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Biomedical subjects

M Baum

Publications and source records attributed to M Baum.

At least 271 records · Page 15Linked to original sources
PubMed1993

Effect of oestrogen receptor status and time on the intra-tumoural accumulation of tamoxifen and N-desmethyltamoxifen following short-term therapy in human primary breast cancer.

While the presence of oestrogen receptors (ERs) in human breast cancer may determine the biological response to tamoxifen, the extent to which ER status governs tumour tamoxifen accumulation is unclear. We investigated the intra-tumoural disposition of tamoxifen (TAM) and its major metabolite N-desmethyltamoxifen (DMT) in 36 human breast carcinomas following short-term therapy. Steady-state serum concentrations appeared to be reached following 2 weeks therapy, after which no significant difference in the intra-tumoural concentrations of TAM between ER-ve and ER+ve tumours was observed (717.9 +/- 166.4 ng/gm, and 518.6 +/- 109.4 ng/gm, respectively). In patients treated for less than 2 weeks, there was significantly less intra-tumoural TAM in ER-ve compared with ER+ve tumours (120.9 +/- 49.9 ng/gm and 450.1 +/- 75.3 ng/gm, respectively; p < 0.04). The rate of tumour TAM accumulation correlated with duration of therapy only for ER-ve tumours (r = 0.72, p < 0.02), whereas for ER+ve tumours the absolute ER value appeared to be weakly associated with TAM accumulation (r = 0.41; p < 0.05). The intra-tumoural ratio of TAM to DMT reflected the serum concentrations in ER-ve tumours, but in ER+ve tumours relatively more TAM to DMT was observed. A similar intracellular distribution of both TAM and DMT was observed, although following 2 weeks therapy relatively less of each compound was found in the cytosol of ER-ve compared with ER+ve tumours (18% vs 34%). These results demonstrate that ER status may influence the rate of accumulation and intra-cellular distribution of tamoxifen and its metabolites, but not the final concentrations which are achieved. Following steady-state, both ER+ve and ER-ve tumours, not all of which would be expected to respond to the drug, achieve intra-tumoural concentrations 5-7 fold greater than serum. Unlike recent reports on acquired resistance, therefore, de novo resistance to tamoxifen is unlikely to represent an inability of the tumour to achieve adequate intra-tumoural concentrations of the drug or its metabolites.

Aged↗
PubMed1993

Maturation of proximal tubular acidification.

Neonatal juxtamedullary proximal convoluted tubules (PCTs) transport bicarbonate at one-third the rate of adult rabbit PCTs. The lower rate of bicarbonate transport could be due to a greater permeability of the neonatal PCT to bicarbonate or to a lower rate of active bicarbonate transport. This review discusses potential factors which could result in a lower rate of bicarbonate transport by the neonatal PCT. In isolated perfused PCT, bicarbonate permeability is lower in neonatal than adult PCT, and thus it does not account for the lower rate of bicarbonate transport in neonatal PCT. In the adult PCT, apical proton secretion occurs via the Na+/H+ antiporter and H(+)-ATPase; basolateral bicarbonate exit occurs via the Na(HCO3)3 symporter. The activity of transporters can be ascertained by measuring intracellular pH with the fluorescent dye BCECF. Apical Na+/H+ antiporter, apical H(+)-ATPase and basolateral Na(HCO3)3 symporter activity are all significantly lower in neonatal PCT. The factors which stimulate PCT maturation are unknown, however glucocorticoids have been postulated to play an important role in this process. Administration of dexamethasone to pregnant does results in higher rates of PCT volume absorption, bicarbonate transport, Na+/H+ antiporter and Na(HCO3)3 symporter activities than in PCT from vehicle-treated controls. Thus, the lower rate of neonatal PCT bicarbonate transport is due to lower activities of the apical Na+/H+ antiporter, apical H(+)-ATPase and basolateral Na(HCO3)3 symporter. Glucocorticoids may be an important factor in the maturation of PCT acidification.

Animals↗
PubMed1993

Side-effects of screening.

