Meeting highlights: adjuvant therapy for primary breast cancer.
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Biomedical subjects
Publications and source records attributed to H J Senn.
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De novo synthesis and excretion into perfusate and bile fluid of hepatic gangliosides were studied in isolated perfused rat livers. Addition of N-acetyl-[6-3H(n)]D-mannosamine to the perfusate resulted in radioactive synthesis of at least eight gangliosides labeled in their sialic acid residues. About 10% of total de novo synthesized gangliosides were excreted into the perfusate, less than 1% into the bile fluid. Labeled gangliosides were tentatively identified by cochromatography with known standards. All of them are known to occur in rat liver and sera. The results indicate that most, if not all, normal serum gangliosides are synthesized in the liver; excretion with bile fluid is negligible. They explain previous observations, and indicate clinical implications, which are discussed.
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Total content, pattern and transport by lipoproteins of gangliosides have been studied in the sera of 10 patients with hypercholesterolemia and manifest cardiovascular disease. Half of the patients with hypercholesterolemia and 3 healthy controls were treated with heparin-induced extracorporeal LDL precipitation (HELP). In the sera of the untreated group total gangliosides and cholesterol were elevated about 2-fold. Ratios of normal ganglioside components were not altered and abnormal ganglioside species not detected. Treatment with HELP resulted in an almost selective removal of lipid-bound sialic acid carried on LDL. The re-increase of total serum gangliosides was strictly correlated to that of LDL-cholesterol and apolipoprotein B. Total gangliosides and ratios of individual components carried on single LDL- and HDL-particles were not altered by the HELP treatment. Our results indicate that gangliosides are excreted into the serum along with nascent apolipoprotein B-containing lipoproteins, which are of hepatic origin. In hypercholesterolemia excretion of gangliosides into the circulation is elevated and surplus of circulating gangliosides is bound to increased numbers of 'atherogenic' LDL. Biosynthesis of different ganglioside components, most probably by the liver, and total amount of gangliosides bound to lipoprotein particles seem not to be altered.
Serial quality of life (QL) assessments are being obtained every 3 months for 2 years from patients with operable breast cancer in two ongoing International Breast Cancer Study Group (IBCSG) randomised clinical trials of adjuvant treatment. The QL-assessments include patient-derived perceived coping (PACIS, personal adjustment to chronic illness scale), well-being (Bf-S, Befindlichkeitsskala von Zerssen), mood, physical well-being and appetite (LASA, linear analogue self assessments). The first assessment within 6 weeks of surgery was performed by 70% of the patients. The analysis of serial assessments for 265 patients with each of the first four assessments completed showed that all measures improved with increasing time from study entry; that the degrees of improvement for the four major language groups were similar; and that measures were sensitive to treatment difference. In conclusion, measurement of QL related aspects in a multicultural clinical trial is feasible and possibly relevant for the evaluation of treatment results.
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We have conducted a randomized crossover comparative trial of a single-dose course of disodium (3-amino-1-hydroxypropylidene) bisphosphonate pentahydrate (pamidronate) and plicamycin in 48 patients with a first occurrence of tumor-related hypercalcemia. All patients had hypercalcaemia-associated symptoms and serum-calcium levels (corrected for total protein) greater than or equal to 2.80 mmol/l. Pamidronate and plicamycin were given concurrently with rehydration immediately after diagnosis of hypercalcaemia was made. Both agents lowered serum calcium levels significantly within 1 week, with 88% of the evaluable patients in the pamidronate group and 45% of those in the plicamycin group achieving normocalcemia (p less than 0.01). In the patients who received pamidronate, the duration of normocalcemia was longer (p less than 0.05) and there was a significant decrease in serum creatinine (p less than 0.05). Vomiting occurred in 8 of 22 evaluable patients (36%) who received plicamycin, but in none of 25 evaluable patients who received pamidronate (P less than 0.01). Phlebitis occurred at the infusion site in more of the pamidronate-treated patients (P less than 0.05). Hypocalcemia, which occurred in 8 of 25 evaluable patients (32%) in the pamidronate group and in 1 of 22 of those (5%) in the plicamycin group, was either clinically asymptomatic or mild, except in one pamidronate-treated patient. Overall, pamidronate was found to be more effective and better tolerated than plicamycin, thereby confirming results of previous studies that showed pamidronate to be an effective, simple, and safe agent for the relief of the morbidity associated with tumor-related hypercalcemia.
