P53, CK20, and FGFR3 Overexpression is Associated with the Characteristics of Urothelial Cell Carcinoma of the Bladder

OBJECTIVES: The aim of this study was to investigate the association between the overexpression of tumor protein (P53), cytokeratin 20 (CK20), fibroblast growth factor receptor 3 (FGFR3), biomarkers and the grading, prognosis, heterogeneity, and relapse tendency of urothelial cell carcinomas (UCCs) of the bladder. METHODS: A cross-sectional study was conducted using 413 samples of Iranian patients diagnosed with UCC of the bladder. The tissue microarray technique was used to evaluate the patterns of tumor tissue. Two pathologists scored tissue staining using a semi-quantitative scoring system. RESULTS: The results showed that P53 was a predictor of a high-grade pattern (the area under the curve (AUC)=0.620) with a best cut-off value of 95.0 using the receiver operating characteristic (ROC) curve. CK20 was another predictor of a high-grade pattern (AUC=0.745) with a best cut-off value of 15. However, the overexpression of both biomarkers was not associated with a heterogeneous pattern and could not predict tumor-associated death or relapse. The heterogeneous (odds ratio (OR)=4.535, p-value=0.001) and non-papillary (OR= 6.363, p-value= 0.001) patterns were effective predictors of tumor recurrence among all baseline variables, including patient and tumor characteristics. FGFR3 was positive in all specimens and was not a valuable biomarker for differentiating patterns. None of the variables predicted tumor prognosis. CONCLUSION: The study findings indicate that the intensity and percentage of cell staining for P53 and CK20 in the UCC of the bladder can aid in differentiating the grading patterns. The tendency of tumor relapse can be predicted by demonstrating heterogeneous and non-papillary patterns.

The effects of different physiologic concentrations of prolactin in association with reproductive hormones on the incidence of type 2 diabetes mellitus in men: Tehran Lipid and Glucose Study.

BACKGROUND: Data is inconsistent and, for the most part, not sufficient to demonstrate the association between serum Prolactin (PRL) concentration within the physiologic range and the incidence rate of type 2 Diabetes Mellitus (DM) among men. Moreover, since both PRL and type 2 DM are associated with reproductive hormones, investigating these hormones might improve our understanding of how PRL might impose its effect on the incidence rate of type 2 DM. METHODS: For the present study, 652 eligible men aged 29-70 with a normal baseline PRL concentration were selected from the Tehran Lipid and Glucose Study (TLGS). Participants were sub-classified into three groups (tertiles) according to the serum concentration of PRL and were followed for 15.8 years. The incidence of type 2 DM and PRL, LH, FSH, testosterone, and AMH concentrations were measured. The effect of hormonal variables on the incidence of type 2 DM was estimated using the log-binomial model, adjusted for major confounding factors. The correlations between PRL and the indicators of glucose and lipid metabolism and other hormonal variables were also explored. RESULTS: In the unadjusted model, PRL was not significantly associated with the incidence rate of type 2 DM (RR = 0.98, 95% CI: 0.94 - 1.03). After adjusting for potential confounders, the inverse effect of AMH on the incidence rate of type 2 DM was the only significant association. The analyses also indicated a significant positive association between PRL and LH/FSH ratio (r = 0.1, P = 0.01). CONCLUSION: No significant association was found between serum PRL concentrations within the physiologic range and the incidence rate of type 2 diabetes mellitus among middle-aged men. Men with higher concentrations of PRL within the physiologic range tended to show higher levels of LH and LH/FSH. AMH was the only variable significantly linked to the incidence rate of type 2 DM in men.

Investigating the Clinical Utility of the Anti-Mullerian Hormone Testing for the Prediction of Age at Menopause and Assessment of Functional Ovarian Reserve: A Practical Approach and Recent Updates.

