Biomedical subjects
Publications and source records attributed to M R Williams.
A simple and inexpensive means of creating autologous fibrin glue is described that avoids the potential disadvantages of conventionally obtained material. This improvement may allow more widespread use of fibrin glue for operative bleeding.
Management of bronchopleural fistula is a challenging clinical problem. Laser-assisted cryoprecipitate bonding techniques offer a means to fix precisely tissue glues into the fistulae through a bronchoscopic approach. Analogous studies exist using fibrin glue with thrombin. Using a canine model, secondary bronchi were sealed with cryoprecipitate made from solvent/detergent-treated plasma (treated to inactivate membrane-enveloped virus) mixed with indocyanine green (absorption 805 nm). Diode laser energy (emission 808 nm, 7.3 W/cm 2) was applied to the solder until dessication was observed. Leakage pressures (n = 7) ranged between 18 and 86 mmHg with a mean of 46 +/- 24 mmHg. Laser-assisted solder techniques provide a reliably strong seal over leaking bronchial stumps and use of dye enhancement prevents undesired collateral thermal injury to surrounding bronchial tissue. Solvent/detergent plasma, prepared by methods shown to inactivate large quantities of HIV, HBV, and HCV, is an effective source of cryoprecipitate and should allow widespread use of pooled human material in a clinical setting.
In a trial conducted in the south of England in January to February 1989, blood samples were obtained from nine dairy herds with more than 30 cases of clinical mastitis/100 cows and from nine herds with less than 30 cases/100 cows during the previous 12 months. Whole blood glutathione peroxidase (GSHPx) activity and plasma vitamin E concentration were determined for 12 cows in each herd. The mean (+/-sd) values for the herds with the lower incidence of mastitis were 7.57 +/- 1.86 micrograms/ml plasma vitamin E and 23.8 +/- 22.8 U/ml rbc GSHPx activity, compared with 7.74 +/- 1.69 micrograms/ml plasma vitamin E and 20.61 +/- 8.8 U/ml rbc GSHPx activity for the herds with the higher incidence of the disease. These values indicate that the vitamin E levels were generally adequate but that some animals and herds had low GSHPx activities, suggesting that their diets may have contained inadequate selenium. The activities of GSHPx and the vitamin E levels in plasma were not significantly different in the two groups of herds, and no relationship was found between the two nutrients and the incidence of clinical mastitis. However, there was a significant negative correlation between the activity of GSHPx and the bulk milk cell counts in the herds with a low incidence of mastitis suggesting that there was an association between the incidence of subclinical mastitis or inflammation and the selenium status of these herds.
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Pregnant heifers were infused intramammarily with ovalbumin in one quarter and killed S. uberis in another quarter. The animals were slaughtered at time intervals after infusion, and tissues were collected from different parts of the gland and from the local lymph nodes. Ovalbumin and bacteria reached the lymph nodes as early as 1 and 3 h after infusion respectively. Ovalbumin was also present in blood 5-10 min after infusion and in non-infused quarters. Both ovalbumin and bacteria were phagocytosed by the epithelium of the mammary gland. However, bacteria were seen in the tissues in small numbers at all stages after infusion. Larger numbers were phagocytosed by neutrophils in the lumen of ducts, 18 h after infusion. Phagocytosis of both ovalbumin and bacteria was not present in the connective tissue of the gland. The results indicate increased permeability of the preparturient gland to soluble proteins, but limited uptake of bacteria. Furthermore, a mechanism of transfer of antigens among quarters has been suggested.
A series of tumour related markers have been examined in 179 patients receiving primary endocrine therapy for metastatic breast cancer. Significant correlations between therapeutic response (UICC criteria after 6 months of treatment) and appropriate alterations in serum concentrations of carcinoembryonic antigen, ferritin, c-reactive protein, orosomucoid and the erythrocyte sedimentation rate, have been observed when changes in these markers were examined only at high serum concentrations. By combining these five markers a 'therapeutic index' of response has been devised which can be employed at an early stage of treatment in more than 90% of patients, giving an overall sensitivity/specificity of 90%/78% for therapeutic response or disease stabilisation over a 6-month period. The design of an objective measurement of response, which is easy to perform, has the potential to replace the existing, largely subjective. UICC criteria for retrospective judgement of response, and may also be used to direct systemic endocrine therapy.
