W. R. Bezwoda

The non-immune inflammatory response: Serial changes in plasma iron, iron-binding capacity, lactoferrin, ferritin and C-reactive protein

The interrelationships between various components of the non-immune inflammatory response (white cell count, plasma lactoferrin, C-reactive protein, ferritin, iron and iron-binding capacity), were studied serially in a variety of inflammatory conditions including acute lobar pneumonia, active pulmonary tuberculosis, rheumatoid arthritis on gold therapy and sepsis in the face of marrow hypoplasia induced by chemotherapy. Lactoferrin concentrations paralleled the white count in all groups. They were highest in pneumonia and tuberculosis, mildly elevated in rheumatoid arthritis and markedly decreased in neutropenic sepsis. Very high initial lactoferrin concentrations were associated with a poor prognosis in acute pneumonia. C-reactive protein and ferritin concentrations remained elevated through the period of study in acute pneumonia and neutropenic sepsis, while they gradually normalised over weeks in subjects with tuberculosis or rheumatoid arthritis on therapy. In pneumonia and tuberculosis moderate hypoferraemia and a reduced iron-binding capacity were evident. In contrast, a raised percentage saturation was present in neutropenic sepsis, probably related to erythroid marrow suppression. Comparisons between ferritin, lactoferrin and C-reactive protein in the various groups supported the concept that ferritin behaves in part as an acute phase reactant and that hypoferraemia in inflammation is due to deviation of iron into ferritin stores. The suggestion that lactoferrin is responsible for the hypoferraemia and hyperferritinaemia was not supported by the present data. Iron deficiency appeared to limit the hyperferritinaemic response in rheumatoid arthritis, while erythropoietic inhibition by chemotherapy dampened the hypoferraemic response in neutropenic sepsis.

Abnormalities of chromosome 12p 13 and malignant proliferation of eosinophils: a nonrandom association

Summary. Four patients representing a spectrum of haematological malignancies are reported. Two patients had Philadelphia chromosome negative myeloproliferative disorders, one had acute lymphoblastic leukaemia and one had eosinophilic leukaemia. In each case eosinophilia was present and demonstrated to be part of the malignancy by the association of clonally abnormal metaphases with eosinophil granules. Abnormalities involving the short arm of chromosome 12 (12p 13) were a constant feature in all four cases and therefore a nonrandom association between this chromosome region and malignant eosinophil proliferation is proposed.

Tissue platelet derived-growth factor (PDGF) predicts for shortened survival and treatment failure in advanced breast cancer.

In a study of plasma and tissue platelet derived growth factor (PDGF) concentration in patients with breast cancer, elevated levels of plasma PDGF were found in a significant proportion, 11/37 (30%), of patients. Sixteen patients (43%) had tumors which expressed PDGF-AA and 6 patients had tumors which in addition expressed the BB isoform of PDGF. All patients with elevated plasma levels of platelet derived growth factor had tumors which expressed the growth factor on immunohistochemical staining of tumor cells. Furthermore there was a significant correlation between plasma levels of platelet derived growth factor and the intensity of tissue staining. Patients with stage four breast cancer with tumors which were positive for platelet derived growth factor had a significantly lower response rate to chemotherapy as well as significantly shorter duration of survival. In addition, patients with stage four breast cancer who had elevated plasma PDGF levels had a significantly shorter survival. These results indicate that elevated plasma levels of platelet derived growth factor in patients with breast cancer are derived from the tumor cells and suggest that platelet derived growth factor may play a significant role in control tumor cell growth.

Lactoferrin and the Inflammatory Response

Polyclonal antibodies were prepared to purified breast milk lactoferrin and used in an ELISA to measure plasma concentrations in investigations of various aspects of the inflammatory response. They were also used, in situ, to evaluate granulocyte lactoferrin content in disease states. The first series of studies addressed the putative role of lactoferrin in the pathogenesis of the hypoferremic, hyperferritinemic response to acute inflammation. Dissociation between the lactoferrin response and the iron related changes in rheumatoid arthritis and after alpha-interferon administration suggested that the relationship observed in acute and chronic bacterial infection may reflect coincidental effects of inflammatory cytokines. That lactoferrin does not mediate the inflammatory hypoferremic response was established by the finding that bone marrow transplant recipients, post-myeloablation, developed a hypoferremic response during septic episodes despite virtually undetectable plasma lactoferrin concentrations. The second series of investigations employed the plasma lactoferrin concentration as an index of granulocyte activation and function in a number of inflammatory conditions. Markedly increased initial plasma concentrations in acute pneumonia reflecting profound intravascular granulocyte activation were documented to predict sepsis related mortality. Plasma and granulocyte lactoferrin studies established that viral infection is associated with an acquired granulocyte lactoferrin deficiency. Plasma measurements indicated that asthmatics, even when clinically asymptomatic, have evidence of persistent granulocyte activation.

