Child type 1 diabetes associated with mother vaginal bacteriome and mycobiome.

Mother vaginal microbes contribute to microbiome of vaginally delivered neonates. Child microbiome can be associated with autoimmune diseases, such as type 1 diabetes (T1D). We collected vaginal DNA samples from 25 mothers with a vaginally delivered child diagnosed with T1D and samples from 24 control mothers who had vaginally delivered a healthy child and analyzed bacteriome and mycobiome of the samples. The total DNA of the samples was extracted, and ribosomal DNA regions (16S for bacteria, ITS2 for fungi) were amplified, followed by next-generation sequencing and machine learning. We found that alpha-diversity of bacteriome was increased (P < 0.002), whereas alpha-diversity of mycobiome was decreased (P < 0.001) in mothers with a diabetic child compared to the control mothers. Beta-diversity analysis suggested differences in mycobiomes between the mother groups (P = 0.001). Random forest models were able to effectively predict diabetes and control status of unknown samples (bacteria: 0.86 AUC, fungi: 0.96 AUC). Our data indicate several fungal genera and bacterial metabolic pathways of mother vaginal microbiome to be associated with child T1D. We suggest that early onset of T1D in a child has a relationship with altered mother vaginal microbiome and that both bacteriome and mycobiome contribute to this shift.

Optimising the antibiotic treatment of uncomplicated acute appendicitis: a protocol for a multicentre randomised clinical trial (APPAC II trial).

BACKGROUND: Based on epidemiological and clinical data acute appendicitis can present either as uncomplicated (70-80%) or complicated (20-30%) disease. Recent studies have shown that antibiotic therapy is both safe and cost-effective for a CT-scan confirmed uncomplicated acute appendicitis. However, based on the study protocols to ensure patient safety, these randomised studies used mainly broad-spectrum intravenous antibiotics requiring additional hospital resources and prolonged hospital stay. As we now know that antibiotic therapy for uncomplicated acute appendicitis is feasible and safe, further studies evaluating optimisation of the antibiotic treatment regarding both antibiotic spectrum and shorter hospital stay are needed to evaluate antibiotics as the first-line treatment for uncomplicated acute appendicitis. METHODS: APPAC II trial is a multicentre, open-label, non-inferiority randomised controlled trial comparing per oral (p.o.) antibiotic monotherapy with intravenous (i.v.) antibiotic therapy followed by p.o. antibiotics in the treatment of CT-scan confirmed uncomplicated acute appendicitis. Adult patients with CT-scan diagnosed uncomplicated acute appendicitis will be enrolled in nine Finnish hospitals. The intended sample size is 552 patients. Primary endpoint is the success of the randomised treatment, defined as resolution of acute appendicitis resulting in discharge from the hospital without the need for surgical intervention and no recurrent appendicitis during one-year follow-up. Secondary endpoints include post-intervention complications, late recurrence of acute appendicitis after one year, duration of hospital stay, pain, quality of life, sick leave and treatment costs. Primary endpoint will be evaluated in two stages: point estimates with 95% confidence interval (CI) will be calculated for both groups and proportion difference between groups with 95% CI will be calculated and evaluated based on 6 percentage point non-inferiority margin. DISCUSSION: To our knowledge, APPAC II trial is the first randomised controlled trial comparing per oral antibiotic monotherapy with intravenous antibiotic therapy continued by per oral antibiotics in the treatment of uncomplicated acute appendicitis. The APPAC II trial aims to add clinical evidence on the debated role of antibiotics as the first-line treatment for a CT-confirmed uncomplicated acute appendicitis as well as to optimise the non-operative treatment for uncomplicated acute appendicitis. TRIAL REGISTRATION: Clinicaltrials.gov , NCT03236961, retrospectively registered on the 2nd of August 2017.

An evaluation of the absolute and relative stability of alexithymia over 11years in a Finnish general population.