Depression of myocardial conduction velocity can be an important mechanism of action of antiarrhythmic drugs but it can also facilitate arrhythmogenesis. We used lidocaine in an anesthetized canine preparation to address the hypothesis that drug-induced rate-dependent conduction velocity depression causes ventricular tachyarrhythmias. A closely spaced square array of 64 electrodes was used to determine conduction velocity longitudinal and transverse to epicardial ventricular fiber direction. Lidocaine caused rate-dependent decreases in conduction velocity that were proportionately greater in the longitudinal direction at the shortest pacing cycle lengths. Conduction velocity depression developed rapidly in the presence of lidocaine with a new steady state present by the second beat of the rapid train. Recovery from rate-dependent depression of conduction velocity was exponential with a time constant of 122 +/- 20 msec (mean +/- SD) in the longitudinal direction and 114 +/- 30 msec in the transverse direction; this difference was not significant. The relation between conduction velocity depression and ventricular arrhythmias was assessed by pacing for 3 minutes at cycle lengths of 1,000, 500, 300, and 250 msec, and for 1 minute at a cycle length of 200 msec. Arrhythmias did not occur in the baseline period in the dogs that received lidocaine, nor in 12 control dogs that were subjected to the same stimulation protocol except that saline was administered in place of lidocaine. Sustained polymorphic ventricular tachycardia (VT) occurred in six of 16 dogs given lidocaine. VT occurred in the presence of relatively high plasma lidocaine concentrations (8.4 +/- 2.3 micrograms/ml) and only at pacing cycle lengths of 300 msec or shorter. The dogs that developed VT demonstrated greater rate-dependent depression of conduction velocity than the other dogs, and activation patterns obtained just before the onset of VT showed marked conduction disturbances. Furthermore, QRS prolongation, loss of one-to-one capture, and increasingly distorted activation patterns preceded the onset of VT during fixed-rate pacing, suggesting progressive sodium channel block. In summary, rate-dependent conduction velocity depression and nonuniform activation were associated with VT in this model and can be responsible for some arrhythmias induced by antiarrhythmic drugs.
Ferritin concentrations have been measured in serum from 266 patients receiving primary endocrine therapy for advanced breast cancer. Concentrations were significantly higher at presentation of advanced disease than in 55 tumour-free control patients. A positive correlation existed between increasing serum ferritin and tumour burden at presentation. A strong correlation was also found between therapeutic response and changes in serum ferritin (above 200 micrograms/l) in patients with distant metastases. More than one third of patients presenting with Stage IV disease developed concentrations in excess of 200 micrograms/l during initial treatment.
Two strains of Streptococcus uberis (0140J and EF20), previously shown to differ markedly in their ability to infect the mammary gland and cause clinical mastitis, showed correlated differences in their resistance to some host defence mechanisms. Both strains produced a hyaluronic acid capsule but strain 0140J, the more infective, was more resistant than EF20 to phagocytosis and killing by bovine neutrophils. Loss of the capsule from strain EF20 during the stationary phase of growth did not affect its resistance to phagocytosis. Strain 0140J also grew more rapidly than EF20 in raw skimmed milk but dithiothreitol substantially reversed this inhibition, suggesting the involvement of the lactoperoxidase system in the inhibitory effect of raw milk.
We have treated 238 patients with advanced breast cancer with megestrol acetate (Megace, Bristol-Myers): 221 were assessable for response at 6 months by UICC criteria. Thirty-six (16%) patients responded, 54 (25%) were static and 131 (59%) progressed. Survival from the time of starting Megace calculated by log-rank analysis showed no significant difference in survival between patients showing response and static disease at 6 months. Patients with progression of disease within 6 months survived significantly shorter than patients who showed response or static disease at 6 months. Categorizing response at 6 months appeared to identify patients who had static disease of worthwhile duration. ER status of the primary tumour correlated significantly with survival from the time of commencing Megace. However, when Megace was used as a second-line hormone therapy the assessment of response or static disease on prior hormone therapy was a better predictor of the effect of Megace than ER status of the primary tumour.
