The concentrations of 6-keto-PGF1 alpha and TXB2 in plasma samples from patients with benign and malignant tumours of the breast

Peripheral plasma concentrations of 6-keto-PGF1 alpha and TXB2 were measured in patients with benign and malignant tumours of the breast, in patients with non-gynecological diseases, and in healthy female controls. The values were significantly higher in female patients with malignant tumours of the breast than in healthy controls (146 +/- 28 vs 13 +/- 2.5 pg/ml for 6-keto-PGF1 alpha p less than 0.01 and 78 +/- 17 vs 11 +/- 2 pg/ml for TXB2, p less than 0.01). Benign tumours of the breast were also associated with significantly raised plasma levels of 6-keto-PGF1 alpha and TXB2 compared to normal controls (52 +/- 5 vs 13 +/- 2.5 pg/ml for 6-keto-PGF1 alpha, p less than 0.01 and 26 +/- 5 vs 11 +/- 2 pg/ml for TXB2, p less than 0.05). The high levels of 6-keto-PGF1 alpha and TXB2 were not found to be correlated with clinical and histopathological data. The surgical removal of the primary tumour has apparently no effect on the plasma concentrations of 6-keto-PGF1 alpha and TXB2 over a follow-up period of 9 days after operation. The lack of alterations in the ratio of TXB2:6-keto-PGF1 alpha in the cancer patients and other subjects studied before and after surgery is indicative of the regulatory power of metabolic systems to preserve the homeostatic balance.     

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF) and soluble interleukin-2 receptor (sIL-2R) concentrations in peripheral blood as markers of pituitary tumours

Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and soluble interleukin-2 receptor (sIL-2R) are important cytokines. They are secreted by normal pituitary glands and those with all types of adenomas and may be involved in pituitary tissue growth. The peripheral blood concentrations of VEGF, bFGF and sIL-2R in nineteen patients (17-70 years) with pituitary tumours and ten healthy subjects (23-34 years) were studied. Hypersecretion of prolactin (five cases), human growth hormone (four cases), and thyroid stimulating hormone (one case) was recorded in some patients, and the remaining subjects were diagnosed as having nonfunctional pituitary tumours. Increased peripheral blood plasma levels of VEGF (310.82 +/- 59.17 pg/ml) compared with controls (40.32 +/- 11.80 pg/ml; p < 0.01), as well as bFGF (87.27 +/- 7.58 pg/ml) versus controls (11.14 +/- 2.43 pg/ml; p < 0.001) were recorded. The levels of sIL-2R did not differ between the pituitary tumour patients (4,490.58 +/- 581.50 pg/ml) and control subjects (3,617.01 +/- 1,397.18 pg/ml; p > 0.05). The concentrations of VEGF and bFGF in the peripheral blood are useful additional markers of the presence of tumours.     

Serum levels of tumor necrosis factor alpha correlate with response to neoadjuvant chemotherapy in locally advanced breast cancer

It has been shown that serum levels of tumor necrosis factor alpha (TNF-alpha) are increased in breast cancer patients. There are few data available on the reduction of serum levels of this cytokine following chemotherapy. The aim of this study was to determine the effect of neoadjuvant chemotherapy on serum concentrations of TNF-alpha and the relation to response rates in locally advanced breast cancer. Twenty consecutive patients with non-inflammatory stage III-B breast cancer achieving a partial or complete clinical response to three courses of neoadjuvant chemotherapy followed by modified radical mastectomy were prospectively included in the study and evaluated. Sera were collected before the start and after the termination of chemotherapy. Serum concentrations of TNF-alpha were measured by an ELISA method. The pathological response rates were also evaluated and recorded. The control group consisted of 12 healthy age-matched women. The mean pre-treatment TNF-alpha value of breast cancer patients was 15.9 +/- 0.9 pg/mL while it was 5.8 +/- 1.7 pg/mL in the control group; the difference was statistically significant (p < 0.0001). The serum levels of TNF-alpha were markedly decreased in patients with partial and complete responses compared to pre-treatment values (p < 0.0001). There was also a difference in TNF-alpha levels in patients with partial vs complete responses (p < 0.0001). The relative change between pre- and post-treatment values correlated significantly with the type of response (p = 0.004). These results suggest that the serum concentration of TNF-alpha can be an indicator of response and could be used in clinical decision-making for patients with locally advanced breast cancer.     

