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Biomedical subjects

J Cunningham

Publications and source records attributed to J Cunningham.

At least 19 recordsLinked to original sources
PubMed1992

Current status of adjuvant chemotherapy for colorectal cancer. Can molecular markers play a role in predicting prognosis?

BACKGROUND: Recent clinical trials establish a beneficial effect for adjuvant chemotherapy after surgical resection of the primary tumor (1) as single treatment for patients with colonic cancer and (2) combined with radiation therapy for patients with rectal cancer. Because adjuvant chemotherapy is not universally effective and is associated with toxicity and some degree of risk, it would be desirable to supplement standard pathologic staging criteria to define more precisely the subset of patients at high risk for tumor recurrence who would benefit most from adjuvant therapy. Tumor cell DNA content and cell proliferation measured by flow cytometry were identified as important and independent prognostic factors for patients undergoing curative resection of colorectal cancer. Basic laboratory investigations show a series of more specific molecular and genetic abnormalities that might provide better prognostic discrimination. Recent molecular studies suggest that the process of tumorigenesis in colorectal cancer proceeds through a series of genetic alterations that include both dominant and recessive protooncogenes. Characterization of these molecular genetic abnormalities may provide valuable prognostic information for use in patient management. METHODS: Allelic loss was studied for chromosomes 5, 17, and 18, and immunohistochemical analysis was done of the p53 protein product in tumors from 91 patients with colorectal cancer. RESULTS: Preliminary analysis of disease-free survival after surgical resection in 60 patients with Dukes' B or C tumors suggests a poorer prognosis associated with allelic loss on chromosome 18q (P = 0.08). CONCLUSIONS: Additional studies involving a much larger population of patients with Dukes' B and C colorectal cancer are needed to define the true prognostic significance of these molecular markers.

Aged↗
PubMed1992

Expression of p53 and 17p allelic loss in colorectal carcinoma.

Mutations in the p53 gene are the most common genetic changes in cancer thus far. Many p53 mutations result in a protein product having a prolonged half-life compared to wild-type p53. The mutant protein is frequently detectable immunohistochemically, whereas the wild-type p53 present in normal cells is not. We examined 90 colorectal carcinomas for increased expression of p53 using 3 p53 specific monoclonal antibodies, PAb1801, PAb421, and PAb240. Overall, 70% of the colorectal carcinomas stained for p53. Each tumor's DNA was also assessed for loss of heterozygosity on chromosome 17p, the location of the p53 gene. Of those tumors that reacted with the anti-p53 antibodies, 76% showed loss on chromosome 17p. Tumors with loss of heterozygosity on 17p generally stained with all 3 antibodies, whereas those without loss tended to stain with just one antibody, typically PAb240. Fifteen tumors were examined for the presence of specific p53 mutations. A total of 10 mutations were found, 6 were missense and 2 were deletions, and all but one of the tumors with missense mutations stained for p53.

Alleles↗
PubMed1992

Pattern of p53 gene mutations in breast cancers of women of the midwestern United States.

BACKGROUND: Mutation in the p53 gene is the most common genetic lesion in human cancers. The pattern of mutation in the p53 gene differs among cancers and may be a useful epidemiological tool for identification of factors contributing to carcinogenesis. PURPOSE: Our purpose was to determine if the pattern of p53 mutation in breast carcinomas in our population of women residing in the midwestern region of the United States is similar to the pattern of p53 mutation in breast cancers in patients from other regions of the United States and Europe and in other epithelial tumors. METHODS: With a technique we recently developed for the analysis of p53 mutations in genomic DNA from tumor cell clusters in touch preparations of solid tumors, we sequenced exons 5-9 and adjacent splice junctions of the gene in 44 breast cancers. Cells from each tumor were also stained with three monoclonal antibodies which recognize different epitopes of the p53 protein. RESULTS: We detected p53 mutations in 14 (32.6%) of 44 breast carcinomas. Only half of the mutations were missense changes. The other half included five microdeletions (three producing frame-shifts), one single-base substitution generating a stop codon, and one single-base substitution generating a splice junction abnormality. Nuclear expression of p53 antigen was present in eight of 44 cancers, including six with hemizygous missense mutations in the p53 gene. CONCLUSIONS: The pattern of p53 mutations in our breast cancer population differs from that reported in breast cancer populations by other investigators in which most p53 mutations were missense. Among 14 mutations in our population, at least five drastically altered the structure of p53, suggesting that a recessive mechanism of inactivation of the p53 gene may be more common than in other populations. IMPLICATIONS: Differences in the pattern of p53 mutation in breast cancers in Midwestern women and in breast cancers in other populations may reflect selection bias or small sample sizes currently available. However, our data are compatible with the possibility that an endogenous or exogenous factor influences p53 carcinogenesis in some women with breast cancer in the Midwest to a greater extent than in other regions of the United States and Europe.

