Adjuvant chemotherapy (CMF) for stage III breast cancer: a randomized trial.

A randomized trial of the effect of adjuvant CMF chemotherapy in patients with Stage III breast cancer receiving primary local radiation or local radiation plus surgery, failed to reveal a survival benefit from early systemic treatment. The subset of premenopausal patients receiving chemotherapy did, however, show a significant prolongation of disease-free survival from 23 to 55 months. Overall survival of this subgroup was not increased. The study included the use of two dose levels of CMF to assess whether higher chemotherapy doses would be more effective. No dose effect was observed. Initial local control with radiation therapy or radiation plus surgery was achieved in the majority (90.9%). Distal recurrence and death from metastatic disease were the major causes of treatment failure. Treatment benefit among premenopausal patients was mainly delayed onset of distal metastatic disease. Among premenopausal patients, salvage therapy for metastatic disease appeared more effective in those not previously exposed to systemic treatment.

A systematic evaluation of bathophenanthroline, ferrozine and ferene in an ICSH-based method for the measurement of serum iron.

The chromogenic substrates ferrozine and ferene were compared to bathophenanthroline disulphonic acid for the measurement of iron concentrations in aqueous and serum samples in an assay based on that of the Iron Panel of the International Committee for Standardisation in Haematology. Ferrozine and ferene were more sensitive than bathophenanthroline. Copper at physiological concentrations in plasma caused only minimal positive interference with all three chromogenic substrates when thioglycollic acid was used as the reducing agent, but when ascorbic acid was used significant positive interference occurred with ferrozine and ferene. Interference due to contaminating haem was comparable with all agents. Bilirubin and carotene produced no interference. Profound reductions in colour development were noted with EDTA plasma.

Sequential hormonal therapy and sequential hormonal and chemotherapy for advanced prostatic cancer.

Ninety-two patients with D2 prostatic cancer were studied. Initial treatment was with either diethylstilboestrol (DES) or orchidectomy. Response to DES (5/63, 81%) was significantly higher than for orchidectomy (18/29, 62%; p less than 0.01). However, duration of response and duration of survival were not significantly different for the 2 forms of hormonal therapy. Fifty-seven patients were randomised to receive second-line treatment with either medroxyprogesterone acetate (MPA), oral chlorambucil or combination chemotherapy (adriamycin + cyclophosphamide + 5-fluoro-uracil). Response to second-line treatment was similar for all 3 regimens (46% overall response). Most of the responses were disease stabilisation and, although there was symptomatic benefit, response to second-line therapy did not significantly improve survival compared to the survival experience of the group as a whole. It is concluded that palliative second-line treatment for advanced prostatic cancer should consist of the least toxic form of treatment which in this study was second-line hormone administration (MPA).

Breast cancer in men. Clinical features, hormone receptor status, and response to therapy.

Stage, estrogen receptor status, treatment and survival of 29 men with breast cancer attending the Breast Clinic of the Johannesburg Hospital between 1976 and 1985 are reviewed. Most patients had locoregionally advanced disease at presentation. Estrogen receptors (ER) were detected in significant concentration in 15/23 (65%). Local control was achieved in the majority, 19/26 (73%), by either surgery or radiation therapy alone or by combined modality treatment. Fifteen of 23 patients tested (65%) were ER-positive (greater than 10 fmol/mg protein). For patients with metastatic disease hormone receptor status was predictive of response to hormonal manipulation. Tamoxifen was the most acceptable and frequently used form of hormone therapy with 7/12 patients responding. Combination chemotherapy gave a response rate comparable to that seen in women with breast cancer.

The HLA linked iron loading gene in an Afrikaner population.

The serum ferritin concentration was used as a screening test to identify the presence of iron overload in 599 Afrikaans subjects (300 males and 299 females) living in the South Western Cape, South Africa. Seventeen of the males with concentrations greater than 400 micrograms/l were reevaluated three and five years later. Serum ferritin concentrations were measured again and further diagnostic procedures were carried out. These included an assessment of alcohol intake and measurements of serum gamma glutamyltransferase, the percentage saturation of transferrin, and HLA-A,-B,-C, and -DR loci typing on the subjects as well as their families. Liver biopsies were performed on some affected subjects. Of the original 16 index subjects, four were diagnosed as homozygous for the HLA linked iron loading gene which is responsible for the clinical disease idiopathic haemochromatosis. Six appeared to be heterozygotes, three were heterozygotes who were also abusing alcohol, and two did not fit into any of the diagnostic groups. The calculated gene frequency was 0.082, with an expected heterozygote frequency of 0.148. The fact that no females were identified in the study suggested that the diagnostic criteria for homozygosity (serum ferritin greater than 400 micrograms/l and % saturation greater than 60%) were set too high. The data were therefore recalculated for the 300 males; when this was done the gene frequency was 0.115 and the heterozygote frequency 0.024. Two subjects were diagnosed as homozygotes in the study of family members and 37 as heterozygotes (33 definite and four probable). Both the homozygotes and nine of the heterozygotes showed mild to moderate disturbances of iron metabolism. There was considerable overlap between the phenotype expression in these nine heterozygotes and the homozygotes, probably as a result of setting the threshold for the serum ferritin concentrations at the relatively high value of 400 microgram/ml. By doing this a small subset of heterozygotes with biochemical abnormalities was identified. The results of the present pilot study suggest a high frequency of the HLA linked iron loading gene in the Afrikaner population of South Western Cape.