Women with node-negative breast cancer have a 30% chance of relapse 5 years after mastectomy. If it is possible to prevent or defer recurrent disease with adjuvant systemic therapy, node-negative patients, with their low tumor burden, should theoretically benefit most from such treatment. In 1974 we started a randomized adjuvant trial in eastern Switzerland, using a subjectively less toxic regimen [chlorambucil, methotrexate, and fluorouracil (LMF)]. Two hundred fifty-four patients were randomly assigned after standardized modified radical mastectomy to observation only or to treatment with oral LMF for 6 months followed by BCG skin scarifications monthly for up to 2 years. While we find no significant statistical difference between the control group and the treated group in terms of relapse-free survival, there is a strong and consistent trend toward prolongation of overall survival within the treated group.
160 patients (53.3%) replied to an anonymous questionnaire distributed to 300 consecutive patients of our Outpatient Oncology Clinic. 83 patients (53%) mentioned some experience of one or more alternative methods of cancer treatment. Most often cited were various herbal teas (35 instances), beetroot juice (16), Vogel plant extracts (15), laying-on of hands (14), homeopathic medicine (13), the mistletoe extract Iscador (13), magnetopathy (12), various diets (10), acupuncture (10) and psychological methods (9). Resort to alternative methods of treatment correlated significantly with lower age (51.5 years vs 59.8 years, p = 0.001). The reasons for using alternative medicine were the desire to do everything possible to regain health (49), to use one's psychological forces as well (35), reports of successful cancer cures (28), desire for a holistic approach (23), hope of "softer" medicine with less severe side effects (18) and, in 7 cases only, disappointment with conventional university medicine. The major source of information was relatives and friends, not the mass media. The physician should be aware of the locally available alternative medicine options and be able to advise his patients accordingly. He should also recognize and give due consideration to the patient's underlying desire for better control of his disease and a more holistic approach to care.
Three case presentations illustrate clinically relevant pharmacokinetic properties of morphine. Morphine given orally is rapidly absorbed and transformed to morphine-glucuronides (M3G, M6G) by the liver. The polar metabolites are excreted by the kidney. In chronic or acute renal insufficiency biologically active metabolites of morphine accumulate in the serum and may be responsible for severe toxic side effects. Hepatic insufficiency decreases the first-pass effect and therefore increases the bioavailability of oral morphine. This has to be considered when changing from parenteral to oral administration of morphine.
In a 59-year-old patient presenting in October 1981 with pancytopenia, hairy cell leukemia was diagnosed. Splenectomy, followed by treatments with oncovin, lithium, and prednisone were essentially without effect. Up to July 1984 the patient had been regularly transfused with a total of 62 unit. In June 1984 he acquired a transfusion associated hepatitis C which followed a chronic course and resulted in biopsy proven cirrhosis in 1989. The patient became independent of transfusions in July 1984. Repeated blood counts have shown a complete hematologic remission which has now lasted nearly 6 years, whereas focal leukemic infiltrates have persisted in the bone marrow. The patient has tolerated 20 courses of erythropheresis performed because of biopsy proven severe hepatic siderosis without a fall in hemoglobin. It is suggested that the spontaneous long-lasting hematologic remission of hairy cell leukemia is due to endogenous interferon produced in the course of chronic hepatitis C. Low serum levels of interferon-alpha and -gamma were detected.
The emotional discussion on a frank information strategy towards cancer patients 10 to 15 years ago has fortunately become more objective today, not the 'if', but the 'how' is now important; however, psychologic problems in the confrontation with the terminally ill are still recognized, mainly in groups of physicians lacking personal contact with dying and death during postgraduate training and later practise. Improvement of primary information and of further adapted communication with cancer patients cannot be solved alone by a larger number of experienced oncologists, since these represent in most instances only the second or third medical authority approaching the patient with neoplastic disease. Therefore, more supporting and less prejudiced patient contacts should be provided by first-line medical care, i.e. the family physician or surgeon. However, a truthful information strategy is a personal challenge for the physician. It demands an individual preoccupation of the therapist with the basic questions regarding his own life and its impermanence. Critical peer-reviewed training (i.e. in discussion and Balint groups) can teach a balanced dimension for a difficult patient interview (information, emotional involvement, patient-oriented behaviour). Deviations from adapted behaviour such as over-identification can thus be recognized and prevented. Since coping with disease does not develop in a linear fashion from initial resistance and negation of disease to mature acceptance in many patients, experienced therapists may always encounter sudden new problems regarding communication and information; therefore, the requirements for a therapist regarding tact, sensitivity and readiness to learn are high. This overview is written in this intent from an oncologists point of view in order to provide practical hints for daily encounters with cancer patients.