We have treated 76 patients with advanced breast cancer with single-agent mitoxantrone: all had previously received hormone therapy and 30 patients had also received prior chemotherapy. The overall response rate at 6 months was 15%, with a further 22% having static disease. Responding and static patients had similar survival curves and were grouped together as patients with "stable disease." Patients with stable disease had a significantly longer survival than patients with progressive disease (p less than 0.001); the median difference in survival was 9 months.
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This study examines the necessity for repeated full skeletal radiographic surveys to assess the response of bone metastases from breast cancer to systemic treatment. This method of evaluating response is compared with that achieved using sequential radiography of the pelvis alone. Sequential changes on pelvic radiographs were identical to those seen on a complete skeletal survey in 87% of the patients studied. In only 6% of the patients were the changes on the pelvic radiographs sufficiently at variance with those on the skeletal survey to suggest a difference in management. It is suggested that sequential radiography of pelvic bones alone is sufficient to assess response of bone metastases in breast cancer in the majority of patients.
Serum carcinoembryonic antigen (CEA) has been measured throughout initial systemic endocrine treatment in 87 patients with stage III and 179 patients with stage IV breast cancer. Clinical response has been assessed after six months according to UICC criteria with external review of clinical and radiological data. Pretreatment CEA concentrations have been compared with those found in 55 'disease free' women attending a diagnostic breast clinic. A strong correlation exists between therapeutic response and alterations in CEA concentration (above 6 ng/ml) in patients presenting with stage IV disease. More than 50% of such patients either present with or develop CEA concentration greater than 6 ng/ml during the first six months of treatment.
Eighty-seven postmenopausal patients have been randomised to receive either radiotherapy or Nolvadex (tamoxifen) as first line treatment for locally advanced (stage III) breast cancer. After a median follow-up of two years no significant differences have been found in the rate of progression of local disease, the time to development of overt metastases or survival.
ER content of primary tumour tissue has been examined in 704 patients presenting with operable breast cancer. The median follow-up is now 84 months and no patient has received adjuvant therapy of any kind. ER status is related to histological grade, menopausal status, initial site of metastases and subsequent response to endocrine therapy. A significant advantage in terms of survival is found in ER positive patients which is confined to those lymph node positive at mastectomy. DFI is also significantly related to ER status in lymph node positive patients. Survival after the symptomatic presentation of metastases and the institution of endocrine therapy is prolonged in patients with ER positive tumours. The overall response rate to endocrine therapy in assessable patients with ER positive tumours is 32%. By combining the ER status and histological grade of tumour tissue, a group of patients comprising 28% of those assessable to endocrine therapy can be identified (ER positive, grade I and II) with a response rate of 46%.
A prognostic index, previously derived in a group of 387 patients with primary breast cancer, has been recalculated for the same patients with over 5 years further follow-up and shown to be unchanged. The prognostic index has also been applied prospectively to a further group of 320 patients and shown to be similarly effective in identifying patients with either a very good or a very poor prognosis. It has been verified that the index applies to patients with primary breast cancer. Patients have now been divided into 5 prognostic groups, predicting 11% of patients with an almost normal survival and a further 10% with a very poor prognosis. The index is used to stratify patients to study the effects of treatment regimes within groups of similar patients.
This study investigates a series of factors, all recordable by the time of presentation of distant metastases from primary breast cancer and relates these to survival after the initiation of endocrine therapies. One hundred and ninety-one patients have received endocrine therapy as initial treatment for distant metastases. In all patients both the histological grade and oestrogen receptor (ER) status of primary tumour tissue; the lymph node stage and menopausal status at mastectomy and the disease-free interval and sites of initial metastases are available for analysis. Four of these factors have been found to contribute independently towards prolonged survival after the initiation of treatment: tumour grade, ER status, disease-free interval and sites of metastases. Employing a multivariate analysis incorporating these four factors, three groups of patients have been identified with survivals of 67, 37 and 0 per cent at 18 months on therapy. These three groups of patients contain 37, 41 and 22 per cent of the patient population respectively.