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

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.

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

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<0.001) and TOT (11.05 vs 4.95, p<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.

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.

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.

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

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.

Cyclins A, B, E and p27 in Endometrial Endometrioid Adenocarcinoma.

BACKGROUND/AIM: We have previously shown that cyclin A, B and E hold prognostic significance in endometrial endometrioid adenocarcinoma. The aim of this study was to investigate the impact of cyclin-dependent kinase inhibitor p27 on cancer-specific survival and other clinicopathological variables, as well as further analyze the relationship between p27 and cyclins A, B and E and their combined relation to prognosis in the disease. PATIENTS AND METHODS: The study comprised of 211 patients surgically treated for endometrial endometrioid adenocarcinoma at the Oulu University Hospital between 1992 and 2000. Tissue samples were immunohistochemically stained for cyclins A, B and E, as well as p27. Clinicopathological data were retrospectively retrieved from the patients' records. RESULTS: In this study, universally low cyclin expression was found to be an independent, favorable prognostic factor in endometrial endometrioid adenocarcinoma. A strong correlation was found between cyclin A and cyclin B expression and weaker correlations between other cyclin and p27 pairs. Nuclear p27 expression correlated with stage and produced near-significant results in univariate survival analysis. CONCLUSION: Combining the expression level of different cyclins may be useful in determining the prognosis in endometrial cancer. Unfortunately, it remains unclear whether high p27 expression is a poor or a favorable prognostic factor. Further large-scale studies are required to assess the effects of cyclins and p27 in endometrial cancer.

Mifepristone and misoprostol is safe and effective method in the second-trimester pregnancy termination.

PURPOSE: The second-trimester medical abortions constitute 10-15 % of all induced abortions worldwide, but are responsible for two-thirds of major abortion related complications. During the last decade, medical methods for the second-trimester-induced abortion have been become safer and more accessible. The aim of this study is to evaluate factors affecting clinical effectiveness of the second-trimester medical terminations using mifepristone and misoprostol combination. METHODS: In this retrospective observational study, 142 consecutive women underwent medical abortion on 12-24 weeks of gestation. Clinical data were collected from Oulu University Hospital patients' records for the period between January 2008 and June 2011. The associations between patient characteristics and different outcomes were evaluated using the standard statistical test for correlation. RESULTS: The majority (92 %) of women aborted successfully within 24 h and were considered as day cases with small complication rate, as compared to hospitalized patients. In nulliparous patients, the time for complete abortion was longer than in other groups (P < 0.0019). Nulliparous women and women with gestation more than 16 weeks required opiate analgesia more often (P = 0.003 and <0.001, respectively). CONCLUSION: Women with previous live births aborted more often within 8 h than women with no previous births. Mifepristone and misoprostol is safe and effective method for the second-trimester pregnancy termination. The second-trimester medical abortion can be provided by a nurse-midwife with the back-up of a gynecologist.

Cyclin E Expression Correlates with Cancer-specific Survival in Endometrial Endometrioid Adenocarcinoma.

AIM: The aim of the present study was to investigate the impact of cyclin E expression on cancer-specific survival, as well as on conventional clinocopathological and prognostic factors in endometrial endometrioid adenocarcinoma. MATERIALS AND METHODS: The study consisted of 211 patients surgically treated for endometrial endometrioid adenocarcinoma at the Oulu University Hospital between 1992-2000. Tissue samples were immunohistochemically stained for cyclin E and clinicopathological data were retrospectively retrieved from the patients' records. RESULTS: Cyclin E expression correlated with grade but not with the Fédération Internationale de Gynécologie Obstétrique (FIGO) stage or myometrial invasion. Univariate and multivariate survival analyses were performed between patients grouped according to a receiver operating characteristic (ROC) curve-derived cut-off value. A statistically significant difference in survival was demonstrated between patient groups in Kaplan-Meier analysis. CONCLUSION: Contrary to previous literature, we found a correlation between cyclin E expression and prognosis. Further large-scale studies are required to confirm our findings.

