Tumor tissue levels of Tissue Inhibitor of Metalloproteinases-1 (TIMP-1) and outcome following adjuvant chemotherapy in premenopausal lymph node-positive breast cancer patients: A retrospective study

<p>Abstract</p> <p>Background</p> <p>We have previously demonstrated that high tumor tissue levels of TIMP-1 are associated with no or limited clinical benefit from chemotherapy with CMF and anthracyclines in metastatic breast cancer patients. Here, we extend our investigations to the adjuvant setting studying outcome after adjuvant chemotherapy in premenopausal lymph node-positive patients. We hypothesize that TIMP-1 high tumors are less sensitive to chemotherapy and accordingly that high tumor tissue levels are associated with shorter survival.</p> <p>Methods</p> <p>From our original retrospectively collected tumor samples we selected a group of 525 pre-menopausal lymph node-positive patients (adjuvant treatment: CMF, 324 patients; anthracycline-based, 99 patients; no adjuvant chemotherapy, 102 patients). TIMP-1 levels were measured using ELISA in cytosolic extracts of frozen primary tumors. TIMP-1 was analyzed as a continuous variable and as a dichotomized one using the median TIMP-1 concentration as a cut point between high and low TIMP-1 groups. We analyzed the benefit of adjuvant CMF and anthracyclines in univariate and multivariable survival models; endpoints were disease-free (DFS) and overall survival (OS).</p> <p>Results</p> <p>In this selected cohort of high-risk patients, and in the subgroup of patients receiving no adjuvant therapy, TIMP-1 was not associated with prognosis. In the subgroup of patients treated with anthracyclines, when analyzed as a continuous variable we observed a tendency for increasing TIMP-1 levels to be associated with shorter DFS (multivariable analysis, HR 1.75, 95% CI 1.00-3.07, P = 0.05) and a significant association between increasing TIMP-1 and shorter OS in both univariate (HR 3.52, 95% CI 1.54-8.06, P = 0.003) and multivariable analyses (HR 4.19, 95% CI 1.67-10.51, P = 0.002). No statistically significant association between TIMP-1 and DFS was observed in the CMF-treated patients although high TIMP-1 was associated with shorter OS when analyzed as a dichotomized variable (HR 1.64, 95% CI 1.02-2.65, P = 0.04).</p> <p>Conclusion</p> <p>In the subgroup of patients receiving adjuvant chemotherapy we found an association between shorter survival after treatment in TIMP-1 high patients compared with TIMP-1 low patients, especially in patients receiving anthracycline-based therapy. This suggests that high tumor tissue levels of TIMP-1 might be associated with reduced benefit from classical adjuvant chemotherapy. Our findings should be validated in larger prospective studies.</p

MMP-2 immunoreactive protein in breast carcinoma and neoplastic cervical lesions:mMP-2 is a new prognostic factor in breast carcinoma

Abstract Tumor invasion and metastasis are the major causes of treatment failure or death for carcinoma patients. Matrix metalloproteinases (MMPs) are zinc dependent endopeptidases implicated in tumor invasion and metastasis. The expression of MMP-2 has been previously linked to invasiveness of carcinoma cells. The MMP-2 immunoreactive protein was studied here in squamous cell carcinoma of the utrine cervix and in adenocarcinoma of the breast by using a specific monoclonal antibody in immunohistochemical stainings. Immunoreactive protein of latent MMP-2 was found to be an early event in neoplastic transformation of the cervix in 60 patients. All cases of early stage cervical carcinoma expressed the latent MMP-2 protein, suggesting that MMP-2 could be a prerequisite for invasive behavior. In early stage cervical carcinoma the high score of MMP-2 expression seemed to be associated with poor histological differentiation and lymph node metastases. The intensitivity (score) of the immunoreaction was not, however, associated with clinical behavior of this disease. New predictive markers would be useful in selecting breast carcinoma patients to different modalities of adjuvant therapy. The MMP-2 protein has been found in breast carcinoma tumor cells in immunohistochemical analyses. MMP-2 has been found to be expressed in breast carcinoma in some preliminary studies, but there are no reports so far that would show a correlation of MMP-2 to survival in breast carcinoma. In the current study comprising 373 patients the expression of MMP-2 protein was found immunohistochemically in primary breast carcinomas. It is shown here for the first time that immunoreactive protein of MMP-2 in primary breast carcinoma is associated with a shortened relapse-free survival (RFS) or relative overall survival (OS). MMP-2 correlated to the risk of failure during the anti-estrogen adjuvant therapy in postmenopausal breast carcinoma patients with axillary lymph node metastasis without a high tumor burden. It was also found here that premenopausal patients with a node positive breast carcinoma showing MMP-2 positivity relapsed early after the primary operation. Young patients (&lt; 40 years) with MMP-2 positive tumors had a poor outcome when compared to other node-positive premenopausal breast carcinoma patients. A patient group with a high risk for an early relapse was identified from node-positive, premenopausal breast carcinoma patients. In conclusion, the present data show for the first time MMP-2 immunoreactive protein to be a prognostic factor in breast carcinoma, indicating further studies to explore the value of this enzyme in clinical decision making