The concentration of 6-keto-PGF1α and TXB2 in plasma samples from patients with benign and malignant tumours of the breast

Peripheral plasma concentrations of 6-keto-PGF_1α and TXB₂ were measured in patients with benign and malignant tumours of the breast, in patients with nongynecological disease,a nd in healthy female controls. The values were significantly higher in female patients with maligants tumours of the breast than in healthy controls (146 ± 28 vs 13 ± 2.5 pg/ml for 6-keto-PGF_1α p<0.01 and 78 ± 17 vs 11 ± 2 pg/ml for TXB₂, p<0.01). Benign tumours of the breast were also associated with significantly raised plasma levels of 6-keto-PGF_1α and TXB₂ compared to normal controls (52 ± 5 vs 13 ± 2.5 pg/ml for 6-keto-PGF_1α, p < 0.01 and 26 ± 5 vs 11 ± 2 pg/ml for TXB₂, p < 0.05). The high levels of 6-keto-PGF_1α and TXB₂ were not found to be correlated with clinical and histopathological data. The surgical removal of the primary tumour has apparently no effect on the plasma concentration of 6-keto-PGF_1α and TXB₂ over a follow-up period of 9 days after operation. The lack of alterations in the ratio of TXB₂: 6-keto-PGF_1α in the cancer patients and other subjects studied before and after surgery is indicative of the regulatory power of metabolic systems to preserve the homeostatic balance.     

M-CSF (monocyte colony stimulating factor) and M-CSF receptor expression by breast tumour cells: M-CSF mediated recruitment of tumour infiltrating monocytes?

Infiltrating immune cells in 30 primary human epithelial breast tumours were studied using specific anti-CD3 (T cells), anti-CD68 (macrophages), anti-CD57 (NK cells), and an anti-pan-B cell antibody (L26). The majority of tumour infiltrating inflammatory cells are T cells (40-50%) and monocytes/macrophages (15-35%). The macrophage specific chemo-attractant and growth factor CSF-1 is detected by immunohistochemical techniques (IHC) at the level of invasive breast cancer cells in 46/50 tumours but not at the level of in-situ (pre-invasive) cancer. A mosaic staining pattern was usually observed, with a very high expression in areas of obvious stromal invasion (90% cells positive) and absent or trace staining in intraductal carcinoma. Macrophages and plasma cells are equally intensely positive. In-situ hybridisation experiments confirm the production of CSF-1 (mRNA) by tumour cells and show the same pattern of expression. Expression of the CSF-1 receptor protein (fms) was also observed by IHC in 41/48 invasive tumours, albeit at weaker intensities than in tumour infiltrating monocytes/macrophages. A concomitant expression of both CSF-1 and fms in in-situ carcinoma was never seen (n = 14). It is therefore proposed that the associated expression of CSF-1 and its receptor may be linked to the invasive potential of breast cancer, the monocytic infiltrate being an indication of the quantitative importance of CSF-1 production by the tumour.     