Claudin-5 is associated with elevated TATI and CA125 levels in mucinous ovarian borderline tumors.

BACKGROUND/AIM: Claudin proteins represent a large family of integral membrane proteins crucial for tight junction (TJ) formation and function and are abnormally regulated in several human cancers. The aim of the present study was to study the expression levels of claudin-5 in pre-malignant disease as borderline mucinous ovarian tumors. Previous reports have suggested that claudin-5 over-expression correlates with aggressive behaviour in serous ovarian adenocarcinoma, breast cancer and in pancreatic andenocarcinoma. PATIENTS AND METHODS: We investigated the expression of claudin-5 in mucinous ovarian borderline tumors and its correlation with clinico-pathological parameters and the expression of serum markers cancer antigen (CA) 125 and tumor-associated trypsin inhibitor (TATI). RESULTS: A total of 29 mucinous borderline tumor tissue samples were analyzed using immunohistochemical staining for claudin-5. An association between strong claudin-5 expression and higher serum levels of TATI (p=0.04) and CA125 (p=0.008) were found. There was also an association between claudin-5 expression and the presence of ascites (p=0.02). CONCLUSION: Changes in claudin-5 expression may play a role in malignant transformation.

Prognostic value of cyclin B in endometrial endometrioid adenocarcinoma.

Cyclins are a group of cell cycle regulatory proteins. Cyclin B acts as an activator to cyclin-dependent kinase 1 (CDK1), a protein kinase essential for G2/M phase transition. Deregulation of cyclins has been linked to a number of malignant neoplasms, but the impact on clinicopathological parameters seems to be cancer-specific. Overexpression of cyclin B has been shown to affect survival in some malignant tumors, including breast and esophageal cancer, but its impact on endometrial cancer has not been extensively studied. For this study, 211 endometrial endometrioid adenocarcinoma samples were obtained from patients surgically treated at the Oulu University Hospital. The samples were immunohistochemically stained and analyzed for cyclin B expression. The relationships between cyclin B expression and conventional prognostic factors were analyzed. A discrimination threshold for survival analyses was calculated by utilizing the receiver operator characteristic (ROC) method. Cyclin B expression correlated with grade and advanced stage. Survival analyses showed that cyclin B expression affects cancer-specific survival in univariate analysis. In multivariate analysis, the results were indicative that cyclin B may hold independent prognostic significance, but further studies are required to assess this.

High expression of cyclin A is associated with poor prognosis in endometrial endometrioid adenocarcinoma.

Cyclins are a group of proteins that act as activators to cyclin-dependent kinases and are required for normal cell cycle transitions. Cyclin A is involved in the transitions between G1 to S and G2 to M. Its deregulation has been linked to a number of neoplasms, including endometrial cancer. The prognostic significance of cyclin A expression seems to be cancer-specific, and current knowledge on its impact on survival of endometrial cancer is limited. This study aimed to investigate the effect of cyclin A expression on cancer-specific survival and its correlation with conventional prognostic factors in endometrioid adenocarcinoma. Biopsies obtained from 211 patients were immunohistochemically stained for cyclin A and differences in expression analyzed at the Oulu University Hospital. Patients were divided into two groups utilizing the ROC curve. Further survival analyses were carried out between these two groups. In this study, we show that cyclin A expression correlates with tumor grade and FIGO stage. We also show that cyclin A is an independent prognostic factor in endometrioid adenocarcinoma. Whether cyclin A plays a role in tumorigenesis or merely is a marker of increased proliferation requires further studies.

A prospective randomized trial comparing tension-free vaginal tape versus transobturator tape in patients with stress or mixed urinary incontinence: subjective cure rate and satisfaction in median follow-up of 46 months.

