Phthalate and DINCH urinary concentrations across pregnancy and risk of preterm birth.

Preconception and prenatal exposure to phthalates has been associated with an increased risk of preterm birth. However, it is unclear whether there are periods of heightened susceptibility during pregnancy. This prospective cohort study included 386 women undergoing fertility treatment who gave birth to a singleton infant during 2005 through 2018. Eleven phthalate metabolites were measured in spot urine samples collected at each trimester. In approximately 50% of participants, two metabolites of 1,2-cyclohexane dicarboxylic acid diisononyl ester (DINCH), a phthalate substitute, were also measured. The molar sum of four di(2-ethylhexyl) phthalate metabolites (∑DEHP) was calculated. We evaluated the associations of mean maternal biomarker concentrations with risk of preterm birth using modified log-binomial models and utilized multiple informant models to compare trimester-specific associations. We examined the relative biomarker concentration across gestation comparing women with preterm birth to women with term delivery using quadratic mixed model. The risk ratio for preterm birth associated with a one-unit increase in the natural log-transformed urinary concentrations of ∑DEHP (mean during pregnancy) was 1.21 (95% confidence interval (CI): 0.84, 1.72). In multiple informant models, these associations were strongest in the third trimester (RR = 1.51; 95% CI: 1.17, 1.95). Estimated mean ∑DEHP concentrations were higher among women with preterm than term delivery, especially late in gestation. Associations with preterm birth were also observed for each of the four individual DEHP metabolites. Detection of cyclohexane-1,2-dicarboxylic acid monocarboxyisooctyl ester (MCOCH), a metabolite of DINCH, appeared to be positively related to preterm birth. In this prospective cohort of subfertile couples, maternal ∑DEHP metabolite concentrations during pregnancy were associated with an increased risk of preterm birth, particularly during late gestation.

Response to ovulation induction treatments in women with polycystic ovary syndrome as a function of serum anti-Müllerian hormone levels.

PURPOSE: To assess whether anti-Müllerian hormone (AMH) can predict response to ovulation induction (OI) with clomiphene citrate (CC), letrozole (LET), or follicle-stimulating hormone (FSH) in women with polycystic ovary syndrome (PCOS) undergoing OI/intrauterine inseminations (IUI). METHODS: A total of 738 OI/IUI cycles from 242 patients at an academic center were stratified in three groups by medication: CC (n = 295), LET (n = 180), and FSH (n = 263), in a retrospective fashion. Ovarian response to treatment (RT, development of at least one dominant follicle) was assessed using mixed effects logistic regression models. RESULTS: Overall, RT cycles had lower AMH levels compared to no-RT cycles (p < 0.001). This finding persisted when analysis was limited to oral agents but attenuated in FSH cycles. For CC and LET cycles, the predicted probability (PProb) for RT decreased as AMH levels increased (PProb (95%CI): 97% (93-100), 79% (70-88), and 75% (61-89); 85% (78-93), 75% (67-83), and 73% (63-86) for AMH pct.: ≤ 25th, ≥ 50th, and ≥ 75th, for CC and LET, respectively)). However, RT was noted in 98.5% of FSH/IUI cycles regardless of AMH. For CC cycles, those with AMH ≥ 75th pct. had lower odds for RT over cycles with AMH < 75th pct. (OR 0.2, 95%CI 0.04-0.8, p = 0.02). Similarly, lower odds for RT were observed in LET cycles with AMH ≥ 75th pct. (0.6, 0.3-1.4, p = 0.25). CONCLUSION: In PCOS, increasing serum AMH levels are associated with lower probability of RT to oral agents. Our findings constitute a valuable tool for the clinician when counseling PCOS patients and designing a personalized ovulation induction treatment strategy.

A patient-specific model combining antimüllerian hormone and body mass index as a predictor of polycystic ovary syndrome and other oligo-anovulation disorders.

OBJECTIVE: To determine whether a patient-specific predictive model combining antimüllerian hormone (AMH) levels and body mass index (BMI) can aid in the diagnosis of polycystic ovary syndrome (PCOS) and other ovulatory dysfunction disorders (OVDYS) among infertile women. DESIGN: Retrospective cohort study. SETTING: Academic fertility center. PATIENT(S): One thousand and ten infertile women undergoing 3,160 intrauterine insemination (IUI) cycles, stratified by diagnosis in three groups: PCOS, OVDYS, and other etiologies. INTERVENTION(S): Ovulation induction followed by IUI or ultrasound-monitored natural cycles. MAIN OUTCOME MEASURE(S): The probability of either PCOS or OVDYS diagnosis based on AMH levels alone and a patient-specific predictive model that combines serum AMH and patient's BMI. RESULT(S): Median and interquartile range (IQR) for the serum AMH levels (ng/mL) were the highest in women with PCOS, and lowest in those with other infertility causes. Overall, for every 1 ng/mL increase in AMH, the odds of PCOS and OVDYS versus other causes increased by 55% and 24%, respectively. Postestimation from multivariate logistic regression models showed that PCOS diagnosis can be predicted with lower AMH values in women with a higher BMI compared with the AMH values predicting PCOS in normal-weight or underweight patients. The receiver operating characteristic curves reinforced these findings, and the best cutoffs for PCOS diagnosis were 7.5, 4.4, and 4.1 ng/mL for women belonging to the BMI groups 18.5-24.9, 25.0-29.9, and ≥30.0 kg/m2, respectively. CONCLUSION(S): Taking into account AMH and BMI, we developed a model that predicts the probability of an oligo-anovulation diagnosis, thus facilitating patient-specific counseling in the infertility setting.