Transforming growth factor beta 1 serum levels in patients with preinvasive and invasive lesions of the breast

Transforming growth factor beta (TGF-beta)1 is thought to be involved in breast carcinogenesis. TGF-beta1 acts in an antiproliferative manner in the early stages of breast carcinogenesis, but promotes tumor progression and metastases in the advanced stages of the disease. No data have been published on serum TGF-beta1 in breast cancer. We investigated TGF-beta1 serum levels in patients with breast cancer (n=135), ductal carcinoma in situ (DCIS) I to III (n=67) or fibroadenoma (n=35), and in healthy women (n=40) to determine its value as a differentiation marker between malignant, pre-invasive and benign diseases and as a predictive marker for metastatic spread. Median (range) TGF-beta1 serum levels in patients with breast cancer, DCIS I-III or benign breast lesions and in healthy women were 48.8 (18-82.4) pg/mL, 45.3 (26.9-58.3) pg/mL, 47.2 (17.2-80.5) pg/mL and 51.6 (30.9-65.1) pg/mL, respectively (p=0.2). In breast cancer patients TGF-beta1 serum levels showed no statistically significant correlation with tumor stage, lymph node involvement, histological grade, estrogen receptor status and progesterone receptor status. Our data fail to indicate any correlation between serum TGF-beta1 levels and clinicopathological parameters of breast diseases. Serum TGF-beta1 levels do not provide clinical information in addition to established tumor markers.     

Reduction in serum IL-6 after vacination of breast cancer patients with tumour-associated antigens is related to estrogen receptor status

Elevated serum IL-6 concentrations have been associated with poor prognosis in a variety of cancers, and decreases in serum IL-6 concentrations have been reported after chemotherapy. We have demonstrated that serum IL-6 concentrations are elevated in breast cancer patients [normal women 0.7 +/- 2.5 pg/ml (n=36), breast cancer patients 38.3 +/- 138.7 pg/ml (n = 111)]. After vaccination of breast cancer patients with a combination of tumour-associated antigens and biological adjuvants (IL-2 and GM-CSF), the concentration of IL-6 decreased significantly (P<0.05) to 8.1 +/- 14.6 pg/ml (n=85). Other studies have shown that oestrogen suppresses IL-6 production in oestrogen receptor positive breast cancer cells. We have demonstrated that the decrease in IL-6 associated with vaccination is related to the oestrogen receptor status of the tumours from breast cancer patients, as a decrease in IL-6 from 124.0 +/- 267.5 pg/ml (n=26) to 6.2 +/- 11.0 pg/ml (n=34) only occurs in patients with oestrogen receptor negative tumours. The IL-6 concentration in breast cancer patients with oestrogen receptor positive tumours remained unchanged (9.5 pg/ml before vaccination, and 9.3 pg/ml after vaccination). These results suggest that postmenopausal women with oestrogen receptor negative breast cancers, who do not respond well to either hormonal therapy with tamoxifen or adjuvant chemotherapy, may have a significant response to vaccination with autologous tumour-associated antigens.     

Overweight in relation to tumour size and axillary lymph node involvement in postmenopausal breast cancer patients—Differences between women invited to vs. not invited to mammography in a randomized screening trial

Objectives: Overweight is associated with advanced stage at diagnosis in breast cancer patients. This could be explained by specific tumour characteristics or tumour promoting factors in the obese, but a diagnostic delay could also be of importance. Mammographic screening has caused a change towards diagnosis of less advanced tumours. This study investigates invitation to mammographic screening and the association between overweight and tumour size/axillary lymph node involvement at breast cancer diagnosis in postmenopausal women. Methods: In 1976 a randomized mammographic screening trial, inviting 50% of all women aged 45–69 was set up in Malmö, Sweden. The present analysis examined overweight (body mass index ≥25) as a determinant for large tumours (>20 mm) and axillary lymph node involvement in postmenopausal women. These associations were studied separately in patients diagnosed prior to the mammographic screening trial, in invited women and in non-invited subjects (controls). In all, 2478 postmenopausal women were diagnosed with invasive breast cancer in these groups between 1961 and 1991. Logistic regression analysis allowed adjustment for other potential determinants of tumours size and axillary lymph node involvement. Results: In women diagnosed before the onset of the screening trial and in women not invited to mammography in the trial (controls), overweight was positively associated with large tumour size and axillary node involvement. There was no statistically significant association between overweight and these factors in women invited to mammographic screening. Conclusion: Invitation to mammographic screening may be particularly important for overweight postmenopausal women in order to detect breast tumours early.     