OBJECTIVE: The aim of this study was to investigate the difference in subjective cure rate and patient satisfaction between tension-free vaginal tape (TVT) and transobturator tape (TOT) surgical methods in the treatment of stress and mixed urinary incontinence. MATERIAL AND METHODS: From January 2004 to November 2006, a total of 100 patients suffering from stress or mixed urinary incontinence and evaluated to benefit from operative treatment were randomized to undergo either TVT or TOT surgery in Oulu University Hospital. There were no significant differences between the study groups concerning the patient characteristics. During the 3, 14 and 46 month follow-up steps, information on subjective cure and patient satisfaction was gathered with Urinary Incontinence Severity Score and Detrusor Instability Score questionnaires and a specific question about satisfaction. RESULTS: The subjective cure rate was 81% in both study groups. The satisfaction rate was 79% in the TVT group and 74% in the TOT group at the final follow-up. Urge symptoms were relieved in 70% of patients in the mixed urinary incontinence subgroup. De novo urgency occurred in 17% of the patients in the stress urinary incontinence subgroup, and 45% of these patients were unsatisfied after the follow-up. CONCLUSIONS: TVT and TOT are equally effective methods in the treatment of urinary incontinence and patient satisfaction is similar in both methods. A large proportion of patients with mixed urinary incontinence found the operation beneficial for urge symptoms.

Combination of strong MMP-2 and weak TIMP-2 immunostainings is a significant prognostic factor in endometrial carcinoma.

OBJECTIVE: The aim of this study was to evaluate the combined effects of MMP-2 and TIMP-2 protein immunoreactivities on the prognosis in endometrial carcinoma. METHODS: Paraffin-embedded tissue samples from 225 primary endometrioid adenocarcinomas and 13 histologies other than endometrioid adenocarcinoma were immunohistochemically stained for MMP-2 and TIMP-2. RESULTS: In Kaplan-Meier analysis, the 5-year cancer-specific survival rate of the endometrioid adenocarcinoma patients with negative MMP-2 and positive TIMP-2 staining was 100%, whereas only 78% of patients presenting with positive MMP-2 and negative TIMP-2 staining results were alive at that time. In Cox regression analysis, patients with positive MMP-2 and negative TIMP-2 immunostaining had a 4.7-fold relative risk of death from endometrial carcinoma compared to the group of patients with negative MMP-2 and positive or negative TIMP-2 immunoreaction. CONCLUSIONS: MMP-2 seems to be the main metalloproteinase determining the prognosis in endometrial carcinoma. Combination of strong MMP-2 and weak TIMP-2 immunostainings was the most potent prognostic marker for poor survival.

Posterior Intravaginal Slingplasty versus Unilateral Sacrospinous Ligament Fixation in Treatment of Vaginal Vault Prolapse.

Objective. To investigate the differences in efficacy, postoperative complications, and patient satisfaction between posterior intravaginal slingplasty (PIVS) and unilateral sacrospinous ligament fixation (SSLF) procedures. Study Design. A retrospective study of thirty-three women who underwent PIVS or SSLF treatment for vaginal vault prolapse in Oulu University Hospital. The patients were invited to a follow-up visit to evaluate the objective and subjective outcomes. Median follow-up time was 16 months (range 6-52). The anatomical outcome was detected by the Pelvic Organ Prolapse Quantification (POP-Q) system. Information on urinary, bowel, and sexual dysfunctions and overall satisfaction was gathered with specific questionnaire. The data were analyzed using Mann-Whitney U test and Fisher's exact test. Results. Mesh erosion was found in 4 (25%) patients in the PIVS group. Anatomical stage II prolapse or worse (any POP-Q point ≥-1) was detected in 8 (50%) patients in the PIVS group and 9 (53%) patients in the SSLF group. Overall satisfaction rates were 62% and 76%, respectively. Conclusion. The efficacy of PIVS and SSLF is equally poor, and the rate of vaginal erosion is intolerably high with the PIVS method. Based on our study, we cannot recommend the usage of either technique in operative treatment of vaginal vault prolapse.

Circulating matrix metalloproteinase MMP-9 and MMP-2/TIMP-2 complex are associated with spontaneous early pregnancy failure.