Adult↗
PubMed1992

Phase I trial of murine monoclonal antibody L6 in combination with subcutaneous interleukin-2 in patients with advanced carcinoma of the breast, colorectum, and lung.

PURPOSE: A phase I trial was undertaken to determine the toxicity and biologic effects of a combination of murine monoclonal antibody L6 (MoAb L6) plus subcutaneous (SC) interleukin-2 (IL-2). PATIENTS AND METHODS: Fifteen patients with refractory adenocarcinoma (five breast, five lung, five colorectal), received L6 at 200 mg/m2 intravenously (IV) daily on days 1 to 7, followed by a 1-week rest period. IL-2 was given at either 2, 3, or 4.5 x 10(6) U/m2 daily doses times 4 days for a total duration of 3 weeks. RESULTS: Side effects of L6 consisted of mild fever and chills along with a rash and serum sickness in one patient. One patient developed dyspnea and urticaria, that resolved with antihistamines. Maximum-tolerated dose (MTD) of SC IL-2 was 3 x 10(6) U/m2, with dose-limiting toxicities that consisted of grade 4 fatigue and dyspnea. Significant decreases in complement levels along with increases in absolute lymphocyte count and eosinophil count were observed. Mean antibody-dependent cellular cytotoxicity from mononuclear cells taken from patients who received IL-2 was elevated significantly compared with baseline in all patients independent of IL-2 dose (P less than .05). Serum IL-2 levels were elevated in 13 of 14 patients (range, 0.9 to 100 U/mL). Human antimouse antibody (HAMA) titers were elevated in nine of 14 (64%) patients who were tested between 3 and 8 weeks after L6 infusion. One patient with breast cancer had a transient mixed response, and one patient with colorectal cancer had a partial response. CONCLUSIONS: L6 and SC IL-2 were well tolerated in the majority of patients when given in the outpatient setting. In view of the clinical efficacy of this combination, more phase II trials are warranted.

Adult↗
PubMed1992

Dialysate calcium reduction in CAPD patients treated with calcium carbonate and alfacalcidol.

The use of oral calcium carbonate as a phosphate binder is often complicated by hypercalcaemia, particularly with concomitant use of vitamin D analogues. We previously found that stepwise reduction of dialysate calcium effectively countered this complication in haemodialysis patients, and have now assessed the strategy in CAPD patients. Seventeen patients underwent conversion from aluminium hydroxide to calcium carbonate and were followed for 5 months, with subsequent addition of alfacalcidol for a further 5 months. Standard CAPD dialysate (1.75 mM calcium) was used, reducing to 1.45 mM and, if necessary, to 1.00 mM in patients who became hypercalcaemic. While receiving calcium carbonate alone, 12 of the 17 patients became hypercalcaemic, this responding in four to dialysate calcium reduction to 1.45 mM. In the remaining eight patients, further reduction to 1.00 mM was required and in two patients even this failed to control hypercalcaemia adequately, necessitating reversion to aluminium hydroxide. Phosphate control remained unchanged, as did calcium x phosphorus product. There were transient increases of blood ionised calcium, and decreases of parathyroid hormone, with progressive reduction of serum aluminium and alkaline phosphatase. The addition of alfacalcidol (0.25 microgram/day) led to hypercalcaemia in six subjects, successfully countered by dialysate calcium reduction in four. The results show that standard CAPD dialysate calcium at 1.75 mM is too high for the majority of calcium carbonate treated patients and that substantial reductions of the dialysate calcium concentration are required if calcium carbonate is to be used effectively.

Aluminum Hydroxide↗
PubMed1992

'Pulse' oral calcitriol in uraemic patients: rapid modification of parathyroid response to calcium.

We performed dynamic parathyroid function tests, with generation of parathyroid hormone/ionized calcium (PTH/iCa) response curves, obtained during sequential hypercalcaemic and hypocalcaemic dialysis, on six haemodialysis patients before and after 4-weekly 'pulse' doses of oral calcitriol. There were no significant changes in the pretreatment, 2-week and 4-week values of blood ionized calcium, serum total calcium, phosphate, and alkaline phosphatase. PTH decreased significantly after 4 weeks of treatment with calcitriol (P less than 0.03), and the post-treatment PTH/iCa curves were all displaced leftwards and downwards, indicating a marked inhibitory effect of calcitriol on parathyroid responsiveness across and beyond the physiological range of calcaemia. The mean shift of the PTH/iCa relationship was equivalent to a reduction of iCa of 0.2 mM for any given concentration of PTH, and conversely to a 70% reduction of PTH for any given blood iCa. The results suggest that wide spacing of oral 'pulse' doses of calcitriol can achieve favourable modification of the PTH/iCa relationship, and that dosing interval and dose size, rather than route of administration, may be the major determinants of the previously reported superiority of intravenous over daily oral calcitriol regimens.

