The expression of p53, bcl-2, bax, fas and fasL in the primary tumour and lymph node metastases of breast cancer.

PURPOSE. It is unknown to what extent lymph node metastases differ from primary tumours of breast cancer. Our aim was to investigate the similarity between primary breast tumours and the matching lymph node metastases in 59 breast cancer patients. EXPERIMENTAL DESIGN. Immunohistochemical stainings of p53, bax, bc-l2, fas and fasL were performed in primary tumours and the parallel lymph node metastases. RESULTS. When using a cut point of 10%, the concordance between primary tumours and parallel lymph node metastases in the expression of p53 was 85%, bcl-2 79%, bax 69%, fas 59% and fasL 43%. In most tumours the staining status of p53, bcl-2 and bax in the primary tumour and the corresponding lymph node did not change more than 20%. However, these variables could fluctuate in both directions. In 15-25% of the cases, nodal expression was more than 20% lower than in the primary tumours, while in 10-17% of the cases, nodal expression was more than 20% higher than in the primary tumours. In half of the tumours, fas status did not change. Most fasL positive tumours lost positivity in the lymph node metastases or showed positively staining cancer cells only in the peripheral region of the node. A phenotype analysis of combined information of tumour fas/tumour fasL/nodal fas/nodal fasL expression (+/ - ) was assessed. The most frequently observed phenotype was tumour fas - /tumour fasL + /nodal fas - /nodal fasL- (22% of the tumours), although almost all combinations were seen. CONCLUSIONS. The expression of p53, bax, bcl - 2, fas and fasL is not maintained in the matching lymph node metastases of breast cancer. Large studies comparing the expression of relevant tumour biology factors in primary tumours and parallel lymph node metastases and their impact on therapy outcome, especially in the adjuvant setting, are warranted.

Prognostic value of syndecan-1 expression in breast cancer.

OBJECTIVE: Syndecan-1 is a cell surface heparan sulphate proteoglycan which participates in cell proliferation, cell migration and cell-matrix interactions. Epithelial syndecan-1 expression is reduced in several malignant tumours, but in breast and pancreatic cancer, increased expression has also been described. Loss of epithelial syndecan-1 has been associated with poor prognosis in some forms of cancer, but previous findings in breast cancer have been contradictory. The objective of this study was to evaluate the prognostic value of the immunohistochemical expression of syndecan-1 in a series of 200 patients with invasive breast cancer with a median follow-up of 17 years. METHODS: Formalin-fixed paraffin-embedded specimens were stained using a monoclonal antibody against syndecan-1. RESULTS: Syndecan-1 was expressed in the epithelium in 61% and in the stroma in 67% of the tumours. Epithelial syndecan-1 expression was associated with negative oestrogen receptor (ER) status (p < 0.01), and stromal syndecan-1 expression with positive ER status (p = 0.02). The breast cancer-specific 10-year overall survival for patients with epithelial syndecan-1 expression was 65%, compared with 82% for those with loss of epithelial expression (p = 0.02). Ten-year survival was 66% for those expressing stromal syndecan-1 and 83% for those lacking stromal expression (p = 0.15). Patients with both epithelial and stromal expression had a 10-year survival of only 56%, compared to 78% in patients with other expression pattern combinations (p < 0.002). In Cox multivariate analysis, only axillary involvement and tumour size were significant predictors of breast cancer-specific survival. CONCLUSION: Concomitant expression of syndecan-1 in both epithelium and stroma may be a predictor of unfavourable prognosis in breast cancer, and in contrast with previous studies, loss of epithelial syndecan-1 was associated with a more favourable prognosis.

Expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor in ovarian cancer: prognostic study on tissue and serum.