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The biosynthesis of gangliosides was studied in developing biliary cirrhosis in rats 14, 28, and 42 days after bile duct obstruction. The total content and patterns of gangliosides in livers and sera, and the activity of six hepatic ganglioside synthases in a cell-free system were determined. Up to 7-fold increased synthase activities were strictly correlated in time and extent with increased total contents of gangliosides in liver and serum. In addition, altered patterns of serum gangliosides were observed. The results clearly demonstrate that the liver is the main source of elevated serum gangliosides in biliary cirrhosis in the rat. Increased hepatic biosynthesis and the secretion of gangliosides into the serum appear to be an important pathogenetic event. Alterations of hepatic enzyme activities indicate that GL2 and GM3 synthase regulate total hepatic ganglioside content. However, certain abnormalities in ganglioside patterns which were observed in the liver and sera of cirrhotic animals can not be explained by changes in hepatic enzyme activity. They indicate additional pathobiochemical mechanisms to be involved, e.g., altered hepatocellular processing and/or impaired secretion into bile.
1. The effect of beta-endorphin (beta-EP) and morphine sulfate (MS), in presence and absence of naloxone (NX), on chicken chorioallantoic membrane was studied as a function of blood vessel proliferation. 2. A 50% reduction in blood vessel proliferation occurred by 10 micrograms of beta-EP or by 5 micrograms of MS per egg compared to controls. 3. An individual dose, i.e. 5 micrograms of beta-EP, did not significantly inhibit blood vessel counts after initial 24 hr period of the drug application when given alone compared to inhibition occurring with combined use of NX. 4. NX (1 microgram) did not significantly reverse the angiostatic effects of MS (10 micrograms) or of beta-EP (5 micrograms). 5. The observed modulation of angiogenesis by opioids suggests involvement of beta-EP and MS in the proliferation of vascular endothelial cells. 6. This may be due to an effect of beta-EP and MS on cell-mediated immunity factors such as interferons, interleukins and prostaglandin E2.
The antiemetic efficacy of cinnarizine was assessed in 17 cancer patients receiving platin-based chemotherapy (cisplatin dose-range 30-160 mg, or carboplatin 270-600 mg) in a randomised, cross-over study. The patients were prophylactically given oral metoclopramide 3 x 1 mg/kg and lorazepam 2 x 1 mg with or without cinnarizine 3 x 75 mg. The antiemetic combination with cinnarizine prevented emesis completely on 51% of 35 days with chemotherapy and less than 3 emetic episodes occurred on 86% of the days, compared with 43% and 57% (p less than 0.01) without cinnarizine respectively. Severe nausea was significantly less frequent with cinnarizine and 59% of the chemotherapy days were without nausea, compared to 46% of the days without cinnarizine (p less than 0.05). Side-effects were uncommon and minor with both antiemetic regimens. The study suggests that addition of cinnarizine to metoclopramide and lorazepam improves antiemetic prophylaxis in low to medium dose platin-based chemotherapy.
Since 1985 44 consecutive patients with testicular cancer have been treated with a modified BEP regimen. 70% had metastatic disease and 30% received adjuvant therapy. After mean follow-up of 26 (8-56) months, 91% of patients are alive and all are in remission. Chemotherapy-related side effects were alopecia (100%), myelosuppression (100%), nausea/vomiting (89%) and fever (66%). Patients reported nausea has been rare. It is concluded that BEP chemotherapy is a highly effective treatment which secures complete remission or cure even in patients with advanced metastatic disease. In retrospect the patients considered the treatment worthwhile despite the stress involved.