Association between human immunodeficiency virus type 1 infection and cancer in the black population of Johannesburg and Soweto, South Africa

A case-control study of 913 black cancer patients (aged 15-50 years) was undertaken to measure the association between human immunodeficiency (HIV) infection and cancers believed to have an infective aetiology. Controls were patients with cancers believed not to be infective in origin. The prevalence of HIV in the controls of 7.3% (24 of 325) was similar to the background HIV seropositivity in this population. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, year of diagnosis, marital status and sex were calculated. There was a strong association between HIV infection and Kaposis sarcoma (KS), with 27 of 33 cases being HIV seropositive, OR = 61.8 (95% CI 19.7-194.2) and an elevated association with non-Hodgkins lymphoma (NHL), with 27 of 40 cases being HIV seropositive [OR = 4.8 (95% CI 1.5-14.8)]. The elevated odds ratio for KS associated with HIV infection accords with the observed increases in the incidence of KS in several sub-Saharan African countries where the prevalence of HIV is high. The odds ratio for NHL associated with HIV infection was lower than that reported in developed countries, and the reason for this is not clear. No other cancers, including cervical and liver cancers, showed significantly elevated odds ratios associated with HIV infection.

The value of estrogen and progesterone receptor determinations in advanced breast cancer. Estrogen receptor level but not progesterone receptor level correlates with response to tamoxifen

Four hundred fifteen patients with metastatic breast cancer with known hormone receptor status received primary treatment with tamoxifen. Measured values for the estrogen receptor (ER, i.e., with estrogen binding) followed a continuous distribution (range, 3 to 1000 fmol/mg of protein). These values correlated positively with age. The response to treatment with tamoxifen correlated with the ER level, with response rates of approximately 80% when the ER level was greater than 30.1 fmol/mg of protein. Two hundred eighteen (218 of 415, 52%) patients had progesterone receptor (PR) values greater than 10 fmol/mg. The PR positivity correlated with the ER level. Patients with PR levels greater than 10 fmol/mg of protein (124 of 226, 55%) had a significantly higher response rate than those with values less than 10 fmol/mg of protein (45 of 189, 24%). However, in a multivariate analysis including both receptor levels, age, site, and number of metastases, only the ER level was significant in predicting the response to treatment with tamoxifen. A quantitative estimation of the ER level thus is the best predictor of response to hormonal treatment with tamoxifen for advanced breast cancer.

Platelet-derived growth factor (PDGF) in plasma of breast cancer patients: Correlation with stage and rate of progression

Plasma levels of platelet-derived growth factor (PDGF) were measured in 58 female patients with breast cancer and in 9 normal female control subjects by means of a specific radioimmunoassay. Levels in normal control subjects were all below the lower limits of detection by the assay (1.56 fmol/100 µl plasma). Two of 17 (12%) patients with stage 2 breast cancer had detectable plasma levels. Among patients with Stage 4 breast cancer 13/41 (32%) had significantly elevated levels (> 2 times the lower limit of sensitivity of the assay). Patients with elevated PDGF levels had a significantly greater degree of metastatic involvement and significantly shorter survival. Apart from being a marker of aggressive high bulk breast cancer, PDGF may be involved in the acceleration of growth of some metastatic breast tumors.

Correlation of Breast Tumour Aromatase Activity and Response to Aromatase Inhibition with Aminoglutethimide

Tumour aromatase, oestrogen (E) and progesterone (P) receptor (R) measurements were carried out in biopsies from 29 patients with advanced or recurrent breast cancer. Patients were then treated with aminoglutethimide according to one of two dosage regimens: (a) aminoglutethimide 1000 mg/day + hydrocortisone 20 mg/day, and (b) aminoglutethimide 250 mg/day. Tumour aromatase values varied from 0.05 to 2.07 pmol ER produced/mg protein/h and ER and PR values from less than 1 to 249 and less than 1 to 132 fmol of steroid bound/mg protein, respectively. There was no correlation between aromatase values and either ER or PR and also no correlation between ER and PR and response to aminoglutethimide. Tumour aromatase values did however correlate with response to treatment. Mean aromatase levels for responders (1.18 +/- 0.64 pmol E produced/mg protein/h) were significantly higher than those of non-responders (0.34 +/- 0.27) (t = 5.20, DF 27; p less than 0.005). Ten out of fourteen patients with aromatase values greater than 0.5 pmol ER produced/mg protein/h responded, whereas 0 out of 15 patients with tumour aromatase values less than this responded. Responses were seen at both dosages of aminoglutethimide. It is concluded that tumour aromatisation will be a useful measurement in predicting response to aromatase inhibitors.

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 (>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.

Positive immunostaining for platelet derived growth factor (PDGF) is an adverse prognostic factor in patients with advanced breast cancer.

Previous studies suggest a prognostic role for PDGF in patients with breast cancer, with patients with high plasma PDGF levels or positive response to therapy. We have examined a further 58 patients with advanced breast cancer for the presence of tissue PDGF immunostaining. Patients displaying positive tissue immunostaining for PDGF had a highly significant shorter survival (p = 0.002) than patients with no immunostaining. In addition PDGF positive patients treated with combination chemotherapy had a significantly lower response rate (p = 0.05) than PDGF negative patients. These results confirm our previous findings that PDGF may be an important indicator of shortened survival and treatment failure in patients with advanced breast cancer.