Prognostic implications of securin expression and sub-cellular localization in human breast cancer.

PURPOSE: Securin belongs to a class of cell cycle regulators that prevent metaphase-to-anaphase transition until sister chromatid separation is complete. Evidence is accumulating that securin has a prognostic impact on a variety of malignancies but, thus far, the role and regulation of securin expression and its sub-cellular localization have not been systematically addressed in breast cancer. METHODS: In total 470 breast cancer specimens with follow-up data for up to 22 years were included. Immunohistochemical staining and immunofluorescence double-staining were performed for securin and its regulating proteins PTTG1IP, CDC20 and BUBR1. Prognostic associations were evaluated between the expression patterns of these proteins and established prognosticators of invasive breast cancer and patient survival. RESULTS: We found that a high fraction of securin expressing cancer cells predicted an unfavorable clinical outcome of the breast cancer patients (p < 0.001). Also in multivariate analyses, the fraction of securin expressing cancer cells served as an independent prognosticator of a poor survival (p < 0.0001). We also found that the sub-cellular localization of securin exhibited prognostic power, since cytoplasmic securin expression in the cancer cells appeared to be associated with aggressive breast cancer subtypes and high breast cancer-associated mortality rates (p = 0.003). Through immunofluorescence double-staining, we found that PTTG1IP, CDC20 and BUBR1 exhibited distinct patterns of co-expression with securin, suggesting a regulatory role in the metaphase-to-anaphase transition in human breast cancer cells. We also noted that a subgroup of triple-negative breast carcinomas exhibited deviant expression patterns for the proteins studied. CONCLUSIONS: Our data indicate that securin expression may serve as a strong and independent prognosticator of breast cancer outcome and that a cytoplasmic localization of the protein may provide additional prognostic information, particularly in the biologically and clinically challenging subgroup of triple-negative breast carcinomas. The sub-cellular localization of securin appears to reflect the expression of PTTG1IP, CDC20 and BUBR1, which may participate in the regulation of securin activity and, ultimately, in the survival of breast cancer patients.

Altered expression of p120catenin predicts poor outcome in invasive breast cancer.

PURPOSE: The study focuses on p120catenin, a regulator of cell adhesion, which has previously been described in many malignancies and suggested with a role in invasion and metastatic behaviour. In this study, we investigate the role of altered immunoexpression of p120catenin isoforms in the prognosis of invasive breast cancer (n = 351). METHODS: We used cDNA microarrays to screen differences in gene expression in invasive breast cancer in general, and between local and metastasized disease particularly. On this basis, we performed p120catenin immunohistochemistry in order to confirm the prognostic value of p120catenin isoforms on tissue microarrays comprising 341 patients from the era of mammographic screening, directed to modern surgical and oncological treatments, and followed-up for maximum of 20 years. RESULTS: In cDNA microarray analysis, p120catenin was discovered down-regulated along with E-cadherin and alpha-catenin. In addition, p120catenin distinguished metastasized breast cancer from local disease. Immunohistochemistry confirmed the value of p120catenin as an independent prognosticator of breast cancer survival. In our results, p120catenin was associated with 3.7-fold risk of breast cancer death in multivariate Cox's regression analyses adjusted for the established prognosticators of breast cancer (p = 0.039). Particularly, the long isoform of p120catenin predicted metastatic disease (p = 0.029). CONCLUSION: The present paper is the first report on p120catenin in invasive breast cancer based on a well-characterized patient material with long-term follow-up. We observed altered expression of p120catenin isoforms in invasive breast cancer and, in our material, the decrease in p120 immunoexpression was significantly associated with poor outcome of disease.

Securin promotes the identification of favourable outcome in invasive breast cancer.