Patterns of initial management of node-negative breast cancer in two Canadian provinces

OBJECTIVE: To describe the patterns of initial management of node-negative breast cancer in Ontario and British Columbia and to compare the characteristics of the patients and tumours and of the physicians and hospitals involved in management. DESIGN: Retrospective, population-based, cohort study. PARTICIPANTS: All 942 newly diagnosed cases of node-negative breast cancer in 1991 in British Columbia and a random sample of 938 newly diagnosed cases in Ontario in the same year. OUTCOME MEASURES: Number and proportion of patients with newly diagnosed node-negative breast cancer who received breast-conserving surgery (BCS) or mastectomy and who received radiation therapy after BCS. RESULTS: BCS was used in 413 cases (43.8%) in British Columbia and in 634 cases (67.6%) in Ontario (p < 0.001). After BCS, radiation therapy was received by 378 patients (91.5% of those who had undergone BCS) in British Columbia and 479 patients (75.6% of those who had undergone BCS) in Ontario (p < 0.001). In both provinces, lower patient age, smaller tumour size, a noncentral unifocal tumour, absence of extensive ductal carcinoma in situ and initial surgery by a surgeon with an academic affiliation were associated with greater use of BCS. Lower patient age and larger tumour size were associated with greater use of radiation therapy after BCS in both provinces. CONCLUSION: Patient, tumour and physician factors are associated with the choice of initial management of breast cancer in these two Canadian provinces. However, the differences in management between the two provinces are only partly explained by these factors. Other possible explanations, such as the presence of provincial guidelines, differences in the organization of the health care system or differences in patient preference, require further research.     

Endothelin-1 is a novel prognostic factor in non-small cell lung cancer

Endothelin-1 (ET-1) is a potent vasoactive peptide and a hypoxia-inducible angiogenic growth factor associated with the development and growth of solid tumours. This study evaluated the expression of big endothelin-1 (big ET-1), a stable precursor of ET-1, and ET-1 in non-small cell lung cancer (NSCLC). Big ET-1 expression was evaluated in paraffin-embedded tissue sections from 10 NSCLC tumours using immunohistochemistry and in situ hybridisation. The production of big ET-1 and ET-1 was studied in six established NSCLC cell lines. The plasma concentrations of big ET-1 were measured in 30 patients with proven NSCLC prior to chemotherapy by means of a sandwich enzyme-linked immunoassay and compared to levels in 20 normal controls. Big ET-1 immunostaining was detected in the cancer cells of all tumours studied. Using in situ hybridisation, tumour cell big ET-1 mRNA expression was demonstrated in all samples. All six NSCLC cell lines expressed ET-1, with big ET-1 being detected in three. The median big ET-1 plasma level in patients with NSCLC was 5.4 pg/mL (range 0-22.7 pg/mL) and was significantly elevated compared to median big ET-1 plasma levels in controls, 2.1 pg/mL (1.2-13.4 pg/mL) (p = 0.0001). Furthermore, patients with plasma big ET-1 levels above the normal range (upper tertile) had a worse outcome (p = 0.01). In conclusion, big ET-1/ET-1 is expressed by resected NSCLC specimens and tumour cell lines. Plasma big ET-1 levels are elevated in NSCLC patients compared to controls with levels > 7.8 pg/mL being associated with a worse outcome. The development of selective ET-1 antagonists such as Atrasentan indicates that ET-1 may be a therapeutic target in NSCLC.     