Administration, Oral↗
PubMed1992

Does the arteriovenous fistula in chronic haemodialysis patients stimulate endothelin-1 release?

Plasma endothelin-1 (ET-1)-like immunoreactivity was measured by radioimmune assay in predialysis plasma samples from 16 chronic haemodialysis patients (7 dialysing through arteriovenous (AV) fistulae and 9 using central venous cannulae for access), from 10 patients with functioning renal transplants (5 with AV fistulae and 5 without), and from 6 healthy subjects as controls. Among dialysis patients, ET-1 was greater in those with AV fistulae than in those using cannulae for dialysis (median (range), 5.5 (3.1) pM versus 3.7 (2.0) pM, P = 0.02), and in all haemodialysis patients ET-1 values were substantially greater than in normal controls (3.9 (3.2) pM versus 0.5 (0.1) pM; P = 0.001). In patients with functioning AV fistulae, ET-1 concentrations obtained directly from the AV anastomosis of the fistula (4.4 (3.0) pM) were less than those taken simultaneously from the contralateral arm (5.5 (3.1) pM; P = 0.04), while samples drawn from the venous side of the fistula were intermediate (4.6 (3.4) pM). In renal transplant recipients, ET-1 values did not differ significantly from those in control subjects (0.7 (1.9) pM versus 0.5 (0.1) pM, n.s.), but in these patients there was a significant difference between peripheral venous ET-1 in transplant patients with and without AV fistulae (0.8 (1.9) pM versus 0.6 (1.1) pM respectively, P = 0.04). The results suggest that the increased blood flow rate through the arterialized venous circulation in the fistula arm stimulates increased ET-1 release in these patients, and that this accounts, at least in part, for the increased ET-1 found in the patients with functioning AV fistulae.

Adult↗
PubMed1992

A prospective randomized trial of routine postoperative nasogastric decompression in patients with bowel anastomosis.

Until relatively recently, the nasogastric (NG) tube has been used routinely for decompression in the patient with small- or large-bowel anastomosis. To determine if routine postoperative NG decompression benefited such patients, 102 patients were randomized prospectively to either NG decompression or no-NG tube. Excluded were patients with chronic bowel obstruction, peritonitis, gross fecal contamination or spillage, and previous abdominal or pelvic irradiation. There were 52 patients in the no-NG group and 50 in the NG group. Patients in the no-NG group had earlier bowel sounds, return of flatus, oral intake and first bowel movement. Four patients (8%) in the no-NG group, compared with one patient (2%) in the NG group, required subsequent decompression. Length of hospital stay was significantly (p < 0.001) shorter in the no-NG group. There were no significant differences in the presence of atelectasis, postoperative fever, wound infections and anastomotic leaks between the two groups. The authors conclude that routine nasogastric decompression is not warranted after elective surgery involving small- or large-bowel anastomosis.

Adolescent↗
PubMed1992

Hypoxia-induced von Willebrand factor release is blocked by verapamil.

Hypoxia-induced stimulation of the rate of von Willebrand factor (vWF) release from human umbilical vein endothelial cells in culture, and the influence of the calcium antagonist verapamil, was studied using a system in which a pO2 of 20 mm Hg was achieved over 60 min. The mean +/- SEM rate of vWF release over 60 min in normoxia was 0.42 +/- 0.07% pooled plasma standard. The addition of verapamil did not alter the basal rate of vWF release, but after 60 min of hypoxia, the rate was increased to 0.71 +/- 0.03% plasma standard (p < 0.01). Verapamil at a concentration of 0.1 microgram/ml of media had no influence on the stimulated rate of release (0.78 +/- 0.07%), but increasing concentrations of verapamil up to a maximum of 1 microgram/ml attenuated the hypoxia induced stimulation (0.48 +/- 0.07%; p = 0.04 vs. hypoxic control). Thus, verapamil at this concentration completely blocked the hypoxia-induced stimulation.

Calcimycin↗
PubMed1992

Changes in total body bone mineral content and regional bone mineral density in renal patients following renal transplantation.

We performed serial measurements of total body bone mineral content (BMC) and bone mineral density (BMD), and of regional BMD at the lumbar spine and femoral neck using dual energy X-ray absorptiometry. Twenty-six patients (15 females and 11 males) were studied at the time of transplantation, and 3 and 6 months post-transplant. At baseline, the total body BMC and regional BMD values of the patients did not differ significantly from age- and sex-matched controls. Total body BMC had fallen progressively at 3 months, followed by partial recovery at 6 months. Significant decreases of BMD were seen in the lumbar spine and femoral neck at 3 months with no evidence of recovery at 6 months. The changes in these indices correlated well with the duration of hospital stay in the first 3 post-transplant months. This preliminary study demonstrated rapid deterioration of skeletal integrity following renal transplantation and that this might be progressive. Preventative strategies to avoid this early bone loss may need to be investigated.