Low ovarian reserve is a serious condition, leading to sterility in up to 10% of women in their mid-thirties. According to current knowledge, serum anti-Müllerian hormone (AMH) levels for age are the best available marker for the screening the quantity of a woman's functional ovarian reserve, better than age alone or other reproductive markers. This review summarizes recent findings, clinical utility and limitations in the application of serum AMH testing as an accurate marker for the screening of functional ovarian reserves and predicting age at menopause. AMH assessment hold promise in helping women make informed decisions about their future fertility and desired family size. However, screening of the functional ovarian reserve could be offered to all women at 26 years of age or older who seek to assess future fertility or in case of personal request, ovarian reserve screening may be considered beyond 30 years; however, it has never been advocated beyond 35 years, since it is not advisable to delay childbearing beyond this age. In this respect, an age-specific serum AMH levels lower than the 10th percentile may be used as a threshold for the identification of a low functional ovarian reserve in an individual woman. Its level should be interpreted with caution in the adolescent and young women aged below 25 years (since AMH levels peak at this age); recent users of hormonal contraceptives (since AMH levels transiently decrease until two months after discontinuation); and women with PCOS (which dramatically increases AMH levels). However, the ability of AMH levels to predict the time to menopause is promising but requires further investigation and routine AMH testing for the purposes of predicting the time to menopause is not recommended.

Does the Anti-Mullerian Hormone Decline Rate Improve the Prediction of Age at Menopause?

Objectives: There are controversial studies investigating whether multiple anti-Mullerian hormone (AMH) measurements can improve the individualized prediction of age at menopause in the general population. This study aimed to reexplore the additive role of the AMH decline rate in single AMH measurement for improving the prediction of age at physiological menopause, based on two common statistical models for analysis of time-to-event data, including time-dependent Cox regression and Cox proportional-hazards regression models. Methods: A total of 901 eligible women, aged 18-50 years, were recruited from the Tehran Lipid and Glucose Study (TLGS) population and followed up every 3 years for 18 years. The serum AMH level was measured at the time of recruitment and twice after recruitment within 6-year intervals using the Gen II AMH assay. The added value of repeated AMH measurements for the prediction of age at menopause was explored using two different statistical approaches. In the first approach, a time-dependent Cox model was plotted, with all three AMH measurements as time-varying predictors and the baseline age and logarithm of annual AMH decline as time-invariant predictors. In the second approach, a Cox proportional-hazards model was fitted to the baseline data, and improvement of the complex model, which included repeated AMH measurements and the logarithm of the AMH annual decline rate, was assessed using the C-statistic. Results: The time-dependent Cox model showed that each unit increase in the AMH level could reduce the risk of menopause by 87%. The Cox proportional-hazards model also improved the prediction of age at menopause by 3%, according to the C-statistic. The subgroup analysis for the prediction of early menopause revealed that the risk of early menopause increased by 10.8 with each unit increase in the AMH annual decline rate. Conclusion: This study confirmed that multiple AMH measurements could improve the individual predictions of the risk of at physiological menopause compared to single AMH measurements. Different alternative statistical approaches can also offer the same interpretations if the essential assumptions are met.

Age-specific cut-off levels of anti-Müllerian hormone can be used as diagnostic markers for polycystic ovary syndrome.

BACKGROUND: The majority of available studies on the AMH thresholds were not age-specific and performed the receiver operating characteristic curve (ROC) analysis, based on variations in sensitivity and specificity rather than positive and negative predictive values (PPV and NPV, respectively), which are more clinically applicable. Moreover, all of these studies used a pre-specified age categorization to report the age-specific cut-off values of AMH. METHODS: A total of 803 women, including 303 PCOS patients and 500 eumenorrheic non-hirsute control women, were enrolled in the present study. The PCOS group included PCOS women, aged 20-40 years, who were referred to the Reproductive Endocrinology Research Center, Tehran, Iran. The Rotterdam consensus criteria were used for diagnosis of PCOS. The control group was selected among women, aged 20-40 years, who participated in Tehran Lipid and Glucose cohort Study (TLGS). Generalized additive models (GAMs) were used to identify the optimal cut-off points for various age categories. The cut-off levels of AMH in different age categories were estimated, using the Bayesian method. MAIN RESULTS AND THE ROLE OF CHANCE: Two optimal cut-off levels of AMH (ng/ml) were identified at the age of 27 and 35 years, based on GAMs. The cut-off levels for the prediction of PCOS in the age categories of 20-27, 27-35, and 35-40 years were 5.7 (95 % CI: 5.48-6.19), 4.55 (95 % CI: 4.52-4.64), and 3.72 (95 % CI: 3.55-3.80), respectively. Based on the Bayesian method, the PPV and NPV of these cut-off levels were as follows: PPV = 0.98 (95 % CI: 0.96-0.99) and NPV = 0.40 (95 % CI: 0.30-0.51) for the age group of 20-27 years; PPV = 0.96 (95 % CI: 0.91-0.99) and NPV = 0.82 (95 % CI: 0.78-0.86) for the age group of 27-35 years; and PPV = 0.86 (95 % CI: 0.80-0.94) and NPV = 0.96 (95 % CI: 0.93-0.98) for the age group of 35-40 years. CONCLUSIONS: Application of age-specific cut-off levels of AMH, according to the GAMs and Bayesian method, could elegantly assess the value of AMH in discriminating PCOS patients in all age categories.