Clinical significance of circulating interleukin-23 as a prognostic factor in breast cancer patients

Little is known about specific IL‐23 alterations associated with breast cancer and the data available are still controversial. Therefore, the evaluation of changes in serum IL‐23 levels may add further information on the role of this cytokine in breast cancer patients. The aim of this study was to evaluate prospectively the prognostic importance of circulating IL‐23 in patients with untreated breast cancer, respect to healthy controls, and the association with clinico‐pathological variables. The study involved 50 women diagnosed with stages I–IV breast cancer and 38 healthy controls. Of the 50 breast cancer patients, 37 women were recruited prior to their initial adjuvant chemotherapy and 13 prior to receive first line chemotherapy for metastatic disease. Adjuvant chemotherapy patients were at least in their 4th week post‐surgery. IL‐23 serum concentrations were measured by a quantitative enzyme immunoassay technique. We found a statistically significant higher systemic cytokine value in women with cancer in comparison with the control group (14.52 ± 11.39 pg/ml vs. 6.35 ± 4.63 pg/ml, P < 0.0001). Patients with shorter overall survival presented higher IL‐23 values, suggesting a negative prognostic correlation. There was no significant differences in IL‐23 levels among patients according to the biomolecular characteristics, the different subtypes and the presence of metastatic disease. This work investigated, for the first time, the role of IL‐23 in breast cancer patients showing a significant increase respect the control group. However, further validations are needed in larger studies to better investigate the implications of IL‐23 increase in these patients. J. Cell. Biochem. 113: 2122–2125, 2012. © 2012 Wiley Periodicals, Inc.     

Plasma adrenomedullin concentrations in patients with adrenal pheochromocytoma.

BACKGROUND: The hypotensive peptide adrenomedullin was first isolated in extracts of human pheochromocytoma. There is, however, no information available on the behaviour of circulating adrenomedullin or on the correlation with catecholamines in patients with pheochromocytoma. OBJECTIVES: 1) to investigate whether plasma adrenomedullin levels were changed in 10 patients with pheochromocytoma when compared to 21 healthy subjects and 16 patients with essential hypertension; 2) to determine whether or not adrenomedullin has a counter-regulatory role in catecholamine excess in pheochromocytoma or is responsible for hemodynamic modifications before and after tumour resection; 3) to determine tissue distribution of iradrenomedullin in the pheochromocytoma. METHODS: Plasma adrenomedullin and catecholamine levels were measured in all patients with pheochromocytoma before and four weeks after tumour removal. In the four patients undergoing resection of tumours, plasma levels of adrenomedullin were measured at different time-points during surgery. RESULTS: The mean plasma adrenomedullin concentrations ( SD) in patients with pheochromocytoma (37.9 +/- 6pg/ml) were significantly higher (p<0.0001) than those in normal subjects (13.7 +/- 6.1 pg/mI) and patients with essential hypertension (22.5 +/- 9.lpg/ml). Adrenomedullin levels correlated with plasma noradrenaline (r = 0.516, p = 0.0124). In all patients with pheochromocytoma, plasma adrenomedullin concentrations decreased after removal of tumours (from 37.9 +/- 6 to 10.9 +/- 4.6 pg/ml; p < 0.0001). In the four patients studied during surgery, baseline plasma adrenomedullin and noradrenaline levels were markedly elevated, and increased significantly with tumour manipulation, decreasing 24 hours after operation. Adrenal medulla cells surrounding the pheochromocytoma site stained for ir-adrenomedullin, whereas only isolated cells of pheochromocytoma stained for the peptide. CONCLUSIONS: This study demonstrates that circulating adrenomedullin is increased in pheochromocytoma, and is also correlated with plasma noradrenaline levels. Adrenomedullin may represent an additional biochemical parameter for clinical monitoring of patients with pheochromocytoma.     