The effects of fruit juices and fruits on the absorption of iron from a rice meal.

The effects of the chemical composition of fruit juices and fruit on the absorption of iron from a rice (Oryza sativa) meal were measured in 234 parous Indian women, using the erythrocyte utilization of radioactive Fe method. The corrected geometric mean Fe absorptions with different juices varied between 0.040 and 0.129, with the variation correlating closely with the ascorbic acid contents of the juices (rs 0.838, P less than 0.01). Ascorbic acid was not the only organic acid responsible for the promoting effects of citrus fruit juices on Fe absorption. Fe absorption from laboratory 'orange juice' (100 ml water, 33 mg ascorbic acid and 750 mg citric acid) was significantly better than that from 100 ml water and 33 mg ascorbic acid alone (0.097 and 0.059 respectively), while Fe absorption from 100 ml orange juice (28 mg ascorbic acid) was better than that from 100 ml water containing the same amount of ascorbic acid (0.139 and 0.098 respectively). Finally, Fe absorption from laboratory 'lemon juice' (100 ml orange juice and 4 g citric acid) was significantly better than that from 100 ml orange juice (0.226 and 0.166 respectively). The corrected geometric mean Fe absorption from the rice meal was 0.025. Several fruits had little or no effect on Fe absorption from the meal (0.013-0.024). These included grape (Vitis vinifera), peach (Prunus persica), apple (Malus sylvestris) and avocado pear (Persea americana). Fruit with a mild to moderate enhancing effect on Fe absorption (0.031-0.088) included strawberry (Fragaria sp.) (uncorrected values), plum (Prunus domestica), rhubarb (Rheum rhaponticum), banana (Musa cavendishii), mango (Mangifera indica), pear (Pyrus communis), cantaloup (Cucumis melo) and pineapple (Ananas comosus) (uncorrected values). Guava (Psidium guajava) and pawpaw (Carica papaya) markedly increased Fe absorption (0.126-0.293). There was a close correlation between Fe absorption and the ascorbic acid content of the fruits tested (rs 0.738, P less than 0.0001). There was also a weaker but significant correlation with the citric acid content (rs 0.55, P less than 0.03). Although this may have reflected a direct effect of citric acid on Fe absorption, it should be noted that fruits containing citric acid also contained ascorbic acid (rs 0.70, P less than 0.002).(ABSTRACT TRUNCATED AT 400 WORDS)

Factors influencing the absorption of iron from soya-bean protein products.

The absorption of iron from soya-bean (Glycine hispida)-based and milk-based infant formulas was assessed in 138 multiparous Indian women, using the erythrocyte utilization of radioactive Fe method. Fe absorption was significantly greater from the basal milk formula (1.5 g protein) than it was from the basal soya-bean formula (2.3 g protein), with geometric mean values of 0.083 and 0.044 respectively. Ascorbic acid markedly increased Fe absorption from the milk-based formula in a dose-dependent fashion. The increase was fivefold when the ascorbic acid:Fe ratio on a weight-for-weight basis was 6:1 and over tenfold when it was 20:1. In contrast, ascorbic acid had a less-marked effect on the absorption of Fe from the soya-bean-based formula, with only a two- to threefold increase at an ascorbic acid:Fe ratio of 20:1. The geometric mean Fe absorption from the soya-bean formula (1.27 mg Fe, 2.3 g isolated soya-bean protein (ISP] was somewhat less than that from the same amounts of ISP and ascorbic acid made up in milk (0.075 and 0.113 respectively). However, a direct comparison between the soya-bean formula in milk and in water showed no significant difference (0.043 and 0.060 respectively). Fe absorption from a drink containing 10 g ISP and 30 mg ascorbic acid was significantly better than that from a similar drink containing the soya-bean flour from which ISP is extracted (0.044 and 0.027 respectively). Heating ISP to 200 degrees for 2 h before its use had no effect on Fe availability.(ABSTRACT TRUNCATED AT 250 WORDS)

Combination chemotherapy of hepatocellular cancer. Comparison of adriamycin + VM 26 + 5-fluorouracil with mAMSA + VM 26 + 5-fluorouracil.