Could Mismatch Repair Status Serve as a Biomarker for Immunotherapy in Endometrial Carcinoma?

AIM: To study whether mismatch repair (MMR) status is related to the expression of programmed cell death-ligand 1 (PD-L1) and CD8 counts in a series of grade 3 endometrial carcinomas. MATERIALS AND METHODS: The expression of MMR protein PD-L1 and CD8+ cell count were evaluated by immunohistochemistry and related to several clinicopathological parameters. RESULTS: Among 105 endometrial carcinomas, 40% were of endometrioid and 60% of non-endometrioid histology. MMR deficiency was observed in 28.6% of cases and was related to endometrioid histology (p<0.001), positive PD-L1 expression (p=0.047) and high CD8+ cell count (p=0.022). When examined by histotype, endometrioid MMR-deficient tumors were related only to PD-L1 expression (p=0.032) but not to high CD8+ cell count (p=0.231), whereas non-endometrioid MMR-deficient carcinomas were not related to either of these markers. MMR deficiency was associated with PD-L1+/CD8high status (p=0.006), whilst MMR proficiency was associated with PD-L1-/CD8low status. In MMR-proficient tumors, high CD8+ cell infiltration alone and combined with PD-L1- status was associated with better progression-free survival (p=0.013 and p=0.04, respectively). CONCLUSION: MMR-deficient high-grade endometrioid tumors might be more likely to benefit from immunotherapy compared to other grade 3 endometrial carcinomas.

Toll-Like Receptors -2, -3, -4 and -7 Expression Patterns in the Liver of a CLP-Induced Sepsis Mouse Model.

Objective: To investigate the expression of toll-like receptors (TLRs) in the liver of septic mouse model. Materials and methods: For this study seventy-two C57BL/6J mice were utilized. Sepsis was induced by cecal ligation and puncture (CLP) in the mice of the three septic (S) groups (euthanized at 24 hours, 48 hours and 72 hours). Sham (laparotomy)- operated mice constituted the control (C) groups (euthanized at 24, 48 and 72 hours). Blood samples were drawn and liver tissues were extracted and examined histologically. The expression of TLRs 2, 3, 4 and 7 was assessed via immunohistochemistry (IHC) and qrt-PCR (quantitative- Polymerase Chain Reaction). Results: Liver function tests were elevated in all S-groups in contrast to their time-equivalent control groups (S24 versus C24, S48 versus C48 and S72 versus C72) (p < 0.05). Liver histology displayed progressive deterioration in the septic groups. IHC and qrt-PCR both showed an increased expression of all TLRs in the septic mice in comparison to their analogous control ones (p < 0.05). Analysis of livers and intestines of the septic animals proved that all TLRs were significantly expressed in higher levels in the intestinal tissues at 24h and 48h (p < 0.05) except for TLR 3 in S48 (p > 0.05); whereas at 72 hours only TLR 4 levels were significantly elevated in the intestine (p < 0.05). Conclusion: TLRs seem to be expressed in significant levels in the livers of septic rodents, indicating that they have a possible role in the pathophysiology of liver damage in septic conditions.

Mismatch repair status in high-grade endometrial carcinomas of endometrioid and non-endometrioid type.