Interleukin 8 in progression of hormone-dependent early breast cancer

The only way to perceive the real clinical course of disease and the prognostic significance of potential biomarkers is follow-up of patients who did not receive any kind of adjuvant therapy. Many studies have confirmed high levels of interleukin 8 (IL8) in HER2-enriched and basal-like (ER–) primary breast tumours, but less is known about the significance of IL8 in hormone-dependent breast cancer. The aim of this study was to evaluate the prognostic significance of IL8 and clinicopathological parameters in hormone-dependent breast cancer, and to examine possible associations between them that might imply possible biological dependence. The study included 91 early-stage breast cancer patients with detectable levels of hormone receptors (ER>0, PR>0). None of the patients received adjuvant therapy according to valid protocol at that time. HER2 status was determined on paraffin-embedded tumour tissue sections by CISH. IL8 levels were determined by ELISA in cytosol tumour extracts of 65 patients with long-term follow-up (144 months). Nonparametric statistical tests were used for data analyses. Patients with low IL8 levels (M<88.8 pg/mg) had significantly longer relapse-free survival (RFS) compared to patients with high IL8 levels (M≥88.82 pg/mg) (Log rank test, p=0.002). Patients with ERhighIL8low phenotype had significantly longer RFS compared to those with ERhighIL8high and ERlowIL8high phenotypes (p=0.04 and p=0.02, respectively); patients with PRlowIL8low phenotype had significantly longer RFS compared to those with PRlowIL8high and PRhighIL8high phenotypes (p=0.003 and p=0.02, respectively); patients with HER2-IL8low phenotype had significantly longer RFS compared to those with HER2-IL8high and HER2+IL8high phenotypes (p=0.01 and p=0.02, respectively). Our results indicate significant contribution of IL8 on survival of hormone-dependent early-stage breast cancer patients and association with established parameters such as ER/PR and HER2.     

Differential Expression of Prognostic Proteomic Markers in Primary Tumour,Venous Tumour Thrombus and Metastatic Renal Cell Cancer Tissue and Correlation with Patient Outcome

Renal cell carcinoma (RCC) is the most deadly of urological malignancies. Metastatic disease affects one third of patients at diagnosis with a further third developing metastatic disease after extirpative surgery. Heterogeneity in the clinical course ensures predicting metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been shown to have prognostic significance, including Ki67, p53, vascular endothelial growth factor receptor 1 (VEGFR1) and ligand D (VEGFD), SNAIL and SLUG. Previous pathway analysis has been from study of the primary tumour, with little attention to the metastatic tumours which are the focus of targeted molecular therapies. As such, in this study a tissue microarray from 177 patients with primary renal tumour, renal vein tumour thrombus and/or RCC metastasis has been created and used with Automated Quantitative Analysis (AQUA) of immunofluorescence to study the prognostic significance of these markers in locally advanced and metastatic disease. Furthermore, this has allowed assessment of differential protein expression between the primary tumours, renal vein tumour thrombi and metastases. The results demonstrate that clinico-pathological parameters remain the most significant predictors of cancer specific survival; however, high VEGFR1 or VEGFD can predict poor cancer specific survival on univariate analysis for locally advanced and metastatic disease. There was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared with the primary tumours and renal vein tumour thrombi. With the exception of p53, these differences in protein expression have not been shown previously in RCC. This confirms the importance of proliferation, angiogenesis and epithelial to mesenchymal transition in the pathogenesis and metastasis of RCC. Importantly, this work highlights the need for further pathway analysis of metastatic tumours for overcoming drug resistance and developing new therapies.     