Forty-seven patients with hepatocellular cancer were treated in a randomised trial comparing adriamycin + VM 26 + 5-Fluorouracil (5-FU) to mAMSA + VM 26 + 5-FU. Thirteen patients had a partial response to treatment (28%) and another 6 (13%) showed disease stabilisation. There were no significant differences in the response rates between the two treatment regimens. Patients who responded to treatment showed significant prolongation of survival (48 weeks) when compared to non-responders (5 weeks).

Relationship between absorption of inorganic and food iron in field studies.

Food iron absorption data on 853 Indian women were compared to the haemoglobin concentrations, other iron-related measurements and the absorption of a reference dose of 3 mg iron given as ferrous ascorbate. The serum ferritin concentration was identified as the best predictor of the absorption of the reference dose (r = -0.54, p less than 0.0001). These two measurements were then compared in terms of their relative ability to predict the absorption of iron from 10 individual meals. Results were comparable, with correlations for the pooled data of -0.50 (p less than 0.0001) for the serum ferritin and 0.47 (p less than 0.0001) for the reference dose. Since serum ferritin is a simple and non-invasive test, it may represent the more satisfactory way of standardising food iron absorption results to a common iron status in field studies. However, the value of such an approach is limited by the wide confidence limits of the relationship between food iron absorption and both the other measurements.

Failure of transferrin to enhance iron absorption in achlorhydric human subjects.

There is evidence in experimental animals that transferrin, produced either by gastrointestinal cells or derived from bile, mediates the luminal absorption of iron. The applicability of these findings to human subjects was tested by administering diferric transferrin labelled with 3 mg 59Fe to seven patients with pernicious anaemia. Achlorhydric subjects were chosen to ensure that the iron transferrin complex did not dissociate in the stomach. The geometric mean absorption of 1.4% was similar to that of 3 mg iron given as ferric chloride (1.9%) and much less than that of ferrous ascorbate (18.9%). These findings suggest that transferrin does not play a physiological role in the absorption of iron in human subjects.

Lack of correlation between iron stores and plasma lactoferrin concentration.

Plasma lactoferrin concentration and indices of iron nutrition including P-Ferritin, P-iron, total iron binding capacity and percentage saturation were measured in 75 otherwise normal females. This was done in order to evaluate previous reports that neutrophil lactoferrin content was altered by variations in iron storage status. Since P-Lactoferrin is derived from and hence reflects neutrophil lactoferrin content it would seem reasonable to assume that P-Lactoferrin would vary in accordance with iron stores. However, there was no statistically significant difference in P-Lactoferrin concentration between iron deficient subjects and those who were iron replete. Furthermore, there was no statistically significant correlation between any iron related parameter and P-Lactoferrin concentration.

Treatment of metastatic and recurrent cervix cancer with chemotherapy: a randomised trial comparing hydroxyurea with cisdiamminedichloro-platinum plus methotrexate.

In a randomised trial comparing single-agent chemotherapy (hydroxyurea) to combination chemotherapy in advanced cervix cancer, response was seen in 57% (including 13% CR) of patients receiving the combination (DDP + MTX) regimen. Responding patients survived significantly longer (11 months) than either those receiving hydroxyurea or those not responding to combination chemotherapy (4 months). Two patients remain in complete remission for 14+ and 17+ months.

Serum ferritin and Hodgkin's disease.

The haemoglobin, serum iron, transferrin saturation, serum ferritin, erythrocyte sedimentation rate (ESR), splenic weight and non-haem iron concentration in the marrow, liver and spleen were measured prior to treatment in 35 patients with Hodgkin's disease who underwent staging laparatomy. The Hb, serum iron and transferrin saturation showed a significant decrease with increasing stage of the disease. In contrast, there was a significant increase in the serum ferritin, ESR, splenic weight and in all the tissue non-haem iron concentrations. The calculated total iron content of the body remained relatively constant throughout at about 2 g but with increasing stage there was an internal redistribution of iron, with a progressive drop in Hb iron and a reciprocal rise in storage iron, especially in the liver. Serum ferritin concentrations, which rose with progression of the disease, were inappropriately high in relation to the size of body stores at all stages but especially in patients with 4B disease and hepatic involvement. It was concluded that the serum ferritin concentrations are raised for several reasons in Hodgkin's disease. They reflect an increase in body iron stores, ferritin's role as an 'acute phase' protein in the inflammatory response and hepatic damage in patients with advanced disease.