OBJECTIVE: We investigated if alexithymia, a personality construct with difficulties in emotional processing, is stable in the general population. METHODS: Altogether 3083 unselected subjects aged 30 and older in Finland completed the 20-item Toronto Alexithymia Scale (TAS-20) in the longitudinal Health 2000 and Health 2011 general population surveys (BRIF8901). The stability of alexithymia at the 11-year follow-up was assessed with t-tests, correlations, and separate linear regression models with base-line and follow-up age, gender, marital status, education, and 12-month depressive and anxiety disorders as confounders. RESULTS: The mean score (SD) of the TAS-20 for the whole sample was 44.2 (10.4) in 2000 and 44.2 (10.9) in 2011 (p=0.731). The mean score of the TAS-20 subscale Difficulty Identifying Feelings increased by 0.3 points, Difficulty Describing Feelings decreased by 0.6 points and Externally Oriented Thinking increased by 0.3 points. The effect sizes of the changes varied from negligible to small. Age had little effect except for the group of the oldest subjects (75-97years): the TAS-20 mean (SD) score was 49.1 (10.1) in 2000 and 53.1 (10.3) in 2011 (p<0.001), the effect size for the increase was medium. TAS-20 score in 2000 explained a significant proportion of variance in TAS-20 score in 2011. Controlling for all baseline confounders improved the model incrementally; the same applied to controlling for confounders at follow-up. Baseline depression or anxiety disorders were not associated with the TAS-20 scores in 2011, whereas current diagnoses were. CONCLUSIONS: According to our large longitudinal study both the absolute and relative stability of alexithymia assessed with the TAS-20 are high in the adult general population.

Heritability of flight and resting metabolic rates in the Glanville fritillary butterfly.

Dispersal capacity is a key life-history trait especially in species inhabiting fragmented landscapes. Evolutionary models predict that, given sufficient heritable variation, dispersal rate responds to natural selection imposed by habitat loss and fragmentation. Here, we estimate phenotypic variance components and heritability of flight and resting metabolic rates (RMRs) in an ecological model species, the Glanville fritillary butterfly, in which flight metabolic rate (FMR) is known to correlate strongly with dispersal rate. We modelled a two-generation pedigree with the animal model to distinguish additive genetic variance from maternal and common environmental effects. The results show that FMR is significantly heritable, with additive genetic variance accounting for about 40% of total phenotypic variance; thus, FMR has the potential to respond to selection on dispersal capacity. Maternal influences on flight metabolism were negligible. Heritability of flight metabolism was context dependent, as in stressful thermal conditions, environmentally induced variation dominated over additive genetic effects. There was no heritability in RMR, which was instead strongly influenced by maternal effects. This study contributes to a mechanistic understanding of the evolution of dispersal-related traits, a pressing question in view of the challenges posed to many species by changing climate and fragmentation of natural habitats.

Large bowel obstruction in a young woman simulating a malignant neoplasm: a case report of actinomyces infection.

Pelvic and intra-abdominal Actinomycosis can be difficult to diagnose preoperatively and it may also mimic many other diseases, including malignancies. We present a patient with pelvic Actinomycosis probably caused by a long-standing intrauterine device (IUD). We emphasize the challenges in diagnostic process and stress that though a rare disease, intra-abdominal Actinomycosis should be suspected in cases with intra-abdominal mass of uncertain etiology. The early recognition may spare the patient from extensive surgical operation.

Toll-like receptor 5 (TLR5) expression is a novel predictive marker for recurrence and survival in squamous cell carcinoma of the tongue.

BACKGROUND: Toll-like receptor 5 (TLR5) is an immune receptor recognising bacterial flagellin. Activation of TLR5 results in cancer invasion and cytokine release. As certain bacteria have been linked to oral cancer, we wanted to study TLR5 expression in oral tongue squamous cell carcinoma (OTSCC). METHODS: Samples from 119 patients with OTSCC were obtained, including 101 samples of adjacent normal lingual mucosa. The TLR5 histoscore (0-300) was assessed semiquantitatively by immunohistochemistry in a blinded manner. RESULTS: Toll-like receptor 5 was expressed in 84 normal epithelia and 118 cancer samples. Expression of TLR5 was increased in cancer when compared with normal lingual epithelium (median histoscore 15 vs 135). In cancer, higher TLR5 was associated with age of >70 years at the time of diagnosis, female gender and disease recurrence. No association between TLR5 expression and tumour grade, stage or treatment was found. In multivariate analysis, TLR5 was an independent predictor of cancer mortality (hazard ratio (HR) 3.587, 95% confidence interval (CI) (1.632-7.882)) and disease recurrence (HR 4.455, 95% CI (2.168-9.158)). CONCLUSION: Toll-like receptor 5 has a previously undescribed role in the pathophysiology of OTSCC and might represent a link between bacteria and cancer. It could be a useful marker for predicting recurrence or survival of OTSCC patients.