There has been a 42% increase in the number of mammograms performed outside the national screening programme (operating in Camberwell, southeast London) which was not anticipated in the Forrest Report, a document to the Health Ministers of the U.K. by a working group chaired by Sir Patrick Forrest. The report compiles recommendations on breast screening, using mammography and breast self-examination, to reduce the mortality in women aged 50-64 years. This 42% increase is attributable mainly to referrals from menopause clinics and general practitioners of patients mainly in the screening age group. When we looked at referrals from general practitioners, suspicious mammographic findings were reported in 20% of patients referred with a breast lump, in contrast to only 4% of patients referred with breast pain or nodularity. Better education of both the public and general practitioners, concerning the signs and symptoms of breast cancer, may reduce demands to perform mammographies outside the current national screening programme.

Ambulatory Care Facilities↗
PubMed1993

Primary medical (neo-adjuvant) chemotherapy for operable breast cancer.

84 patients with large operable breast cancer have been treated with primary medical chemotherapy rather than mastectomy in three sequential studies. 86% had tumours greater than 4 cm in diameter; median diameter was 6 cm (range 1-12). Median age was 46 years (range 23-66). In the first two studies 64 patients were treated with either CMF [cyclophosphamide 100 mg orally days 1-14, methotrexate 50 mg intravenously (i.v.) days 1 and 8, and 5-fluorouracil 1 g i.v. days 1 and 8, repeating at 28-day intervals for six courses] or MMM (mitozantrone 8 mg/m2 i.v. once every 3 weeks, methotrexate 50 mg i.v. once every 3 weeks, mitomycin C 8 mg/m2 once every 6 weeks, for 8 courses). 69% achieved an overall response including 17% complete remissions. 27% have had local relapse but only 3% uncontrolled local relapse. Only 14% have required mastectomy. In the third study which is ongoing, 19 patients have been treated with infusional FEC (5-fluorouracil 200 mg/m2 i.v. 24 hourly by continuous infusion via a Hickman line for 6 months, epirubicin 50 mg/m2 i.v. bolus once every 3 weeks for 6 months, cisplatin 60 mg/m2 i.v. once every 3 weeks for 6 months with appropriate intravenous hydration). Overall response rate so far is 84% with 58% complete remissions. There have been no local relapses and no patient has required mastectomy. This study demonstrates that primary medical chemotherapy can be used to avoid mastectomy in the great majority of patients presenting with large operable primary breast cancer. Infusional FEC may be more active than conventional chemotherapy in terms of overall response and complete remission rate, and infusional FEC chemotherapy now needs to be compared with conventional chemotherapy. The concept of primary medical therapy should also be compared with conventional mastectomy followed by adjuvant chemotherapy.

Adult↗
PubMed1993

Radioimmunolocalisation in breast cancer using the gene product of c-erbB2 as the target antigen.

Lymph node status is still the single most important prognostic factor in breast cancer. Axillary surgery remains the only reliable means of providing this information. This pilot study evaluates using a highly specific radiolabelled monoclonal antibody to provide equivalent information by a non-invasive technique. After optimisation of labelling conditions, our first antibody, ICR12 (against the gene product of c-erbB-2) was evaluated in a mouse model system. Twenty-four hours post i.v. injection the mice were killed and their organs, blood and tumours harvested for counting. Tumour localisation was four times greater than that into normal tissues, reaching 20% injected dose per gram of tumour. Eight patients have had this Tc99m-ICR12. Patient selection was by immunocytochemical staining of fine needle aspirates from the patient's own breast cancer. After intravenous administration of the immunoconjugate, tomographic images were obtained at 24 h. These results were compared to the subsequent histopathological examinations. Three patients acted as normal controls, one patient was negative due to inappropriate sampling, and two patients had strong membrane staining and provided excellent tumour localisation to both breast primary and regional node metastases. A further two patients only had moderate antigen expression on staining and did not localise well. The good performance of this radiolabelled antibody with patients that strongly stain for the antigen encourages the development of this system as both a method of staging breast cancer and a potential means of immunotherapy in this subgroup of patients.

Adult↗
PubMed1993

A daily diary for quality of life measurement in advanced breast cancer trials.

The Qualitator is a daily diary card to measure Quality of Life, developed for use in chemotherapy trials for patients with advanced breast cancer. In a trial at King's College Hospital, 29 patients completed the Qualitator and their scores were compared with scores in the Linear Analogue Self-Assessment and Nottingham Health Profile taken four-weekly. In a separate study at Guy's Hospital, 31 patients completed the diary. The Qualitator offers accurate prognostic data regarding subsequent UICC response and survival and is simple to use.