BACKGROUND: Securin is a recently recognised oncogene with multiple known functions in initiation, progression and cell cycle regulation in several malignant diseases, including breast carcinoma. METHODS: In this paper, the prognostic value of securin is evaluated by immunohistochemistry in 310 patients diagnosed with invasive breast cancer during a mammographic screening programme in Central Finland. All patients were directed to modern surgical and oncological treatments and were followed up for a maximum of 20 years. RESULTS: Our results suggest that securin immunopositivity is an independent prognosticator of invasive breast cancer. In our study, securin predicted breast cancer-specific survival among all cases of invasive breast cancer and subgroups divided according to histological type, Ki-67 proliferation status and tumour size. Especially in a multivariate analysis standardised for axillary lymph node status, patient's age and tumour size at the time of diagnosis, securin immunopositivity indicated a 13.1-fold risk of breast cancer death (P=0.024) among invasive ductal breast carcinomas with low Ki-67 positivity. CONCLUSION: Our present and previous results suggest that securin could be useful in clinical pathology to intensify the power of the established prognosticators of invasive breast cancer and, especially, to assist in identifying patients with a more favourable outcome than that indicated by Ki-67 alone.

Role of mammography screening as a predictor of survival in postmenopausal breast cancer patients.

We examined the effect of population-based screening programme on tumour characteristics by comparing carcinomas diagnosed during the prescreening (N=341) and screening (N=552) periods. We identified screen detected (N=224), interval (N=99) and clinical cancer (N=229) cases. Median tumour size and proportion of axillary lymph node negative cases were 1.5 cm and 65% in the screen detected group, 2.0 cm and 44% in cases found outside the screening, and 3.2 cm and 41% in the cases from the prescreening period. Survival of the breast cancer patients was 66% (95% CI, 60-71%) in the prescreening era group and 73% (95% CI, 66-78%) in the screening era group after 10 years of follow-up. In the screening era group the survival of the screen detected cases was 86% (95% CI, 80-90%) and that of the clinical cancer cases 73% (95% CI, 66-78%) after 10 years. In multivariate analysis the risk of breast cancer death was not significantly different between the prescreening and screening periods (HR 0.82; 95% CI 0.59-1.12, P=0.21). Detection by screening was not an independent prognostic factor in multivariate analysis (HR 0.75; CI 95% 0.50-1.12; P=0.17).

Predicting aggressive outcome in T1N0M0 breast cancer.

Despite the excellent overall prognosis, unpredictable breast cancer recurrences and deaths also occur among T1N0M0 patients. We have evaluated clinically applicable methods for identifying aggressive outcome in T1N0M0 breast cancer. The material is based on aggressive T1N0M0 invasive ductal and lobular carcinomas diagnosed in Turku University Hospital and Jyväskylä Central Hospital, Finland, during 1987-1997. We studied all the T1N0M0 breast cancers that had led to recurrency or death (n=21, 95% T1cN0M0) during the follow-up period (4-14 years). The study is based on statistical analyses of matched case-control data in which the prognostic factors of each individual patient with aggressive disease were compared with control patients (n=45) individually matched by tumour size, age at diagnosis, histological type of tumour and length of follow-up. The cancer cases were examined for clinically applicable conventional and immunohistochemical pathologic prognostic factors. High Ki-67 immunopositivity was the strongest prognosticator of breast cancer death or recurrence in T1N0M0 breast cancer. Also, high p53 immunopositivity, low oestrogen receptor immunopositivity and Her-2/neu oncogene amplification by chromogen in situ hybridisation were reliable indicators of unfavourable outcome. Our statistical methods also allowed us to determine for the present material a range of clinical significance for each immunohistochemical prognostic feature with the associated relative risk for breast cancer death and recurrence. The paper suggests guidelines for predicting aggressive outcome in T1N0M0 breast cancer.

Complications of nephropathia epidemica: three cases.

Haemorrhagic fever with renal syndrome (HFRS) in Scandinavia is called nephropathia epidemica (NE), and is caused by the Puumala-virus, which belongs to the Hanta-virus genus. The clinical course of NE is mostly benign, complications are uncommon, and deaths are rarely observed. We report the cases of three patients who developed serious complications in the course of NE caused by the Puumala-virus. One patient died within 24 h after admission, another developed progressive neuromuscular dysfunction (Guillain-Barré syndrome) which required auxiliary ventilation for several weeks before a slow recovery, and a third patient developed empty sella syndrome with pituitary gland insufficiency. In the first two cases the diagnosis of NE was confirmed by a rapid avidity assay for IgG antibody against Puumala-virus. In the third case the clinical course, and demonstration of NE immunity 16 years later, suggested that NE might have caused the hypopituitarism. Some patients with NE caused by the Puumala-virus may require intensive-care treatment, and the development of late complications such as empty sella syndrome and hypopituitarism should be taken into consideration.