PURPOSE: To evaluate mismatch repair (MMR) status in a series of high-grade endometrial carcinomas and correlate it with several clinicopathological characteristics and with survival. METHODS: One hundred and one patients with high-grade endometrial carcinoma, both of endometrioid and of non-endometrioid type were included in the study. The expression of MLH1, MSH2, MSH6 and PMS2 was evaluated by immunohistochemistry. RESULTS: In our cohort, 41 women had an endometrioid and 60 women a non-endometrioid carcinoma. Endometrioid histotype was statistically more frequent in deficient MMR (dMMR) tumors (73.3%), while non-endometrioid carcinomas in proficient (pMMR) cases (73.8%) (p<0.001). When analyzing the group of endometrioid and non-endometrioid carcinomas separately, only dMMR endometrioid cancers were found to be statistically related to deep myometrial invasion, lymph-node metastases and advanced stage (p=0.035, p=0.011 and p=0.028, respectively). Univariate and multivariate analysis revealed no relation between MMR status and progression-free survival (PFS) or overall survival (OS). Adjuvant treatment was not found to influence the course of the disease. When MMR proteins were studied separately, MLH1/PMS2 loss was related to deep myometrial invasion (p=0.019 and p=0.036, respectively) and MSH6 loss to lymph-node metastases (p=0.04). CONCLUSIONS: In our group of high-grade endometrial carcinomas, MMR deficiency was statistically more frequent in endometrioid than in non-endometrioid cancers. Furthermore, only dMMR endometrioid type grade 3 carcinomas were found to be related with features indicative of aggressive behavior. Considering some unique relation of each MMR protein with distinct clinicopathological features, the assessment of all four proteins is proposed.

The impact of programmed cell death-ligand 1 (PD-L1) and CD8 expression in grade 3 endometrial carcinomas.

BACKGROUND: To evaluate the expression of programmed cell death-ligand 1 (PD-L1) and CD8 in high-grade endometrial carcinomas and relate it to several clinicopathological parameters. METHODS: One hundred and one (101) patients with high-grade endometrial carcinomas who were completely surgically staged were included in this study. PD-L1 and CD8 + expression was evaluated by immunohistochemistry. RESULTS: In our cohort, 47 women (46.5%) had endometrioid carcinomas and 54 patients (53.5%) were diagnosed with non-endometrioid cancers. In endometrioid carcinomas, there was a significantly higher rate of positivity for PD-L1 expression (p = 0.042) and of intraepithelial CD8 + cell counts (p = 0.004) as opposed to non-endometrioid cancers. There were no significant relationships with any of the other clinicopathological features under study. Univariate and multivariate analysis revealed that only high intraepithelial CD8 + counts (p = 0.01) was associated with longer progression-free survival. Tumors positive for PD-L1 and high intraepithelial CD8 expression were mainly of endometrioid histology, whilst PD-L1-positive/CD8 low and PD-L1-negative/CD8 low tumors were mostly non-endometrioid carcinomas (p = 0.01). PD-L1 negative/CD8 high tumors had the longest progression-free survival (p = 0.032). CONCLUSIONS: In grade 3 endometrial carcinomas, both of endometrioid and non-endometrioid type, high intraepithelial CD8 + counts represent an independent favorable prognostic factor and when related to PD-L1-negative tumors, a longer progression-free survival can be predicted. Immunotherapy could probably be considered for PD-L1-positive/CD8 + high tumors, which were mostly of endometrioid histology.

Ovarian preservation for low-grade endometrial stromal sarcoma: a systematic review of the literature and meta-analysis.

OBJECTIVE: To evaluate the effect of ovarian preservation on oncologic outcomes for women with low-grade endometrial stromal sarcoma of the uterus. METHODS: A systematic search of the Medline, Embase, Cohrane, and Web of Science databases was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Studies including patients with low-grade endometrial stromal sarcoma who had hysterectomy were identified. Data on tumor recurrence and death rate were pooled using a random effects model. RESULTS: A total of 17 studies met the inclusion criteria and reported on 786 patients. Based on available information, ovarian preservation was noted in 190 patients while 501 had bilateral salpingo-oophorectomy. A significantly increased tumor recurrence rate was observed in the ovarian preservation group (89/190, 46.8%) compared with the bilateral salpingo-oophorectomy group (121/501, 24.2%) (OR 2.70, 95% CI 1.39 to 5.28). Based on data from 162 patients, no difference in death rate was noted between the ovarian preservation (2/34, 5.9%) and bilateral salpingo-oophorectomy (9/128, 7%) groups (OR 0.80, 95% CI 0.18 to 3.47). CONCLUSIONS: Approximately one-quarter of patients with low-grade endometrial stromal sarcoma were managed with ovarian preservation. These women experienced a higher recurrence rate. Hormone exposure may be responsible for this elevated risk. Given the apparent high salvage rate, however, ovarian preservation may be an option only in a well-informed patient population.

Update on Surgical Management of Small Bowel Neuroendocrine Tumors.

The widespread use of endoscopy and imaging in combination with the continuous update of the staging systems for neuroendocrine tumors has led to an increase in the incidence of small intestinal neuroendocrine tumors (si-NENs) globally. Despite high survival rates, severe complications may occur even in early stages due to the anatomic location of the primary site and the desmoplastic reaction. Surgery plays a central role in the management of patients with si-NENs. Excision of locoregional disease along with extensive lymph node dissection should be performed in fit patients, even in the presence of metastases. Multimodality treatment of liver metastases includes hepatectomy, ablative techniques and liver transplantation. Hormone therapy with somatostatine analogs is of high importance for symptomatic control; special caution should be exercised both pre- and intra-operatively. A multidisciplinary approach is essential in order to provide personalized therapeutics for patients with si-NENs. Clinical research and specialization in this field should be further encouraged.