Effect of natural killer cells on syngeneic bone marrow: in vitro and in vivo studies demonstrating graft failure due to NK cells in an identical twin treated by bone marrow transplantation.

Bone marrow transplantation for severe idiopathic aplastic anemia was undertaken in a patient, using his monozygotic twin brother as the donor. In spite of the use of syngeneic bone marrow, failure of engraftment occurred on two occasions. In vitro studies demonstrated that natural killer (NK) cells from the recipient markedly inhibited the growth of donor bone marrow granulocyte progenitor cells. On a third attempt, successful bone marrow engraftment was achieved following high-dose cyclophosphamide, which has previously been shown to be inhibitory to NK cells. We conclude that NK cell activity may play an important role in bone marrow failure as well as being responsible for at least some cases of aplastic anemia.

Treatment of neutropenic infection: a randomized trial comparing latamoxef (moxalactam) with cephradine plus tobramycin.

Sixty neutropenic patients with infection were studied in a randomized trial comparing treatment with latamoxef (moxalactam) alone or with cephradine and tobramycin. The two treatment groups were comparable in respect to their clinical sites of infection, degree of neutropenia underlying malignancy, and organisms. Forty-two bacterial isolates were obtained from various clinically infected sites. All but two of these isolates were sensitive to latamoxef (30 highly sensitive, ten moderately sensitive). In contrast 29 of the isolates were resistant to cephradine and eight were resistant to both cephradine and tobramycin. Control of infection was achieved in 72% of patients treated with latamoxef and 55% treated with cephradine plus tobramycin. Latamoxef appears to be an effective antibiotic for the treatment of neutropenic patients with infection.

Relative value of oestrogen receptor assay, lactoferrin content, and glucose-6-phosphate dehydrogenase activity as prognostic indicators in primary breast cancer.

Oestrogen receptor content, lactoferrin, hexokinase, and glucose-6-phosphate dehydrogenase levels were measured in cytosol from 25 primary breast cancers and 3 fibroadenomas. Both hexokinase and glucose-6-phosphate dehydrogenase activity were higher in malignant tissue as compared to benign breast lesions. Oestrogen receptor concentration and lactoferrin content failed to predict the development of metastatic disease, while glucose-6-phosphate dehydrogenase activity was significantly higher in cytosol from those tumours which subsequently metastasized compared to those which remained localized.

Treatment of advanced breast cancer with aminoglutethimide--response after previous tamoxifen treatment.

Thirty-one postmenopausal patients with advanced breast cancer either unresponsive to tamoxifen or progressing after responding to tamoxifen were treated with aminoglutethimide (1 000 - 1 250 mg/d) plus hydrocortisone replacement. The response rate was 33% in patients who had never responded to tamoxifen and 47% in patients who had previously responded to tamoxifen. The overall response rate was 42%. These results show that aminoglutethimide is an effective second-line hormonal treatment for patients with advanced breast cancer.

The value of pleural fluid carcinoembryonic antigen estimation in the diagnosis of malignant tumours of the pleural cavity.

Measurement of pleural fluid and blood carcinoembryonic antigen (CEA) concentrations as well as estimations of pleural fluid protein, lactic acid dehydrogenase and sugar levels were carried out in 45 patients with pleural effusions in order to determine the value of these biochemical parameters in the diagnosis of malignant tumours involving the pleural space. The study population included individuals with epithelial and non-epithelial malignant tumours involving the pleural cavity as well as patients with inflammatory effusions and patients with transudates due to cardiac, renal or hepatic disease. Pleural fluid CEA content was the single most useful measurement in distinguishing epithelial malignant tumours from other causes of pleural effusion. In addition, the pleural fluid CEA/blood CEA ratio was greater than 1 in most patients with epithelial cancer of the pleural space, suggesting that local production of CEA is responsible for elevated values in the pleural fluid.

Chemotherapy in porphyria.

The clinical courses of 5 patients with hepatic porphyrias (4 with porphyria variegata) who required chemotherapy for disseminated malignant diseases are reviewed. Antineoplastic agents were employed without evidence that these drugs precipitated porphyric crises. It is concluded that the chemotherapeutic approach to these patients should be based on the appropriate treatment for the malignant condition.