PURPOSE: The purpose is to study the prognostic significance of tissue expression of trypsinogen-1, trypsinogen-2, and tumor-associated trypsin inhibitor (TATI) and serum concentration of trypsinogen-2, trypsin-2-API (complex of trypsin-2 with alpha-1-proteinase inhibitor), and TATI in epithelial ovarian cancer. EXPERIMENTAL DESIGN: Expression of trypsinogen-1, trypsinogen-2, and TATI was determined by immunohistochemistry with monoclonal antibodies in tissue sections of tumors from 119 patients with untreated primary epithelial ovarian cancer. Preoperative serum concentrations of trypsinogen-2, trypsin-2-API and TATI were analyzed using specific immunoassays. RESULTS: Fifty-four percent of the tumors expressed trypsinogen-1, 45% expressed trypsinogen-2, and 30% expressed TATI. In patients with stage III and IV disease, TATI tissue expression (P = 0.002) and elevated TATI concentration in serum (P = 0.048) were associated with adverse cancer-specific and progression-free survival in univariate analysis. In multivariate analysis, TATI tissue expression (P = 0.005), tumor grade (P = 0.0001), histological type (P = 0.02), and stage (P = 0.0005) were independent prognostic factors for adverse cancer-specific survival and TATI tissue expression (P = 0.006) and grade (P = 0.0003) for progression-free survival. In multivariate analysis of all patients and those with advanced disease, serum trypsin-2-API concentration was an adverse prognostic factor for cancer-specific and progression-free survival, and it was independent of stage and histological type of the tumor (P

Satellite cell proliferation, reinnervation, and revascularization in human free microvascular muscle flaps.

BACKGROUND: Satellite cell proliferation, reinnervation, and revascularization were studied in human nonreinnervated free microvascular muscle flaps to characterize mechanisms of muscle regeneration after flap surgery. MATERIALS AND METHODS: Patient biopsies (n = 19) were taken at operation and five timepoints up to 9 months after operation, and corresponding clinical data were obtained. Immunohistochemistry for Ki-67 was used to detect proliferating satellite cells, CD-31 to identify endothelial cells, and S-100 and PGP 9.5 proteins to detect reinnervation. RESULTS: Two weeks after operation, the expression of PGP 9.5 and S-100 had virtually disappeared in all larger nerve fibers and half of smaller nerve fibers. By 6 months, however, a strong expression of PGP 9.5 and S-100 had reappeared in larger nerve fibers in three of four flaps, suggesting that reinnervation had taken place. The number of mitotic satellite cells already peaked at 2 weeks, indicating onset of muscle regeneration. The number of intramuscular capillaries first increased but later decreased to lower than original level. Flaps with more muscle volume showed more reinnervation and satellite cell mitotic activity. In cases of a delay occurring in reconstructive surgery, a low level of reinnervation was seen. CONCLUSION: Three patients of four showed spontaneous muscle reinnervation in microvascular free flaps with satellite cell activation followed by restored morphology. Late reconstruction and obesity lead to poor reinnervation, placing emphasis on timing of surgery and patient selection.

Lower concentration of pulmonary hepatocyte growth factor is associated with more severe lung disease in preterm infants.

OBJECTIVES: Hepatocyte growth factor (HGF) participates in normal lung development and in regeneration after lung injury in animals. We studied the role of HGF during the perinatal period and in the development of bronchopulmonary dysplasia (BPD). STUDY DESIGN: HGF was measured in 172 tracheal aspirate fluid samples (TAF) from 17 preterm infants in whom BPD subsequently developed (gestational age, 27.2+/-1.7 weeks; body weight, 828+/-210 g) and from 15 who survived without BPD (gestational age, 26.8+/-1.9 weeks; body weight, 994+/-265 g) during the first 2 postnatal weeks. RESULTS: Infants with subsequent development of BPD had lower HGF in TAF (45+/-9 pg/mL per IgA-sc) than those surviving without BPD (102+/-32 pg/mL per IgA-sc; P=.028). Lower HGF in TAF were seen in infants with more severe acute respiratory distress as defined as requirement for surfactant therapy (50+/-14 vs 146+/-50 pg/mL per IgA-sc in infants requiring no surfactant; P=.0001), for higher number of surfactant doses (r=-0.16, P=.06), and for mechanical ventilation >1 week (167+/-51 vs 51+/-14 pg/mL per IgA-sc in infants intubated <1 week; P=.0012). CONCLUSIONS: These data show an association between lower HGF concentration in TAF and more severe lung disease in human preterm infants in the early neonatal period.

Tenascin-C expression correlates with prognosis in gastric cancer.