Difficulties in emotional regulation: association with poorer oral health-related quality of life in the general population.

Personality is one of the strongest predictors of subjective well-being and may, according to a few previous studies, affect how people report oral health-related quality of life (OHRQoL). Alexithymia, a personality trait involving difficulties in emotional regulation, is associated with poorer health-related quality of life in the general population. We studied if alexithymia is also associated with poorer OHRQoL in a general population sample of 4,460 adults. Oral health-related quality of life was measured using the 14-item Oral Health Impact Profile (OHIP-14) and alexithymia was measured using the 20-item Toronto Alexithymia Scale (TAS-20). Controlling for clinically assessed dental health, depression, anxiety, and socio-demographic variables, higher scores on the TAS-20 as well as on its three dimensions [difficulties in identifying feelings (DIF), difficulties in describing feelings (DDF), and externally oriented thinking (EOT)] were associated with higher OHIP-14 composite scores according to Poisson regression analyses. In adjusted logistic regression analyses, the TAS-20 and two of its dimensions (DIF and DDF) were positively and significantly associated with the seven OHIP-14 dimensions and the prevalence of those reporting one or more OHIP-14 items fairly often or very often. The study showed that difficulties in emotional regulation might be reflected in poorer OHRQoL, regardless of the dental health status, depression, anxiety, and socio-demographic variables.

Tumor tissue inhibitor of metalloproteinases-1 (TIMP-1) in hormone-independent breast cancer might originate in stromal cells, and improves stratification of prognosis together with nodal status.

Tissue inhibitor of metalloproteinases-1 (TIMP-1) is shown to be a potential marker for poor prognosis in breast cancer, but the biology of TIMP-1 is only partially understood. In this study, TIMP-1 production was studied in a co-culture model of hormone-independent breast cancer cell lines and mesenchymal stem cells mimicking the stromal components of the tumor. In addition, the prognostic value of TIMP-1 was histologically evaluated in a clinical material of 168 patients with hormone-independent breast tumors. The hormone-independent breast cancer (BC) cell lines MDA-MB-231, M4A4 and NM2C5 did not produce TIMP-1 protein in measureable quantities. Six tested primary mesenchymal stem cell lines all produced TIMP-1. Co-culturing of mesenchymal stem cells and breast cancer cells resulted in positive immunocytochemical diffuse staining for TIMP-1 for both cell types. Culturing breast cancer cells with MSC-conditioned media resulted in a positive cytoplasmic immunoreactivity for TIMP-1, and TIMP-1 protein concentration in cell lysates increased 2.7-fold (range 1.1-4.7). The TIMP-1 mRNA levels remained unaffected in BC cells. This might suggest that breast cancer cells can take up TIMP-1 produced by stromal cells and are thus displaying cellular immunoreactivity. In addition, TIMP-1 was shown to improve stratification of prognosis in clinical material.

Comparison of gamma-ray coincidence and low-background gamma-ray singles spectrometry.

Aerosol samples have been studied under different background conditions using gamma-ray coincidence and low-background gamma-ray singles spectrometric techniques with High-Purity Germanium detectors. Conventional low-background gamma-ray singles counting is a competitive technique when compared to the gamma-gamma coincidence approach in elevated background conditions. However, measurement of gamma-gamma coincidences can clearly make the identification of different nuclides more reliable and efficient than using singles spectrometry alone. The optimum solution would be a low-background counting station capable of both singles and gamma-gamma coincidence spectrometry.

Claudins 1, 3M, 3S, 4, 5 and 7 in vulvar neoplasms compared with vulvar squamous cell carcinoma.