The serum levels of circulating matrix metalloproteinase MMP-9, MMP-2/TIMP-2 complex and TIMP-1 do not change significantly during normal pregnancy:a pilot study

Abstract Objective: Matrix metalloproteinases (MMPs) are important regulators of vascular and uterine remodeling. They exhibit proteolytic activity implicating the efficiency of trophoblast invasion to the uterine wall involving marked hemodynamic and uterine changes. In this pilot study sera of 13 women with normal pregnancy was analyzed to evaluate the usage of MMPs as diagnostic tool. The concentrations of circulating MMP-9, MMP-2/TIMP-2 complex and TIMP-1 in different time points during normal pregnancy has not been studied. The serum levels of MMP-9, TIMP-1, TIMP-2 and MMP-2/TIMP-2 complex were determined by enzyme-linked immunosorbent assay (ELISA). Using the same method, we have shown that serum MMPs are elevated in spontaneous early pregnancy failure as compared to normal pregnancy. Results: The serum levels of MMP-9 and TIMP-1 were stable throughout pregnancy. The level of MMP-2/TIMP-2 complex was slightly increased after week 15 without statistical significance. For our best knowledge, this is a first study of the serum levels of MMP-9, MMP-2/TIMP-2 and TIMP-1 on different time points during normal pregnancy. Further measurements with the correlation to the outcome of the pregnancy are needed

Histological findings of patients with adnexal torsion who underwent surgical treatment:short reminder

Abstract Background: Ovarian torsion is a rare emergency condition in women. Early diagnosis is necessary to preserve fertility. Case: Our study evaluated 40 patients, who underwent laparoscopic surgery. The aims of this retrospective study were to emphasize the importance of early diagnosis in ovarian torsion, evaluate the process of patient treatment, and investigate the number of patients treated by minimally invasive surgery. In this article, we present the outcomes from the patient data. Results: Thirty-two percent (13/40) of patients were first evaluated by the surgeon to investigate right-sided lower abdominal pain. These patients were first misdiagnosed with appendicitis or urinary tract stones. Among these patients, necrotic ovary tissue was more common, most likely due to a longer delay seeking medical attention. A total of 77% (31/40) of patients underwent laparoscopic surgery on the same date that they were admitted to the hospital. No severe complications occurred in this group of patients. All histological findings were benign. In 52% (21/40) of patients, the adnexa was removed, whereas in 37% (15/40) of patients the torsed adnexa was treated by detorsion. A total of 27% (11/40) of patients had no diagnosis before undergoing surgery. Conclusions: Rapid and accurate diagnosis is essential to preserve ovarian function

Association of prevalent vaginal microbiome of mother with occurrence of type I diabetes in child

Abstract Type I diabetes (T1D) is a rapidly increasing autoimmune disease especially in the Western countries and poses a serious global health problem. Incidence of T1D cannot be fully explained by genetic background, and environmental factors have been assumed to play a role. Environmental conditions and composition of human microbiome have been found to correlate with the incidence of T1D. We asked whether mothers’ prevalent vaginal microbiome could correlate with the incidence of T1D in child. To test this hypothesis, we collected samples of vaginal microbiomes from eight mothers that had at least one child with T1D (child age maximum of 11 years at the time of sampling), born with a vaginal delivery. Eight control mothers had child/children with vaginal delivery and no diabetic child/children. The microbiomes were studied by using 16S rRNA Ion Torrent high throughput sequencing. We found that composition of total and Lactobacillus microbiome was altered, and saw an indication that diversity of vaginal microbiomes of the mothers with a diabetic child could be higher. Based on these pilot observations, we strongly encourage a larger population study to verify whether mother vaginal microbiome diversity and composition are linked to the prevalence of T1D in children