Adult↗
PubMed1993

Combination or mild single agent chemotherapy for advanced breast cancer? CMF vs epirubicin measuring quality of life.

Forty patients with advanced breast cancer, randomised to receive CMF or weekly low dose Epirubicin, were evaluated by UICC criteria of response and WHO toxicity criteria, in addition to three QoL instruments: the 'Qualitator' daily diary card, 4 weekly Nottingham Health Profile (NHP) and Linear Analogue Self-Assessment (LASA). Response rates were 58% for CMF and 29% for epirubicin (chi 2 = 3.51, 1 d.f., P > 0.05). Median time to treatment failure was 24 weeks for CMF, 7 weeks for epirubicin (P < 0.05) but survival was similar in both groups. Survival was better for responders than for non-responders (medians 87 and 30 weeks, P = 0.02). CMF caused more objective alopecia (P < 0.001), nausea and vomiting (P < 0.001) and haematological toxicity (P < 0.02). However, QoL measures only recorded a significant difference in energy and pain, influenced primarily by the non-responders in each treatment group but with no difference in overall global scores. Scores for responders, irrespective of treatment, were better to start with (LASA P = 0.001); at 12 weeks, scores had improved (Qualitator P < 0.05; NHP P < 0.05). Scores in non-responders showed no change. In this small study aggressive chemotherapy gave better response and similar survival without impairing Quality of life overall. Detailed QoL measurement should be integral to all cancer chemotherapy trials.

Adult↗
PubMed1993

Comparison of mask and nasal continuous positive airway pressure after extubation and mechanical ventilation.

OBJECTIVE: To examine the effects of continuous positive airway pressure applied via face masks and nose masks on the change in functional residual capacity and gas exchange. DESIGN: Descriptive and prospective study. SETTING: Intensive care unit of a university hospital. PATIENTS: Ten patients with acute lung injury who had required mechanical ventilation. INTERVENTIONS: Continuous positive airway pressure at a level of 10 cm H2O applied in random order via face and nose masks. MEASUREMENTS AND MAIN RESULTS: Both continuous positive airway pressure methods resulted in an almost identical increase of functional residual capacity. During nasal continuous positive airway pressure, the increase in functional residual capacity was 294 +/- 82 mL. During mask continuous positive airway pressure, the increase in functional residual capacity was 290 +/- 85 mL. PaO2 increased and the alveolar-arterial oxygen tension/alveolar oxygen tension quotient decreased significantly during mask continuous positive airway pressure and nasal continuous positive airway pressure at a level of 10 cm H2O. Two patients showed a periodic change in their breathing patterns; they took a few breaths at an increased lung volume, followed by one deep expiration caused by mouth opening. Change in mask pressure was negligible in these two patients. Using a visual analog scale (10 = highly comfortable; 0 = severely uncomfortable), the patients rated nasal continuous positive airway pressure (8.6 +/- 0.9) significantly more comfortable than mask continuous positive airway pressure (2.6 +/- 0.8). CONCLUSION: The major advantages of continuous positive airway pressure (the improvement of functional residual capacity and oxygen transfer) can also be achieved with nasal continuous positive airway pressure in the postextubation period in patients who have been mechanically ventilated for acute lung injury.

Acute Disease↗
PubMed1993

Glucocorticoids stimulate Na+/H+ antiporter in OKP cells.

Previous studies have demonstrated that systemic administration of glucocorticoids stimulates proximal tubule acidification in part by increasing Na+/H+ antiporter activity; however, these studies could not exclude the possibility that changes in Na+/H+ antiporter activity were secondary to glucocorticoid-induced hemodynamic changes. The present study examined the effect of dexamethasone on Na+/H+ antiporter activity in quiescent OKP cells. Na+/H+ antiporter activity was assayed as the initial rate of Na(+)-dependent pH recovery from an acid load. Intracellular pH was measured using the pH-sensitive dye 2',7'-bis(carboxyethyl)-5(6)-carboxyfluorescein (BCECF). Dexamethasone produced a dose- and time-dependent stimulation of Na+/H+ antiporter activity in OKP cells. Dexamethasone produced a 24% stimulation in Na+/H+ antiporter activity at 10(-9) M and an approximately 40% stimulation of Na+/H+ antiporter activity at both 10(-8) and 10(-6) M. The effect of 10(-6) M dexamethasone was seen within 4 h of incubation and was due to an increase in maximal velocity (Vmax, 3.03 vs. 1.79 pH units/min) with no change in the affinity constant for sodium (KNa, 47.2 vs. 42.0 mM). The stimulatory effect of dexamethasone on Na+/H+ antiporter activity was blocked by cycloheximide and was not observed with 10(-8) M aldosterone. These data demonstrate a direct effect of glucocorticoids to stimulate Na+/H+ antiporter activity in OKP cells.