Contiguous enlarged dental follicles with histologic features resembling the WHO type of odontogenic fibroma.

Defective odontogenesis and/or retarded eruption of teeth can be associated with histologic features akin to odontogenic fibroma in the dental follicles. Unerupted mandibular premolar and molar teeth of a 24-year-old man were surgically exposed, yet the teeth failed to erupt. About a year and a half later, radiographs indicated further enlargement of the follicle of the premolar, and both teeth were subsequently surgically removed. Histologically, the follicles were composed of mature collagenous tissue among which epithelial islands and numerous clusters of calcified bodies were present. Indirect immunofluorescence showed positive staining for type I and type III collagen, which exhibited a sparse distribution, but not for the aminoterminal propeptide of type III procollagen. The hamartomatous nature of the lesions is discussed with emphasis on their histologic resemblance to the WHO type of odontogenic fibroma.

Post-mortem findings of tracheal injury after cuffed intubation and tracheostomy. A clinical and histopathological study.

The tracheas of 37 tracheostomized patients (31 men and 6 women) were studied in connection with obduction. Twenty-six patients had been intubated before tracheostomy and 29 of the tracheostomized patients were treated with a respirator. At autopsy, the damage caused to the tracheal wall by the cuff was studied macroscopically; the finding was photographed for later investigation and samples were taken from the damaged area for microscopic examination. The purpose of the study was to determine the damage caused to the tracheal wall by the low-volume cuff we have used during the last 4 years. The cuff diameter was nearly the same as that of the trachea. The injuries were grouped according to their extent and depth as mild, moderate or severe, and the groups contained, respectively, 5, 12 and 20 patients. It seemed that cuff pressure played a greater part in causing damage than the duration of cuff strain. Factors in the clinical condition of patients, like hypotension, uraemia, respiratory infections, sepsis and use of steroids, may have had an effect on the development of damage. The injuries caused by the cuff used are so severe that there is every reason to use instead the low-pressure, high-volume cuff, which has been shown to cause less damage, whenever long-term treatment is involved.

Ultrastructural and functional changes in pancreatic acinar cells during autolysis.

Effects of anoxemic cell injury on rat pancreatic acinar cells were studied in a preparation where tissue samples were incubated at temperature between 18-20 degrees C in a moist atmosphere for 0, 0.5, 1, 3, 6, 12, and 24 h in vitro. Electron microscopy revealed that disintegration of acinar cells began by swelling of various cell compartments and gradual breakdown of cell membranes. Zymogen granules remained morphologically intact for at least 3 h. There were no signs of increased autophagic activity during the period of observation. Myelin figures and other membranous remnants of disintegrated cells, together with individual cells and cell organelles whose morphology was relatively well preserved were seen even after w4 h incubation. The secretory response of acinar cells to pancreozymin stimulation, as measured by amylase release into the incubation medium in vitro, decreased progressively closer to zero during 12 h autolysis. No active trypsin could be detected in the tissue samples during the 24 h observation time. It was concluded that during hypoxic autolysis at room temperature between 18-20 degrees C in vitro: 1. Acinar cell disintegration results from breakdown of cellular membranes, 2. autophagocytosis is not involved, 3. most of zymogen granules remain morphologically intact even at the time when cell membranes show evidence of damage, 4. there is no trypsin activation taking place in the tissue, and 5. the acinar cells are capable of responding to secretory stimulation for 3 to 6 h after removal of the tissue from the experimental animal.

Intra-articular triamcinolone hexacetonide and osmic acid in persistent synovitis of the knee.

43 rheumatoid knees with persistent effusion were treated by intra-articular injections of triamcinolone hexacetonide (40 mg) or combined triamcinolone - osmic acid. Both treatments produced long-lasting improvements in the treated knees. Osmic acid seemed to potentiate the effect of the steroid. This demonstrated by measurement of joint circumference and local 99mTc uptake. In the general clinical evaluation the difference between the treatments was not noticeable. The percentage of 'excellent' and 'good' improvements was 36 at 12 months in the steroid-group and 44 in the steroid-osmic acid group.