BACKGROUND: Trophoblast cell (CTB) invasion into the maternal endometrium plays a crucial role during human embryo implantation and placentation. This invasion is facilitated by the activity of matrix metalloproteinases, which are regulated by tissue inhibitors of MMPs (TIMPs). METHODS: This study compares the serum levels of MMP-9, MMP-2/TIMP-2 complex, TIMP-1 and TIMP-2 in 129 patients with ongoing pregnancy (n = 40) or spontaneous early pregnancy failure (n = 89). RESULTS: MMP-9 was markedly (p < 0.0001) elevated in missed abortions, as was MMP-2/TIMP-2 complex (p < 0.0005). However, the serum levels of TIMP-1 and TIMP-2 were markedly elevated (p < 0.0001) in ongoing pregnancies. CONCLUSIONS: Human placentation is mediated by fetal trophoblastic cells that invade the maternal uterine endometrium. Trophoblast invasion requires a precisely regulated secretion of specific proteolytic enzymes able to degrade the endometrial basement membrane and extracellular matrix. The elevated levels of MMP-9 and MMP-2/TIMP-2 complex may play a role in spontaneous termination of pregnancy.

Immunoreactivity for TIMP-2 is associated with a favorable prognosis in endometrial carcinoma.

Tissue inhibitors of metalloproteinases are important regulators of metalloproteinase activity, and the balance of active enzyme and inhibitor is a critical determinant of tumor cell invasiveness. This study aimed to evaluate the prognostic and clinical implications of the two main inhibitors of matrix metalloproteinases, TIMP-1 and TIMP-2, in endometrial carcinoma. The material consisted of 241 patients with primary endometrial carcinoma. The median follow-up time was 77 months. Expressions of TIMP-1 and TIMP-2 proteins were examined in paraffin-embedded tumor sections by immunohistochemical methods. Positive staining for TIMP-1 and -2 was observed in 88% and 86% of the primary tumors, respectively. The Kaplan-Meier analysis showed that the 5-year cancer-specific survival rate of the patients with TIMP-2 positive immunostaining was 89% and that of the TIMP-2 negative patients 78%. Positive immunoreaction for TIMP-2 correlated with favorable cancer-specific and overall survival. When including only endometrioid adenocarcinomas, a similar trend towards favorable survival was seen. Excluding stage IA carcinomas, the difference became again statistically significant. For TIMP-1, there was no statistically significant association with overall or cancer-specific survival. The Cox regression analysis showed stage, grade and TIMP-2 to be significant predictors of survival. We suggest that TIMP-2 may have a more important role in endometrial carcinoma progression than TIMP-1 and might serve as a potential marker for favorable prognosis in this type of cancer.

Clinical efficacy of mifepristone and misoprostol in second trimester pregnancy termination.

OBJECTIVE: the aim of this study was to evaluate factors affecting clinical effectiveness of 2nd trimester medical terminations using mifepristone and misoprostol combination. DESIGN: a retrospective observational study. POPULATION: ninety consecutive women who had undergone medical termination of pregnancy after 12-24 weeks of gestation. METHODS: clinical data were collected from Oulu University Hospital patient records for the period between February 2003 and August 2005. The associations between patient characteristics and different outcomes were evaluated using standard statistical tests for correlation. MAIN OUTCOME MEASURES: the time elapsed from induction to successful abortion. RESULTS: the majority (94%) of women aborted successfully within 24 hours. Those who were considered day cases (no overnight hospitalization) were more likely to have a successful termination (p = 0.004), while those who were hospitalized for three or more days were more likely to have a complication (p = 0.046). Women with no previous live births or women with gestation ≥ 17 weeks required opiate analgesia more often (p = 0.019, p = 0.02, respectively). Induction to abortion time was shorter (p < 0.001) when pregnancy had lasted <17 weeks. Nulliparous women were more likely to have a longer induction-to-abortion interval (p < 0.001) than uni- and multiparous women. Women with previous live births aborted more often within 8 hours than women with no previous births (p = 0.032). CONCLUSIONS: multiparous women and women with early gestation complete medical termination faster. Multiparity and shorter gestation time are also associated with lesser need for opiate analgesia, compared to nulliparous women or longer gestation time (≥ 17 weeks).