OBJECTIVES: Tenascin-C is a hexameric extracellular matrix glycoprotein that is expressed during embryonic development and re-expressed in proliferative processes such as wound healing and tumorigenesis. Stromal tenascin-C may block tumor invasion and thus have a significant influence on tumor spread and prognosis. METHODS: In the present study, tissue expression of stromal tenascin-C was studied by immunohistochemistry in a series of 314 patients with gastric cancer. RESULTS: Strong tenascin-C positivity was seen in the stroma of the tumor in 122 (39%) cases. There was a correlation between strong tenascin-C expression and low stage (p = 0.002), superficial tumor penetration (p = 0.02), location of tumor at the distal third of the stomach (p = 0.03), and potentially curative surgery (p = 0.008). No significant correlation was found between tenascin-C positivity and nodal status, distant metastases, age, Laurén classification, gender, tumor size, or Borrmann classification. The cumulative 5-year survival in patients with strong tenascin-C expression was 42% compared to 26% in those with negative-to-moderate expression (p = 0.0053). In multivariate survival analysis stratified for estimated cure of surgery, stage of disease was the only independent prognostic factor. CONCLUSION: In conclusion, tenascin-C expression seems to correlate with cancer related survival in patients with gastric cancer, but may not add significant prognostic information to that provided by TNM stage.

The prognostic value of p27 in gastric cancer.

OBJECTIVES: p27 is a cyclin-dependent kinase inhibitor and a putative tumor suppressor preventing progression of the cell cycle from G1 phase. Recent studies have suggested loss of p27 to correlate with poor prognosis in patients with a variety of solid tumors. Results in gastric cancer are contradictory. We therefore decided to study the potential of p27 as a prognostic marker in a consecutively surgically treated, single-institution series of patients. METHODS: Using a monoclonal antibody against p27, immunohistochemistry was performed in paraffin-embedded tumor specimens from 316 patients. RESULTS: Loss of p27 immunoreactivity (< or = 5% of the cancer cell nuclei positive) was observed in 241 (76%) out of 316 stained tumors. We observed no significant correlation between the expression of p27 and stage of disease, tumor size, depth of tumor invasion, lymph node metastases, distant metastases, Laurén classification, Borrmann type, grade of differentiation, age or gender. There was no significant difference in gastric cancer specific overall survival between patients with low and high p27 expression. CONCLUSION: Our results add further doubt to the usefulness of p27 as a prognostic marker in gastric cancer.

The predictive value of bcl-2, bax, bcl-xL, bag-1, fas, and fasL for chemotherapy response in advanced breast cancer.

PURPOSE: The purpose was to evaluate the utility of some bcl-2 family proteins fas and fasL as predictive indicators for chemotherapy response in advanced breast cancer. EXPERIMENTAL DESIGN: Between October 1994 and October 1997, 283 patients with advanced breast cancer were included in a multicenter randomized study comparing docetaxel (D) to sequential methotrexate and 5-fluorouracil (MF) after anthracycline failure. The response rates (complete response + partial response) were 42 and 21% in the D and MF arms, respectively (P < 0.001). In 126 patients, histological blocks of primary tumors were available for immunohistochemical analysis of bax, bcl-2, bcl-xL, bag-1, fas and fasL. RESULTS: Of the investigated factors, bag-1 correlated positively with bax, bcl-2, and fasL, and fasL correlated positively with fas and bax. None of these apoptosis-related factors was associated with a response to chemotherapy either in the whole patient population or in the D or MF arms. Interestingly, low bcl-2 expression was associated with shorter time to progression (P = 0.02) and shorter overall survival (OS; P = 0.001). High fasL expression showed a trend toward shorter OS. In multivariate backwards stepwise Cox analysis, in which histological grade and estrogen receptor status (ER) were also included, bcl-2 (P = 0.01) and fasL (P = 0.005) remained highly significantly associated with OS, whereas histological grade and ER lost their significance. CONCLUSIONS: None of the investigated apoptosis-related factors of primary tumor could predict the later response to either D or MF treatment. However, fasL and bcl-2 were strong prognostic factors. Patients who had tumors with high fasL and low bcl-2 expression had the shortest OS.