The purpose of this study was to evaluate the expression of claudins 1, 3M (membrane-bound), 3S (cytoplasmic), 4, 5 and 7 in vulvar epithelial neoplasia (VIN I-III) and to compare those with invasive vulvar squamous cell carcinoma. Paraffin tissue sections from 73 vulvar neoplasms (12 VIN I, 12 VIN II-III and 49 vulvar carcinomas) were studied by immunohistochemistry for the expression of claudins 1, 3M, 3S, 4, 5 and 7. Claudin 1 stained strongly in all groups, whereas claudin 3M, 3S and 4 immunostaining were moderate in all groups. Claudin 7 stained strongly in all groups. Claudin 3M expression was higher in VIN I compared to carcinoma, while no difference was found between VIN I and VIN II-III or between VIN II-III and carcinoma. Claudin 1 and claudin 3S expressions also showed the same decreasing tendency from VIN towards vulvar carcinoma. Claudin 5 showed only weak staining in VIN I and VIN II-III, and positive expression was also low in the carcinoma group. Expressions of claudins 1, 3M, 3S, 4 and 7 were found in VIN and vulvar carcinoma. Changes in claudin 1 and claudin 3 expression during progression from VIN to vulvar carcinoma suggests a connection with claudin expression and differentiation of vulvar squamous cells. Claudin 5 does not seem to be important in VIN or vulvar carcinoma.

Tracking of airborne radionuclides from the damaged Fukushima Dai-ichi nuclear reactors by European networks.

Radioactive emissions into the atmosphere from the damaged reactors of the Fukushima Dai-ichi nuclear power plant (NPP) started on March 12th, 2011. Among the various radionuclides released, iodine-131 ((131)I) and cesium isotopes ((137)Cs and (134)Cs) were transported across the Pacific toward the North American continent and reached Europe despite dispersion and washout along the route of the contaminated air masses. In Europe, the first signs of the releases were detected 7 days later while the first peak of activity level was observed between March 28th and March 30th. Time variations over a 20-day period and spatial variations across more than 150 sampling locations in Europe made it possible to characterize the contaminated air masses. After the Chernobyl accident, only a few measurements of the gaseous (131)I fraction were conducted compared to the number of measurements for the particulate fraction. Several studies had already pointed out the importance of the gaseous (131)I and the large underestimation of the total (131)I airborne activity level, and subsequent calculations of inhalation dose, if neglected. The measurements made across Europe following the releases from the Fukushima NPP reactors have provided a significant amount of new data on the ratio of the gaseous (131)I fraction to total (131)I, both on a spatial scale and its temporal variation. It can be pointed out that during the Fukushima event, the (134)Cs to (137)Cs ratio proved to be different from that observed after the Chernobyl accident. The data set provided in this paper is the most comprehensive survey of the main relevant airborne radionuclides from the Fukushima reactors, measured across Europe. A rough estimate of the total (131)I inventory that has passed over Europe during this period was <1% of the released amount. According to the measurements, airborne activity levels remain of no concern for public health in Europe.

Hepatitis A, B, C and HIV infections among Finnish female prisoners--young females a risk group.

OBJECTIVES: Previous prison studies have shown that the female gender is associated with higher hepatitis C prevalence. However, there are few prison studies of gender differences concerning the risk factors of hepatitis C infections. We studied the prevalence of hepatitis and HIV infections and the risk factors among Finnish female prisoners. METHODS: The material consisted of 88 females and 300 male prisoners as controls. RESULTS: The prevalence of hepatitis C virus antibodies was 52%, hepatitis B surface antigen 0%, hepatitis A virus antibodies 38% and HIV antibodies 1% among women, and 44%, 0.7%, 4% and 0.7% respectively among men. Among women, 71% of the age group 16-24 had HCV. There was no significant association between gender and HCV. Women were more commonly sharing syringes/needles and had unsafe sexual habits. Among women, HCV was associated only with IDU and syringe/needle sharing whereas among men also with tattoos, cumulative years in prison and age. CONCLUSIONS: Especially young females had a high prevalence of HCV. The study showed that the risk factors are differentiated by gender. This should be taken into account when assessing earlier studies which mainly concentrate on men.

Immunohistochemical study of matrix metalloproteinase 9 and tissue inhibitor of matrix metalloproteinase 1 in benign and malignant breast tissue--strong expression in intraductal carcinomas of the breast.