Do trends of adiposity and metabolic parameters vary in women with different ovarian reserve status? A population-based cohort study.

OBJECTIVE: To investigate whether trends of adiposity and glucose metabolism parameters in women with low ovarian reserve status based on their anti-Mullerian hormone (AMH) levels differ from those with high ovarian reserve. METHODS: In this population-based prospective study, eligible women, aged 20 to 50 years, were selected from among participants of the Tehran Lipid and Glucose Study (TLGS). Generalized estimating equation (GEE) models were applied to compare changes in various adiposity and metabolic parameters across time between women in the first and fourth quartiles of age-specific AMH, after adjustment for confounders. Pooled logistic regression was used to compare progression of prediabetes mellitus (pre-DM) and diabetes mellitus (DM) between the women of these two age-specific AMH quartiles. RESULTS: In this study of a total of 1,015 participants and with a median follow-up of 16 years, we observed that over time, both groups of women in the first and fourth quartiles of age-specific AMH experienced significant positive trends in their adiposity indices including central obesity, waist-to-hip ratio (WHR), waist-to-height ratio (WHtR), a body shape index (ABSI), and a negative trend in visceral adiposity index (VAI), whereas there was no significant difference in these parameters between the two groups. This study revealed that odds ratios of diabetes and prediabetes in women in the first quartile of age-specific AMH were not significantly different, compared with those in the fourth quartile. CONCLUSION: Women with lower ovarian reserve do not experience different over time trends of adiposity and glucose metabolism parameters during their reproductive life span.

Improving Prediction of Age at Menopause Using Multiple Anti-Müllerian Hormone Measurements: the Tehran Lipid-Glucose Study.

CONTEXT: Several statistical models were introduced for the prediction of age at menopause using a single measurement of anti-müllerian hormone (AMH); however, individual prediction is challenging and needs to be improved. OBJECTIVE: The objective of this study was to determine whether multiple AMH measurements can improve the prediction of age at menopause. DESIGN: All eligible reproductive-age women (n = 959) were selected from the Tehran Lipid and Glucose Study. The serum concentration of AMH was measured at the time of recruitment and twice after that at an average of 6-year intervals. An accelerated failure-time model with Weibull distribution was used to predict age at menopause, using a single AMH value vs a model that included the annual AMH decline rate. The adequacy of these models was assessed using C statistics. RESULTS: The median follow-up period was 14 years, and 529 women reached menopause. Adding the annual decline rate to the model that included single AMH improved the model's discrimination adequacy from 70% (95% CI: 67% to 71%) to 78% (95% CI: 75% to 80%) in terms of C statistics. The median of differences between actual and predicted age at menopause for the first model was -0.48 years and decreased to -0.21 in the model that included the decline rate. The predicted age at menopause for women with the same amount of age-specific AMH but an annual AMH decline rate of 95 percentiles was about one decade lower than in those with a decline rate of 5 percentiles. CONCLUSION: Prediction of age at menopause could be improved by multiple AMH measurements; it will be useful in identifying women at risk of early menopause.

Mucoromycosis and Wegner's Granulomatosis: A Case Report.

Wegener's granulomatosis is a rare vasculitis affecting the upper and lower respiratory tracts and kidneys. The cornerstone of treatment in these patients is immunosuppressive therapy, which may predispose the patient to super-infections such as fungal diseases per se. However, the fungal infection mimics the clinical manifestations of Wegener's diseases would lead to neglected course of the infection and subsequent morbidity and mortality especially if unusual organs are involved. Here we report a 21-yr-old female patient referred to a hospital, Tehran, Iran in 2013 with a neglected skin mucormycosis and the course of the disease and outcome with Wegener's granulomatosis.