%) showed a complete response (three confirmed histologically) and nine (39%) showed a partial response following two courses of MIC. Resection was completed in 21 patients, with three hospital deaths (14%). Of the 18 patients who were discharged from hospital, eight have died at 4-24 months (median 13) from the start of treatment and 10 are alive at 5-35 months, with known recurrence in one. In the non-operated group, five of 20 patients (25%) showed a response, one complete, following one to four (mean 2.6) courses of MIC. Nineteen patients have died (at median 5 months), and one, who had a complete response, is alive and free from disease at 29 months. Neo-adjuvant therapy with MIC in squamous carcinoma of the oesophagus has shown encouraging early results, with acceptable toxicity.

Aged↗
PubMed1994

Effects of chemotherapy on ultrastructure of oesophageal squamous cell carcinoma.

Seven oesophageal squamous carcinomas, treated with pre-operative chemotherapy (mitomycin-C, ifosfamide and cisplatin-MIC), with a course finishing 21 days prior to resection, were examined by electronmicroscopy. In one treated case detailed light microscopy failed to reveal any tumour. Five of the remaining six tumours showed cytotoxic damage in that apoptosis and unusual necrotic changes were observed in almost all the neoplastic cells. These features were not seen in untreated cases. In four additional cases, who received one pulse of MIC followed by biopsy or resection within 3-6 days, apoptotic changes were very pronounced and extensive and most neoplastic cells presented unusual degeneration with characteristic derangement of the cytoskeleton, destruction of organelles and accumulation of glycogen. The ultrastructural appearance of 18 untreated resected oesophageal squamous carcinomas was studied for comparison with the treated tumours. The study has demonstrated ultrastructural changes resulting from chemotherapy. Results suggest that the regimen is more effective against squamous carcinomas than against adenocarcinomas of the oesophagus, as judged by comparison with the results of a previous study.

Adult↗
PubMed1993

Time-course of free radical activity during coronary artery operations with cardiopulmonary bypass.

Myocardial and pulmonary impairment after cardiopulmonary bypass may be caused by oxygen free radicals produced by reperfusion and by activated neutrophils. Free radical activity was assessed by assays for lipid peroxidation (thiobarbituric acid-reactive material) and phospholipid-esterified diene conjugation (18:2[9,11]/18:2[9,12] molar ratio) in 25 patients during coronary artery operations. Arterial blood samples were obtained before, during the ischemic period, and for 24 hours thereafter. There were no significant changes in free radical indices during the ischemic periods, but after cessation of bypass they increased significantly. Ten minutes after bypass thiobarbituric acid-reactive material rose from 96 (median; range 65 to 145) nmol/gm albumin to 138 (85 to 200) nmol/gm albumin (p < 0.001), and molar ratio rose from 2.23% (0.45% to 7.70%) to 2.51% (0.39% to 7.93%) (p < 0.02). Values of thiobarbituric acid-reactive material subsequently decreased, but molar ratio reached a peak at 4 hours after bypass, 2.64% (0.55% to 10.08%) (p < 0.001), thereafter returning to baseline. The postoperative increases in thiobarbituric acid-reactive material and in molar ratio were correlated (r = +0.53; p = 0.006). These increases in thiobarbituric acid-reactive material and in molar ratio were not related to age, preoperative left ventricular function, or the number of grafts performed. Increase in thiobarbituric acid-reactive material correlated with the duration of cardiopulmonary bypass (r = +0.43; p = 0.03). In 10 patients in whom cardiopulmonary bypass was performed using a bubble oxygenator, the increases in thiobarbituric acid-reactive material were significantly greater than in the 15 in whom a membrane oxygenator was used (p < 0.02). These data show that after apparently uncomplicated coronary operations with bypass there is an increase in lipid peroxidation and diene conjugation, indicating increased free radical activity. This increase varies between patients and does not relate to patient or surgical factors but may depend on the type of oxygenator employed during bypass.

Adult↗
PubMed1989

Spontaneous aortocaval fistula--preoperative diagnosis and management.

Spontaneous aortocaval fistula is an uncommon complication of an abdominal aortic aneurysm. This report details two cases of this condition presenting with symptoms attributable to arteriovenous shunting. Pain was not a prominent feature so that attention was not initially drawn to the abdomen. Diagnosis and management of the condition are discussed.

Aged↗
PubMed1985

Noninvasive assessment of electroconvulsive-induced changes in cardiac function.

Systolic time intervals were used to noninvasively evaluate the cardiac effects of electroconvulsive therapy (ECT) in eight psychiatric patients. ECT produced a hyperdynamic cardiac state in which there was a significant increase in blood pressure, a shortening of the pre-ejection period (PEP), and an increase in rate pressure product (RPP). Changes in the PEP and the RPP are compatible with increased cardiac contractility and oxygen consumption, respectively. These effects were apparently mediated by an ECT-induced increase in circulating catecholamines, particularly epinephrine.

Adolescent↗
PubMed1984

Serum haloperidol concentrations and clinical response in acute psychosis.

Steady state serum haloperidol concentrations measured by gas-liquid chromatography and a neuroleptic radioreceptor assay were compared to clinical response in 21 acutely psychotic inpatients. Serum concentrations measured by the two assay methods correlated well with each other, although the neuroleptic radioreceptor assay was much less sensitive. There was also a significant linear relationship between haloperidol dose (mg/kg/day) and steady state serum concentration. The correlation between haloperidol serum concentrations and clinical response after 2 to 3 weeks was nonlinear and most pronounced in the intermediate range (15 to 40 ng/ml). Further studies will be needed to establish with certainty the existence and exact limits of a therapeutic window.

Adolescent↗