Pregnant individuals with obesity (body mass index, BMI ≥ 30 kg/m2) are more likely to experience prolonged labor and have double the risk of cesarean compared with individuals with normal weight (BMI < 25 kg/m2). The aim of this study was to evaluate whether obesity in pregnancy is associated with reduced spontaneous and oxytocin-stimulated myometrial contractile activity using ex vivo preparations. We also assessed the relationship between maternal BMI and the expression of oxytocin (OXTR) and prostaglandin (FP) receptors in the myometrial tissue. We enrolled 73 individuals with a singleton gestation undergoing scheduled cesarean delivery at term in a prospective cohort study. This included 49 individuals with a pre-pregnancy BMI ≥ 30 kg/m2 and 24 with BMI < 25.0 kg/m2. After delivery, a small strip of myometrium was excised from the upper edge of the hysterotomy. Baseline spontaneous and oxytocin stimulated myometrial contractile activity was measured using ex vivo preparations. Additionally, expression of oxytocin and prostaglandin receptors from myometrial samples were compared using qRT-PCR and western blot techniques. Spontaneous and oxytocin-stimulated contraction frequency, duration, and force were not significantly different in myometrial samples from the obese and normal-weight individuals. Myometrial OXTR gene and protein expression was also similar in the two groups. While FP gene expression was lower in the myometrial samples from the obese group, protein expression did not differ. These data help to address an important knowledge gap related to the biological mechanisms underlying the association between maternal obesity and dysfunctional labor.

OBJECTIVES:The American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) recommend cold ischemia time (cIT) be <60 min, and formalin fixation time (FFT) 6-72 h, to optimize immunohistochemistry (IHC) based on breast cancer data. We assessed whether cIT and FFT impact IHC in endometrial cancer (EC), and determined which factors affect cIT and FFT. METHODS:Surgical EC cases from 2019 to 2023 were reviewed. cIT was calculated by subtracting time of tissue devascularization intra-operatively from time the specimen was placed in formalin. Demographics, clinicopathologic and peri-operative factors, and IHC for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and mismatch repair (MMR) proteins were compared between patients with cIT <60 min versus ≥60 min (prolonged), and compliant FFT (6-72 h) versus non-compliant FFT (<6 or > 72 h). Categorical variables were compared using χ2 tests. RESULTS:941 patients were included in the analysis. Median cIT was 33 min. Prolonged cIT occurred in 95 (10 %) cases. African American/Black race (p < 0.001), advanced stage (p < 0.001), mini-laparotomy (p < 0.001), performance of surgical procedures beyond standard EC staging (p < 0.001), longer surgical length (p < 0.001), and increased uterine weight (p < 0.001) were independently associated with prolonged cIT. There were no significant differences in ER, PR, HER2, or MMR protein expression based on cIT or FFT. CONCLUSION:Prolonged cIT was not associated with differences in biomarker expression via IHC at time of surgical staging for EC. Despite variability in cIT, which is largely due to non-modifiable factors, tumor molecular features remain consistent and can reliably be utilized for prognostic and therapeutic decision-making.

OBJECTIVE:To examine the presentation, management, and outcomes of pregnancies complicated by diabetic ketoacidosis (DKA) in a contemporary obstetric population. METHODS:This is a case series of all admissions for DKA during pregnancy at a single Midwestern academic medical center over a 10-year period. Diabetic ketoacidosis was defined per the following diagnostic criteria: anion gap more than 12 mEq/L, pH less than 7.30 or bicarbonate less than 15 mEq/L, and elevated serum or urine ketones. Demographic information, clinical characteristics, and maternal and neonatal outcomes were assessed. Patient characteristics and clinical outcomes were compared between individuals with type 1 and those with type 2 diabetes mellitus. RESULTS:Between 2012 and 2021, there were 129 admissions for DKA in 103 pregnancies in 97 individuals. Most individuals (n=75, 77.3%) admitted for DKA during pregnancy had type 1 diabetes. The majority of admissions occurred in the third trimester (median gestational age 29 3/7 weeks). The most common precipitating factors were vomiting or gastrointestinal illness (38.0%), infection (25.6%), and insulin nonadherence (20.9%). Median glucose on admission was 252 mg/dL (interquartile range 181-343 mg/dL), and 21 patients (17.6%) were admitted with euglycemic DKA. Fifteen admissions (11.6%) were to the intensive care unit. Pregnancy loss was diagnosed during admission in six individuals (6.3%, 95% CI, 2.3-13.7%). Among pregnant individuals with at least one admission for DKA, the median gestational age at delivery was 34 6/7 weeks (interquartile range 33 2/7-36 3/7 weeks). Most neonates (85.7%, 95% CI, 76.8-92.2%) were admitted to the neonatal intensive care unit and required treatment for hypoglycemia. The cesarean delivery rate was 71.9%. Despite similar hemoglobin A 1C values before pregnancy and at admission, individuals with type 1 diabetes had higher serum glucose (median [interquartile range], 256 mg/dL [181-353 mg/dL] vs 216 mg/dL [136-258 mg/dL], P =.04) and higher serum ketones (3.78 mg/dL [2.13-5.50 mg/dL] vs 2.56 mg/dL [0.81-4.69 mg/dL] mg/dL, P =.03) on admission compared with those with type 2 diabetes. Individuals with type 2 diabetes required intravenous insulin therapy for a longer duration (55 hours [29.5-91.5 hours] vs 27 hours [19-38 hours], P =.004) and were hospitalized longer (5 days [4-9 days] vs 4 days [3-6 days], P =.004). CONCLUSION:Diabetic ketoacidosis occurred predominantly in pregnancies affected by type 1 diabetes. Individuals with type 1 diabetes presented with greater DKA severity but achieved clinical resolution more rapidly than those with type 2 diabetes. These results may provide a starting point for the development of interventions to decrease maternal and neonatal morbidity related to DKA in the modern obstetric population.