Hiperparatiroidismo secundario en el cáncer de próstata avanzado

Background and ObjectiveHigh parathyroid hormone (PTH) concentrations are associated with increased bone resorption and bone matrix degradation. Some studies show elevated PTH concentrations and hypocalcemia in patients with advanced prostate carcinoma, although the pathophysiological significance of these findings is not well defined.Materials and methodsWe performed a retrospective study of 60 patients diagnosed with advanced prostate cancer (44 nonmetastatic and 16 metastatic) treated with androgen deprivation. In all patients, PTH, calcium, phosphorus, 25 (OH) vitamin D and prostate-specific antigen (PSA) were determined. Bone scintigraphy had previously been performed.ResultsIn patients with bone metastases, mean concentrations were as follows: calcium 9.19 mg/dl, phosphorus 3.47 mg/dl, 25 (OH) vitamin D 13.85 ng/ml, PTH 66.8 pg/ml and total PSA 101.27 ng/ml. For those without bone metastases, the results were calcium 9.39 mg/dl, phosphorus 3.38 mg/dl, 25 (OH) vitamin D 20.50 ng/ml, PTH 52.23 pg/ml and total PSA 2.52 ng/ml. PTH levels were significantly higher in patients with prostate cancer and bone metastases than in those without metastases (p=0.03). Vitamin D levels were also significantly lower in this group (p=0.03). There were no differences in other values.ConclusionsThe present study found increased PTH concentrations in patients with advanced prostate cancer. This finding could be useful to predict disease progression.     

Aromatase inhibitors: basic and clinical studies

Application of aromatase inhibitors to the treatment of conditions in which estrogen plays, a role is discussed. Studies in vitro demonstrate that 4-hydroxyandrostenedione (4-OHA) is a potent inhibitor of aromatase. The compound reduces ovariant estrogen production and causes regression of carcinogen (DMBA)-induced mammary tumors in the rat. In the rhesus monkey, 4-OHA was also shown to inhibit peripheral aromatization. To date 58 postmenopausal breast cancer patients with advanced metastatic disease have received 500 mg im weekly while 31 patients received 250 mg 4-OHA orally per day. Estradiol levels were significantly reduced in all patients from a mean of 7.2 + 0.8 pg/ml to 2.8 + 0.3 pg/ml. Of patients receiving 4-OHA im 27% had partial or complete responses and in 10% of patients the disease was stabilized. Similar responses occurred in the patients receiving 4-OHA orally. These results suggest that 4-OHA is effective and that this compound and other aromatase inhibitors could be valuable new additions to the treatment of breast cancer.     

Oestrogen Receptor in Human Breast Cancer Tissue and Response to Endocrine Therapy

Oestrogen receptor determinations were done in metastatic breast cancer tissue of patients with advanced breast cancer. In 37 patients with progressive disease evaluation of the response to endocrine treatment was possible, following the criteria of the E.O.R.T.C. Co-operative Breast Cancer Group. In 20 patients with receptor-negative tumours two objective remissions were noted; in 17 patients with receptor-positive tumours 14 objective remissions were seen. There seems to be a striking correlation between the presence or absence of oestrogen receptor in tumour tissue and the clinical response to hormonal therapy.     

Testicular germ cell tumours: the paradigm of chemo-sensitive solid tumours

Testicular germ cell tumours (TGCTs) are the most frequent solid malignant tumour in men 20–40 years of age and the most frequent cause of death from solid tumours in this age group. Up to 50% of the patients suffer from metastatic disease at diagnosis. The majority of metastatic testicular cancer patients, in contrast to most other metastatic solid tumours, can be cured with highly effective cisplatin-based chemotherapy. From a genetic point of view, almost all TGCTs in contrast to solid tumours are characterised by the presence of wild type p53. High p53 expression levels are associated with elevated Mdm2 levels and a loss of p21^Waf1/Cip1 expression suggesting a changed functionality of p53. Expression levels of other proteins involved in the regulation of cell cycle progression indicate a deregulated G1–S phase checkpoint in TGCTs. After cisplatin-induced DNA damage, the increasing levels of p53 lead to the trans-activation of a number of genes but not of p21^Waf1/Cip1, preferentially directing TGCT cells into apoptosis or programmed cell death, both via the mitochondrial and the death receptor apoptosis pathways. The sensitivity of TGCTs to chemotherapeutic drugs may lay in the susceptibility of germ cells to apoptosis. Taken together, this provides TGCT as a tumour type model to investigate and understand the molecular determinants of chemotherapy sensitivity of solid tumours. This review aims to summarise the current knowledge on the biological basis of cisplatin-induced apoptosis and response to chemotherapy in TGCTs.