Kristina von Boguslawski

Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer.

The prognostic value of the immunohistochemical expression of epithelial and stromal syndecan‐1 was evaluated in 296 patients with gastric carcinoma. Formalin‐fixed, paraffin‐embedded specimens of gastric adenocarcinomas were stained with mouse monoclonal antibody B‐B4 against human syndecan‐1. Loss of immunoreactivity (≤60% of cancer cells stained) was observed in 197 (67%) patients. Stromal immunoreactivity was observed in 28 (9%) patients. Loss of epithelial syndecan‐1 immunoreactivity correlated with a higher stage of disease (stages II–IV), tumour location in the upper third of the stomach, nodal metastases (N1 or N2), positive stromal syndecan‐1 staining, deep tumour penetration (to subserosa or deeper = T2–T4), larger tumour size (≥5 cm) and intestinal type of cancer. No correlation between epithelial syndecan‐1 immunoreactivity and age, gender, distant metastases, grade of differentiation or Borrmann classification was observed. Positive stromal syndecan‐1 immunoreactivity correlated with decreased epithelial syndecan‐1 expression, intestinal type of cancer and Borrmann type I. Patients with low epithelial syndecan‐1 expression in cancer cells had worse overall survival than patients with strong epithelial syndecan‐1 staining (p = 0.0012). Stromal syndecan‐1‐positive patients had a worse outcome than patients with syndecan‐1‐negative stroma (p = 0.0193). In Cox multivariate analysis, stromal syndecan‐1 immunoreactivity was a prognostic factor independent of TNM stage, surgery for cure and tumour size. Thus, the immunohistochemical expression of syndecan‐1 might be a predictor of outcome in patients with gastric adenocarcinoma.

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.

STn and prognosis in breast cancer

Sialyl-Tn (STn) is a carbohydrate antigen formed by the premature 2–6 sialylation of N-acetylgalactosamine. It belongs to a family of antigens widely expressed in carcinomas but only to a limited degree in normal tissue. The expression of STn has been associated with prognosis in different tumors. In this immunohistochemical study of 218 patients with invasive stage I–III breast cancer, STn was expressed in 39% of the tumors. High expression of STn correlated with estrogen and progesterone hormone receptor negativity (p = 0.0002 and p = 0.0003, respectively), and marginally with large tumor size (p = 0.04), high S-phase fraction (p = 0.04) and aneuploidy (p = 0.04), but not significantly with node status, grade or age. The patients had a median follow-up of 17 years. The breast-cancer-specific survival rate of patients with STn-negative cancers was higher than that of patients with cancers that expressed STn during the first 5 years of the follow-up (p = 0.013), but the difference between the groups decreased during the long-term follow-up. STn expression seems to be a marker for short-term, but not for long-term breast cancer outcome prediction.

Infantile onset spinocerebellar ataxia with sensory neuropathy (IOSCA): neuropathological features

Infantile onset spinocerebellar ataxia (IOSCA, MIM 271245) is a recessively inherited, progressive neurological disease, which we have described in 19 Finnish patients. The clinical symptoms of IOSCA include ataxia, athetosis, hypotonia, hearing deficit, ophthalmoplegia, sensory neuropathy, female hypogonadism, and epilepsy as a late manifestation. We have mapped the IOSCA locus to 10q24. In our two autopsy cases of IOSCA, the neuropathological findings were almost uniform. The cerebral hemispheres were quite well preserved, but the brain stem and the cerebellum were moderately atrophic. The most severe atrophic changes were seen in the spinal cord: in the dorsal roots, the posterior columns and the posterior spinocerebellar tracts. There was a severe neuronal loss in the dorsal nucleus (Clarkes column) of both cases and slight atrophy of the intermediolateral column in one case. The cerebellar peduncles, the inferior olives, the accessory cuneate nuclei and especially the dentate nuclei were atrophic and gliotic. The eighth cranial nerve and nucleus were atrophic. The ventral pontine nuclei and transverse fibers were slightly affected. Tegmental nuclei and tracts, especially sensory structures, were more severely affected. In mesencephalon, there was atrophy of the oculomotor nuclear complex and periaqueductal gray matter. The cerebellar cortex showed patchy atrophy. Degenerative changes were seen in dorsal root ganglia, and there was a severe axonal loss in the sural nerve. The neuropathological picture of IOSCA thus seems close to that reported in Friedreichs ataxia, another recessively inherited usually childhood-onset ataxia.

Tumor-associated trypsin inhibitor in normal and malignant renal tissue and in serum of renal-cell carcinoma patients.

Tumor‐associated trypsin inhibitor (TATI) is a 6‐kDa peptide, which is identical to the pancreatic‐secretory‐trypsin inhibitor (PSTI). TATI is produced by several tumors and cancer cell lines, and is used as a serum marker for mucinous ovarian cancer. Elevated serum levels of TATI have also been observed in renal‐cell carcinoma (RCC). However, it is unclear whether the increase of serum TATI in this disease is caused by production of TATI by the tumor tissue, by the acute‐phase reaction frequently associated with cancer, or by impaired renal function. We examined the expression of TATI in malignant and histologically normal renal tissue by immunohistochemistry, in situ hybridization and reverse‐transcriptase‐polymerase‐chain reaction (RT‐PCR). Furthermore, we measured pre‐operative serum TATI levels in 21 patients with RCC. Immunohistochemically, TATI was detected in 13 of 20 histologically normal renal‐tissue samples, but not in 32 tissue samples from RCC. By RT‐PCR, TATI mRNA was detected in all of 10 histologically normal kidneys and in 6 of 11 RCCs, while in situ hybridization analysis gave negative results. Pre‐operative serum TATI was elevated in 57% of RCC patients. We also studied expression of TATI mRNA and protein in 7 renal‐cancer cell lines, by RT‐PCR and immunofluorometric assay respectively: 6 cancer cell lines were positive for TATI mRNA, while 4 of them also produced TATI protein at low levels. These results indicate that TATI is synthesized by the histologically normal renal tissue and by some renal cancers, and suggest that the elevation of serum TATI associated with renal‐cell carcinoma may be caused by the release of TATI produced by the tumor. Int. J. Cancer 83:486–490, 1999.

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 α-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 ≤ 0.01). Conclusions: Tissue expression of TATI and an elevated preoperative serum concentration of trypsin-2-API are strong independent prognostic factors in advanced epithelial ovarian cancer. These results suggest that trypsin expression plays a role in the progression of ovarian cancer. TATI and trypsin-2-API are of potential use as an aid for stratification of randomized studies and for selecting treatment strategies.

p27 expression correlates with short-term, but not with long-term prognosis in breast cancer.

New prognostic and predictive factors are needed to adjust more appropriate therapy for individual patients after operation. p27 is a cell cycle regulator, and a low tissue expression of this protein has been shown to correlate with poor prognosis in colorectal, lung, gastric, prostate, and breast cancer. In this study on 197 breast cancer patients with a median follow-up of 17 years, the prognostic value of immunohistochemical p27 expression was evaluated. After 5 years of follow-up patients with a p27 expression in less than 50% of the tumor cells had a significantly lower survival rate than those with an expression above this level (p=0.01). However, after longer follow-up the difference decreased and was no longer significant at 7 years (p=0.1) or when the entire follow-up period was examined (p=0.67). Tests for associations showed that a low p27 expression correlated with a high histologic grade, a high S-phase fraction (SPF), an advanced TNM stage and negative hormone receptor status. In conclusion: Tissue expression of p27 is a significant predictor of 5-year, but not of 10- or 15-year breast cancer specific survival.

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 (≤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.

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.