Amiloride↗
PubMed1993

Glucocorticoids stimulate rabbit proximal convoluted tubule acidification.

Glucocorticoids have an important role in renal acidification; however, a direct effect of glucocorticoids on proximal convoluted tubule (PCT) acidification has not been directly demonstrated. In the present in vitro microperfusion study PCT from animals receiving dexamethasone (600 micrograms/kg twice daily for 2 d and 2 h before killing) had a significantly higher rate of bicarbonate absorption than did controls (92.0 +/- 13.3 vs 59.9 +/- 3.2 pmol/mm.min, P < 0.01). To examine if glucocorticoids had a direct epithelial action, dexamethasone was added to the bath of PCT perfused in vitro. After 3 h of incubation in paired experiments 10(-6) M and 10(-5) M dexamethasone resulted in an approximately 30% stimulation in the rate of bicarbonate absorption. 10(-7) M dexamethasone and 10(-6) M aldosterone had no effect on bicarbonate absorption. The stimulation of acidification by 10(-5) M dexamethasone was blocked by actinomycin D and cycloheximide. These data are consistent with a direct effect of glucocorticoids on PCT acidification, and this effect is dependent upon protein synthesis.

Aldosterone↗
PubMed1993

Selecting ventilator settings according to variables derived from the quasi-static pressure/volume relationship in patients with acute lung injury.

Knowledge of the pressure/volume (P/V) relationship of the lung may allow selection of tidal volume and positive end-expiratory pressure (PEEP) to optimize gas exchange without adversely affecting lung function or hemodynamics. Ten patients with acute lung injury were stabilized on controlled mechanical ventilation, based on conventional practice, using criteria from arterial blood gas data. The P/V relationship was determined under quasi-static conditions (end-expiratory and end-inspiratory, no flow periods > 0.8 s) during mechanical ventilation with an automated procedure that changed PEEP in a stepwise fashion. Differences in expiratory tidal volumes before and after a change in PEEP equaled the change in functional residual capacity (delta FRC). PEEP was set above the lowest point of the steepest section of the P/V curve (inflection pressure) to prevent end-expiratory lung collapse. Inspiratory tidal volumes (VTI) were adjusted to avoid an end-inspiratory lung volume reaching the flat part of the P/V curve. Averaged delta FRC versus PEEP curves were shifted to the left and the slope increased 1, 6, and 12 h after changing ventilator settings compared to baseline (P < 0.01). Averaged baseline delta FRC versus PEEP curves showed a marked inflection pressure that decreased after adjusting ventilator settings (P < 0.01). PEEP was increased from 7.4 +/- 1.8 cm H2O (baseline) to 11.9 +/- 1.6 cm H2O (1 h) (P < 0.001) according to measured baseline inflection pressures. Simultaneously, VTI had to be reduced from 759 +/- 161 mL (baseline) to 664 +/- 101 mL (1 h) (P < 0.01) to avoid end-inspiratory overinflation. To maintain minute volume constant ventilator frequency was increased from 14 +/- 1.2 (baseline) to 16 +/- 1.2 breaths/min (1 h) (P < 0.01). Maximum quasi-static compliance of 38 +/- 7 mL/cm H2O (baseline) increased to 46 +/- 9 mL/cm H2O (1 h) (P < 0.01). Maintaining FIO2 constant, PaO2 increased from a baseline of 90 +/- 16 mm Hg to 122 +/- 24 mm Hg (1 h) (P < 0.001), to 130 +/- 20 mm Hg (6 h) (P < 0.01), and to 138 +/- 19 mm Hg (12 h) (P < 0.01). Intrapulmonary shunt decreased from 0.28 +/- 0.08 (baseline) to 0.14 +/- 0.05 (12 h) (P < 0.001). Hemodynamic variables did not change. Our data suggest that using variables derived from a quasi-static P/V loop during mechanical ventilation under muscle paralysis is clinically superior compared to blood gas criteria for titration of ventilator settings.