Absorptiometry, Photon↗
PubMed1991

Reserpine-induced post-receptor reduction in muscarinic-mediated airway smooth muscle contraction.

Radioligand binding was conducted on airways of the rat and human, surgically subdivided into trachea, lung airways, and parenchyma. 3H-QNB bound uniformly to receptors in separate sections of the rat and human airway. Receptor densities generally were ranked: lung airways greater than trachea greater than parenchyma. Receptor subtypes were identified mostly by pirenzepine displacement of bound 3H-QNB. The rat trachea, and rat and human lung airways had a uniformly low affinity for pirenzepine while rat and human parenchyma demonstrated both high and low affinity pirenzepine binding. Inhibition of methacholine-stimulated smooth muscle contraction by the M1 receptor antagonist, pirenzepine, and M2 receptor antagonist, gallamine, was studied in rat trachea and bronchus in vitro. Schild plot pA2 values were compatible with low potency antagonism, thereby favoring the presence of M3 receptors at these smooth muscle sites. Reserpine treatment of rats (0.5 mg kg-1 day-1 for 7 days) produced a decrease in peak tension in response to methacholine without changing the muscarinic receptor character (Kd 3H-QNB), population density (Bmax in fmol mg-1 protein), or function (methacholine EC50). These results indicate that muscarinic receptor heterogeneity exists in the airway of both laboratory rat and man. While the muscarinic receptor subserving airway smooth muscle contraction appears to be the M3 subtype, decreased contractile responses to methacholine by trachea and bronchus from reserpine-treated rats were receptor independent.

Animals↗
PubMed1991

Mycobacterial infection is an important infective complication in British Asian dialysis patients.

To define the extent and nature of mycobacterial infection in patients on an adult dialysis unit whose catchment population contains a large proportion of non-Caucasian subjects, a retrospective survey of all new patients accepted onto our maintenance dialysis programme between January 1987 and December 1989 was carried out. Twenty-six Asian, 13 Afro-Caribbean, two Oriental and 170 Caucasian patients were accepted onto the dialysis programme in the three-year recruitment period. Eight of the 26 Asian patients, but none of the others, had developed mycobacterial infection by the end of December 1990. One patient had a cerebral tuberculoma with miliary mottling on chest X-ray, one pulmonary tuberculosis, one tuberculous adenitis and 5 tuberculous peritonitis (four due to Mycobacterium tuberculosis and one Mycobacterium kansasii). All the patients had been living in the UK for an average of 15 (range 6-24) years, with no known recent exposure to tuberculosis. Five patients are now alive and well, one developed malabsorption following M. kansasii peritonitis, but two with tuberculous peritonitis died before treatment could be instituted. Mycobacterial infections were associated with a high level of mortality and morbidity. No Asian patient developed mycobacterial infection during post-transplant immunosuppressive therapy in the study period, probably because of the routine anti-tuberculous chemoprophylaxis employed in this group of patients. The diagnosis of mycobacterial infection should be suspected when an Asian dialysis patient develops a pyrexia of unknown origin. It is likely, though not proven, that anti-tuberculous chemoprophylaxis might reduce this high incidence of tuberculous infection in Asian dialysis patients.

Adult↗
PubMed1991

Crescentic transformation in primary membranous glomerulonephritis.

A 31 year old man first developed steroid-resistant idiopathic membranous glomerulonephritis in 1981. Stable normal renal function was maintained until August 1988 when he suffered a clinical relapse with heavy proteinuria and declining renal function. Immunosuppressive therapy with prednisolone and cyclophosphamide was instituted in an attempt to arrest this relapse. Despite this, he later developed acute renal failure with histological evidence of crescentic transformation of his nephritis. This unusual transformation was not associated with features of systemic vasculitis or positive anti-glomerular basement membrane and anti-neutrophil cytoplasmic antibodies.

Adult↗
PubMed1991

Pneumocystis carinii pneumonia: detection of parasites by immunofluorescence based on a monoclonal antibody.

A monoclonal antibody-based immunofluorescence test for the detection of Pneumocystis carinii was evaluated in comparison with the conventional direct staining by Grocott's silver methenamine technique. A total of 254 respiratory samples from HIV positive and other immunocompromised patients were examined. Cysts were detected in 30 (12%) of samples using the monoclonal test, but only 15 (6%) positives were found using the Grocott method. There is need for a speedy and efficient test for detection of these organisms, and the monoclonal test was found to be more reliable, quicker and more sensitive than the Grocott technique.

Acquired Immunodeficiency Syndrome↗