OBJECTIVE: Matrix metalloproteinases (MMPs) are involved in carcinogenesis due to their tissue remodeling capability, and there is convincing evidence linking gelatinase B (MMP-9) with malignant cell invasion. Tissue inhibitor 1 of MMP (TIMP-1) is a strong inhibitor of MMP-9 but has also tumor-enhancing effects. Only few data exist on MMP-9 or TIMP-1 expression in tissue samples of different breast histology. METHODS: MMP-9 and TIMP-1 immunoreactivity was examined in a wide range of breast tissue samples differing in histology from usual ductal hyperplasia (UDH) to fully developed ductal breast carcinoma. Immunohistochemical expression of MMP-9 was studied in 178 samples: 31 UDH samples, 29 atypical ductal hyperplasia (ADH) samples, 28 ductal carcinoma in situ (DCIS) samples and 90 ductal invasive carcinoma samples (30 samples of malignancy grades I, II and III, respectively). TIMP-1 expression was also analyzed in 178 breast tissue samples: 41 UDH, 21 ADH and 34 DCIS lesions, and 82 invasive ductal breast carcinomas (25 in grade I, 30 in grade II and 27 in grade III). RESULTS: A significantly distinctive pattern of MMP-9 protein expression was shown in DCIS samples, where 85.7% of the cases showed moderate or strong positivity and negative staining was rare (p = 0.021). Negative or weakly positive MMP-9 staining was the most prominent finding in UDH (71%), ADH (69%) as well as in invasive carcinoma samples (64.4%). Various degrees of TIMP-1 expression were seen in 86.5% of all cases. DCIS and invasive carcinoma samples revealed similar immunostaining: at least some positivity was seen in 91.1% of the DCIS samples and 91.5% of infiltrative carcinomas. Thus, TIMP-1 negativity (22.2%) was significantly associated with hyperplastic lesions (p = 0.026). CONCLUSIONS: These results suggest that MMP-9 and TIMP-1 overexpression are early markers of breast carcinogenesis preceding tumor invasion. Apparently, DCIS carries the risk to evolve into a malignant phenotype according to these markers. The clinical importance of these findings is discussed.

Claudin-5 overexpression correlates with aggressive behavior in serous ovarian adenocarcinoma.

BACKGROUND: Claudins are essential tight junctional proteins between adjacent epithelial, mesothelial or endothelial cells, and are responsible for the permeability of the paracellular space. The expression of claudin-5 and its correlation to ovarian cancer behavior was investigasted. MATERIALS AND METHODS: A total of 85 serous ovarian cancer tissue samples were analyzed using immunohistochemical staining. RESULTS: An association between claudin-5 expression and cancer grade (p=0.016) and advanced stage (p=0.022), strongest claudin-5 expression was found in advanced stage and high-grade carcinomas. An association between claudin-5 expression and cancer-specific (p=0.032) and overall survival (p=0.026) was also found. Only 25-30% of claudin-5-positive patients, but 60% of claudin-5-negative patiens were alive at the 5-years follow-up. CONCLUSION: Increased claudin-5 expression is associated with aggressive behavior in serous ovarian adenocarcinoma.

Responses to rituximab vary among follicular lymphoma B cells of different maturation stages.

The chimeric anti-CD20 monoclonal antibody rituximab has been used for the treatment of non-Hodgkin's lymphomas with varying responses. Rituximab has been demonstrated to act by direct complement-dependent cytotoxity (CDC) and by inducing apoptosis, complement-, and antibody-dependent cellular cytotoxity. In the present study, we determined whether rituximab's effector mechanisms differed between two human follicular lymphoma cell lines that originate from different maturation stages of B cell germinal centre (GC) development. The tested HF-1 and HF-4b lymphoma cells represent GC centrocytes and centroblasts, respectively. Both cell lines responded to rituximab treatment by undergoing apoptosis yet the HF-1 cells were more sensitive. A major difference was seen in the proliferation response as only the proliferation of HF-1 cells was inhibited by rituximab. In the presence of normal human serum (NHS) rituximab almost completely inhibited DNA synthesis and induced necrosis of both cell lines because of CDC. Our results show that the CD20-positive HF-1 and HF-4b cells respond differentially to rituximab-induced apoptosis and inhibition of proliferation but similarly to complement-mediated killing. The increased sensitivity of the HF-1 cell line to apoptosis and inhibition of proliferation may reflect a tendency of centrocytic cells for negative selection and a role for CD20 in this process.

High serum TIMP-1 correlates with poor prognosis in breast carcinoma - a validation study.