[Update on current care guidelines. Diagnosis, treatment and follow-up of cytological changes in the cervix, vagina and vulva]. / Kohdunkaulan, emättimen ja ulkosynnytinten solumuutokset--diagnostiikka, hoito ja seuranta.

Approximately 150 cervical cancer cases are diagnosed in Finland annually. Both incidence and mortality have decreased by 80% since organised screening began. Recently, screening based on primary HPV-testing with Pap-smear triage has been shown to be more sensitive and more specific among women over 35 years old in randomised studies and thus may be implemented in routine. Abnormal findings in Pap smears indicate management. Confirmed CIN1 lesions are followed up and CIN2 and worse lesions treated. Follow-up after treatment should be reliably arranged, because elevated risk of cancer remains over 20 years after treatment. Quality control is of utmost importance.

Increased matrix metalloproteinases 2 and 9 and tissue inhibitor of matrix metalloproteinase 2 expression is associated with progression from vulvar intraepithelial neoplasia to invasive carcinoma.

OBJECTIVE: The expression of matrix metalloproteinases 2 (MMP-2) and 9 (MMP-9) and tissue inhibitors of matrix metalloproteinases 1 (TIMP-1) and 2 (TIMP-2) in vulvar intraepithelial neoplasia (VIN I-III) and in vulvar invasive carcinoma were evaluated. DESIGN: A retrospective study. SETTING: Oulu University Hospital, Finland. SAMPLE: The study population consisted of 68 patients with vulvar neoplasia (13 VIN I, 5 VIN II, 6 VIN III and 44 squamous cell carcinomas). METHODS: Paraffin-embedded tissue samples were examined by immunohistochemistry. MAIN OUTCOME MEASURES: MMP-2, MMP-9, TIMP-1 and TIMP-2 expression in VIN compared to vulvar carcinoma. RESULTS: In VIN I-III MMP-2 expression was positive in 13%, MMP-9 in 13%, TIMP-1 in 50% and TIMP-2 in 17% of patients. The positive expressions in patients with vulvar carcinoma were 52% for MMP-2, 36% for MMP-9, 41% for TIMP-1 and 78% for TIMP-2. CONCLUSIONS: We conclude that over-expression of MMP-2, MMP-9 and TIMP-2 may be associated with the progression from VIN to invasive vulvar squamous cell carcinoma.

Intravaginal slingplasty sling is associated with increased risk of vaginal erosion.

OBJECTIVE: Two structurally different polypropylene tapes are used in tension-free vaginal tape (TVT) and intravaginal slingplasty sling (IVS) procedures for the treatment of female stress urinary incontinence. This study aimed to compare TVT and IVS operations for late postoperative complications, especially vaginal erosion. DESIGN: A retrospective study. SETTING: Oulu University Hospital, Finland. SAMPLE: The study sample was constituted by 373 patients operatively treated for female urinary incontinence between January 2000 and June 2004. A total of 293 patients underwent the TVT operation and 80 patients the IVS operation. METHODS: We analyzed the data using Fisher's Exact test, Pearson's chi-squared test, and log linear test. For categorical variables we used risk ratios with 95% confidence intervals. MAIN OUTCOME MEASURES: The incidence of late complications, especially vaginal erosion. RESULTS: Symptomatic erosion (p < 0.001; risk ratio 13.7; 95% confidence interval 4.03-46.8) was seen in 3 patients (1%) in the TVT group and in 13 patients (16%) in the IVS group. The median time to the onset of symptoms was 9 and 12 months in these groups, respectively. CONCLUSIONS: We suggest that the high vaginal erosion rate in the IVS group is associated with the tape material.