Safety and oncologic outcomes of robotic liver resections: A systematic review.

The robotic system has emerged as a new minimally invasive technology with promising results. We sought to systematically review the available literature on the safety and the oncologic outcomes of robotic liver surgery. A systematic review was conducted using Medline (PubMed), Embase and Cochrane library through November 12th, 2017. A robotic approach may be a safe and feasible surgical option for minor and major liver resections.

Neuroendocrine Neoplasms of the Appendix: A Review of the Literature.

Appendiceal neuroendocrine neoplasms (ANENs) comprise rare tumors of the appendix, mainly affecting young populations and characterized by a rather favorable prognosis. The aim of this review was to summarize the current knowledge on these neoplasms, focusing on the management and follow-up of such patients, which still remain under debate. ANENs account for 0.16-2.3% of appendectomies and are usually diagnosed incidentally. The histopathological diagnosis includes the immunohistochemical profile of the tumor in regard to synaptophysin and chromogranin A, as well as the Ki-67 index. The surgical management of ANENs is either simple appendectomy or a more extensive oncological operation including right hemicolectomy. This depends on the stage and the presence of risk factors suggesting a more aggressive disease, such as the exact location, mesoappendiceal or lymphovascular invasion, and the proliferative rate of the tumor. Despite their indolent course, ANENs may relapse. Therefore, lifetime observation is necessary for patients with tumors >2 cm and >1 cm plus additional risk factors; however, more studies should be conducted in order to determine the optimal follow-up strategy.

Clear cell "sugar tumor" of the lung: Diagnostic features of a rare pulmonary tumor.

Clear cell tumor of the lung (CCTL) is an extremely rare neoplasm with about 50 cases reported in the literature so far. CCTL belongs to a family arising from putative perivascular epithelioid cells and is otherwise named as "sugar tumor" due to its high cellular glycogen concentration. Due to its rarity, diagnostic features of this entity are not widely known and this usually leads to misdiagnosis. Herein, we report a case of benign CCTL, which was primarily evaluated intraoperatively by FNA cytology and then by a pathological examination of the resected tumor. The cytologic preparations were moderately cellular and showed multiple large, irregular, cohesive clusters of ovoid or spindle tumor cells. Cells had clear cytoplasm, showing positivity with the periodic acid-Schiff (PAS) staining method owing to the glycogen (sugar) content. The rapid cytologic report excluded the possibility of malignancy and a middle lobectomy along with an anterior upper segmentectomy was performed. Immunochemistry revealed a diffuse positivity for HMB45, MART-1, SMA and focally for desmin, while specimen was negative for pancytokeratin cocktail AE1/AE3, cytokeratin7, cytokeratin20 and EMA. These findings confirmed the diagnosis of a benign CCTL. Due to its rarity and similarity with other clear cell tumors of the lung, awareness of this entity, recognition of the cytomorphologic features and familiarity with the associated clinical features can help clinicians avoid certain pitfalls in the diagnostic process. Considering its benign course, unnecessary extensive lung resections may also be avoided thus permitting conservative management of these patients.

Identifiable Risk Factors for Lymph Node Metastases in Grade 1 Endometrial Carcinoma.

OBJECTIVE: The aim of this study was to evaluate the clinicopathological features related to lymph node metastases in grade 1 endometrial carcinomas. MATERIALS AND METHODS: Five hundred ninety-nine cases of endometrial carcinoma treated with total hysterectomy bilateral salpingo-oophorectomy and pelvic lyphadenectomy between 2001 and 2015 were retrieved from the pathology files of IASO Women's Hospital, Athens, Greece. Of these, 345 were grade 1 endometrioid carcinomas and were included in the study. Features such as the age of the patients, the stage, the location, and size of the tumors, as well as the existence of microcystic, elongated, and fragmented pattern invasion or lymph vascular space invasion, were estimated. RESULTS: In our cohort of endometrial carcinomas, features related to an increased risk of lymph node metastases were stages IB or higher; the location of the tumor in the lower uterine segment; the identification of microcystic, elongated, and fragmented pattern of invasion; and the existence of lymph vascular emboli. When considering the size of the tumors, only stage IA myoinvasive cancers of larger than 4 cm in diameter were significantly associated with nodal disease. In addition, a statistically significant relationship was found between the number of excised lymph nodes and the possibility to detect nodal disease. CONCLUSIONS: Full surgical staging carries a substantial risk of operative complications, and, indeed, it can be avoided in most cases of grade 1 endometrial carcinomas. Nevertheless, even in the low-risk group of patients, there are clinicopathological parameters that should alert the clinician for the possibility of a more disseminated disease.