Adult↗
PubMed1993

Breast cancer 2000 BC to 2000 AD--time for a paradigm shift?

In this paper I trace the history of the development of the treatment of breast cancer over a 4000-year period. I point out that there have basically been three paradigms within which we have studied and developed treatment for this disease. Clinical trials over the last twenty years as an expression of the scientific method in action, have demonstrated the limited success of the contemporary paradigm with its therapeutic sequelae of breast conserving surgery and adjuvant systemic therapy. At the same time a critical review of the natural history of breast cancer and the results of current treatments suggest logical inconsistencies in the model. I have therefore constructed a novel paradigm which better fits the available information by suggesting that metastases are not only a result of cellular transmission of breast cancer but sub-cellular transmission using the mechanism of in vivo transfection. Although this may sound far fetched, there are a series of remarkable studies in the literature which supports this conceptual revolution. This is surely a fertile field for research and the therapeutic consequences would be obvious. They might suggest that more aggressive adjuvant systemic chemotherapy based on the conventional model is unlikely to achieve any additional benefit, whereas therapy based on anti-viral drugs might produce the next therapeutic advance. It is not the intention of this article to persuade readers that the alternative paradigm is true but merely to open minds to the study of history and scientific philosophy to ensure that we do not repeat the errors of the past.

Breast Neoplasms↗
PubMed1993

Contralateral renal abnormalities in patients with renal agenesis and noncystic renal dysplasia.

The prevalence of contralateral renal abnormalities in noncystic-dysplastic kidney (NCDK) disease and renal agenesis is unknown. Twenty-four patients with NCDK disease and 16 patients with renal agenesis were studied in this 11-year retrospective study. In all patients the urinary system was evaluated by renal ultrasonography, and excretory urography or radionuclide scan. In addition, voiding cystourethrography was performed in 21 of 24 patients with NCDK disease and in 10 of 16 patients with renal agenesis. In those patients where voiding cystourethrography was performed, 14 (67%) patients with NCDK disease and 9 (90%) patients with renal agenesis had contralateral urologic abnormalities. Contralateral vesicoureteral reflux was the most common contralateral abnormality identified in 9 (43%) patients with NCDK disease and in 3 (30%) patients with renal agenesis. It is concluded that contralateral urologic abnormalities are common in patients with NCDK disease and in patients with renal agenesis and that vesicoureteral reflux is the most common contralateral abnormality noted.

Abnormalities, Multiple↗
PubMed1993

Efficacy of albumin and diuretic therapy in children with nephrotic syndrome.

OBJECTIVE: To examine the efficacy and complications of albumin and diuretic therapy in the treatment of edema due to the nephrotic syndrome. METHODS: The clinical and biochemical effects of 35 treatment courses of albumin and diuretics administered to 21 children with nephrotic syndrome were retrospectively examined. Treatment consisted of intravenous infusion of 25% albumin and furosemide. A second diuretic was administered in addition to furosemide during 10 treatment courses. There was an average of 5 infusions per hospitalization. RESULTS: Albumin and furosemide therapy resulted in a 1.2 +/- 0.2% (SEM) body weight loss per infusion. The administration of albumin with two diuretics did not result in improved weight loss compared to albumin and furosemide alone. Patients whose nephrotic syndrome was in remission at the time of posthospitalization follow-up (n = 8) had a sustained weight loss both during and after albumin and diuretic treatment. Patients with persistent proteinuria (n = 27) transiently lost weight during therapy, but returned to a weight similar to their pretreatment weight at 2-week follow-up. Albumin infusion resulted in hypertension, requiring acute antihypertensive therapy in 16 treatment courses (46%) and increased maintenance antihypertensive therapy in 12 treatment courses (34%). In addition, hypokalemia, hypernatremia, and hyperbicarbonatemia developed in 40%, 17%, and 11% of treatment courses, respectively. Albumin and diuretic therapy resulted in the development of respiratory distress during four treatment courses, including one patient who developed respiratory failure and one patient who developed congestive heart failure. CONCLUSIONS: Albumin and diuretic therapy results in fluid removal and weight loss in children with the nephrotic syndrome; however, this effect is transient unless remission of proteinuria occurs. While this is a retrospective study, the findings suggest that albumin and diuretic therapy can be associated with frequent and potentially serious complications.

Adolescent↗