Long-term results of a prospective randomized trial comparing tension-free vaginal tape versus transobturator tape in stress urinary incontinence

Abstract Introduction and hypothesis: This study was aimed at investigating the long-term effectiveness of minimally invasive mid-urethral sling (MUS) surgery and at comparing the outcomes between retropubic (tension-free vaginal tape, TVT) and transobturator tape (TOT) methods in the treatment of stress urinary incontinence (SUI) and mixed urinary incontinence (MUI) with a predominant stress component in a long-term follow-up of a randomized controlled trial. Methods: This work is a long-term follow-up study of a previous prospective randomized trial conducted in the Department of Obstetrics and Gynecology at Oulu University Hospital between January 2004 and November 2006. The original 100 patients were randomized into the TVT (n=50) or TOT (n=50) group. The median follow-up time was 16 years, and the subjective outcomes were evaluated using internationally standardized and validated questionnaires. Results: Long-term follow-up data were obtained from 34 TVT patients and 38 TOT patients. At 16 years after MUS surgery, the UISS significantly decreased from a preoperative score in the TVT (11.88 vs 5.00, p&lt;0.001) and TOT (11.05 vs 4.95, p&lt;0.001) groups, showing a good long-term success of the MUS surgery in both groups. In comparing the TVT and TOT procedures, the subjective cure rates did not differ significantly between the study groups in long-term follow-up according to validated questionnaires. Conclusion: Midurethral sling surgery had good long-term outcomes in the treatment of SUI and MUI with a predominant stress component. The subjective outcomes of the TVT and TOT procedures were similar after a 16-year follow-up

Novel human lymph node-derived matrix supports the adhesion of metastatic oral carcinoma cells

Abstract Background: 3D culture is increasingly used in cancer research, as it allows the growth of cells in an environment that mimics in vivo conditions. Metastases are the primary cause of morbidity and mortality in cancer patients, and solid tumour metastases are mostly located in lymph nodes. Currently, there are no techniques that model the pre-metastatic lymph node microenvironment in vitro. In this study, we prepared a novel extracellular matrix, Lymphogel, which is derived from lymph nodes, mimicking the tumour microenvironment (TME) of metastatic carcinoma cells. We tested the suitability of the new matrix in various functional experiments and compared the results with those obtained using existing matrices. Methods: We used both commercial and patient-derived primary and metastatic oral tongue squamous cell carcinoma (OTSCC) cell lines. We characterized the functional differences of these cells using three different matrices (human uterine leiomyoma-derived Myogel, human pre-metastatic neck lymph node-derived Lymphogel (h-LG), porcine normal neck lymph node-derived Lymphogel (p-LG) in proliferation, adhesion, migration and invasion assays. We also performed proteomic analyses to compare the different matrices in relation to their functional properties. Results: OTSCC cells exhibited different adhesion and invasion patterns depending on the matrix. Metastatic cell lines showed improved ability to adhere to h-LG, but the effects of the matrices on cell invasion fluctuated non-significantly between the cell lines. Proteomic analyses showed that the protein composition between matrices was highly variable; Myogel contained 618, p-LG 1823 and h-LG 1520 different proteins. The comparison of all three matrices revealed only 120 common proteins. Analysis of cellular pathways and processes associated with proteomes of each matrix revealed similarities of Myogel with h-LG but less with p-LG. Similarly, p-LG contained the least adhesion-related proteins compared with Myogel and h-LG. The highest number of unique adhesion-related proteins was present in h-LG. Conclusions: We demonstrated that human pre-metastatic neck lymph node-derived matrix is suitable for studying metastatic OTSCC cells. As a whole-protein extract, h-LG provides new opportunities for in vitro carcinoma cell culture experiments