A number of studies have demonstrated that high tumor tissue levels of tissue inhibitor of metalloproteinases-1 (TIMP-1) are associated with a poor prognosis in breast cancer, suggesting that TIMP-1 could be a valid prognostic marker in this disease. Recently, our laboratories have presented results showing that TIMP-1 also carries prognostic information when measured in serum. This is an important finding, since serum is a much more preferable material compared with tumor tissue extracts. The aim of the present study was to validate the previous results concerning the prognostic value of TIMP-1 in serum obtained preoperatively from 68 patients with primary breast cancer. This was done by measuring the same serum samples as in the previous study but in a different laboratory using a different ELISA assay. We confirmed that patients with the highest serum levels of TIMP-1 (> 197.7 ng/ml) had significantly shorter disease-specific survival compared with patients with low serum TIMP-1 levels. In the group of node-negative patients, 53% of the patients with high levels of TIMP-1 survived after 10 years of follow-up compared to 92% of the patients with low levels. This study thus confirms the reproducibility across laboratories of the results concerning the prognostic value of TIMP-1 in serum. We also investigated whether measurements of the specific fraction of uncomplexed TIMP-1 improved the prognostic value of TIMP-1 in serum, as has been shown to be the case for tumor tissue extracts. However, including information of the level of uncomplexed TIMP-1 did not seem to provide additional prognostic information to that already provided by total TIMP-1.

Seven-year outcome of depression in primary and psychiatric outpatient care: results of the TADEP (Tampere Depression) II Study.

The objective of this article was to determine a 7-year naturalistic progression of depression as well as a number of potential prognostic factors among Finnish primary care and psychiatric care patients. Depression-screened patients from primary care and psychiatric care, aged 18-64, were interviewed in 1991-92 with the Present State Examination (PSE) as the diagnostic instrument. The patients were re-contacted in 1998-99, and their depression at final assessment (FinalA) and during the follow-up period (F-up) was assessed by telephone interview using the Composite International Diagnostic Interview--Short Form (CIDI-SF). 250 primary care (58.1%) and 170 (40.2%) psychiatric care patients were successfully followed. Of the primary care patients with severe depression at baseline, 42.4% had had depression during F-up and 21.2% had depression at FinalA. For the patients with mild depression at baseline, the corresponding figures were nearly the same, but for the patients with depressive symptoms clearly lower. Of the psychiatric care patients with severe depression at baseline, 61.0% had had depression during F-up and 26.2% had depression at FinalA. As with primary care patients, the corresponding figures were nearly the same for mild depression at baseline but clearly lower for depressive symptoms. Experienced lifetime mood elevation was associated with having depression during F-up in both primary care and psychiatric care patients. High Depression Scale (DEPS) score at baseline was associated with having depression at FinalA in primary care patients, but in psychiatric care patients, it was the high Hamilton Rating Scale for depression (HAM-D) and drinking problems. Severe depression and mild depression are predictive for subsequent depression at both levels of care. The long-term prognosis for depression is better in primary care. DEPS and HAM-D are useful, prognostic instruments.

MMP-2 expression associates with CA 125 and clinical course in endometrial carcinoma.

OBJECTIVE: Matrix metalloproteinases have long been associated with aggressive behavior of several malignancies, but their role in endometrial cancer has not been conclusively established. This study aimed to evaluate the roles of matrix metalloproteinase-2 (MMP-2) and -9 (MMP-9) as prognostic factors in endometrial carcinoma and their association with CA 125 and other conventional prognostic markers. METHODS: The MMP-2 and MMP-9 immunoreactive proteins were evaluated from primary tumors of endometrial carcinoma in 266 specimens by using a specific monoclonal antibody in immunohistochemical stainings. The median follow-up time was 79 months. RESULTS: Expression of the MMP-2 and MMP-9 proteins was found in 88% and 70% of the primary tumors, respectively. Positive MMP-2 immunostaining was associated with a shortened recurrence-free (P=0.04) and cancer-specific survival (P=0.05). MMP-2 negativity was linked with a favorable prognosis; only one patient developed recurrent disease and died during the follow-up. Preoperative serum levels of CA 125 were higher in the patients presenting with tumors positive for MMP-2 than in those with negative immunostaining (P=0.03). CONCLUSIONS: We suggest that MMP-2 is linked with biologically aggressive nature of this cancer type. It seems that MMP-2, but not MMP-9, has some prognostic value in endometrial carcinoma. However, the conventional prognostic markers are superior to MMP-2 in assessing aggressive behavior and cancer-specific survival in endometrial cancer.