Objectives. To describe stage, treatment patterns, and survival for glassy cell carcinoma of the cervix (GCCC), a poorly understood rare tumor. Methods. Clinical data and survival were compared between GCCC and more common histologic types using the National Cancer Database (NCDB) from 2004 to 2017. A retrospective review of GCCC cases at our institution from 2012 to 2020 was simultaneously performed with staging updated according to 2018 FIGO staging. Descriptive statistics and survival analyses were performed, and outcomes compared to historical references. Results. 143/89,001 (0.16%) NCDB cervical cancer cases were GCCC. Compared to other histologies, GCCC cases were younger, with 74.8% diagnosed before age 50. Stage distribution was similar. Stage I cases were less commonly treated with surgery alone (19/69, 27%). 79.4% of locally advanced (stage II-IVA) cases were treated with definitive chemoradiation. GCCC demonstrated worse OS for early-stage and locally-advanced disease. No survival differences were observed for patients with stage IVB disease. Our institutional review identified 14 GCCC cases. Median age at diagnosis was 34 years. All nine early-stage cases underwent radical hysterectomy. Adjuvant radiation was given for cases meeting Sedlis criteria (4/9, 44%). All five advanced stage cases were stage IIIC and received definitive chemoradiation. Recurrence rate was 0% (0/9) for early-stage and 60% (3/5) for advanced-stage cases. 3-year PFS was 100% for early-stage and 40% for advanced-stage. 3-year OS was 100% for early-stage and 60% for advanced-stage GCCC. Conclusions. GCCC presents at earlier ages than other cervical cancer histologic types. Although NCDB showed worse OS, our more contemporary institutional review, which incorporates updated staging and newer treatment modalities found outcomes more similar to historical references of more common histologic subtypes. (c) 2023 Published by Elsevier Inc.

Objectives: Glassy cell carcinoma of the cervix (GCCC) is a rare histologic subset of adenosquamous carcinoma of the cervix, historically considered to demonstrate aggressive clinical behavior. Given its rarity, there is a lack of standardized guidelines. We performed a retrospective review of cases incorporating updated 2018 FIGO staging to evaluate variation in treatment patterns and oncologic outcomes. Methods: This retrospective review was performed at a comprehensive cancer center from 2012 to 2020. Cases were identified through keyword search for “glassy cell” among cervical cancer patients identified by ICD code. The electronic medical record was utilized to obtain demographic, clinical, and pathologic data. Descriptive statistics and Kaplan-Meier survival analyses were performed. Results: We identified 14 cases of GCCC diagnosed between 2012 and 2020. The median age at diagnosis was 34 years, and the median BMI was 29.91. Patients were all re-staged according to the 2018 FIGO staging system for uniformity. Cases were grouped as early-stage (stage I, n=9) and advanced-stage (stage IIIC, n=5). All nine early-stage cases underwent type III radical hysterectomy (3-MIS, 6-open). Adjuvant external beam radiation with sensitizing cisplatin was given for cases meeting Sedlis criteria (4/9, 44%). The remaining 5/9 cases received no adjuvant therapy. All five advanced stage cases received definitive chemoradiation. After a median follow-up of 47 months, the recurrence rate was 0% (0/9) for early-stage and 60% (3/5) for advanced-stage cases. The median time to recurrence was four months. Chemotherapy was given for 2/3 recurrent cases as second-line treatment. Those same two cases were tested for PD-L1. Both had CPS scores >1 and received pembrolizumab subsequently, one of which had a complete response and was without evidence of disease 21 months later. The 3-year PFS was 100% for early-stage and 40% for advanced-stage. The 3-year OS was 100% for early-stage and 60% for advanced-stage. Kaplan-Meier PFS and OS curves are shown in Figure 1. Conclusions: Among patients with early-stage GCCC, the most common treatment modality was radical hysterectomy with the use of adjuvant radiation for those meeting Sedlis criteria. Overall, treatment decision-making largely mirrored NCCN guidelines for squamous cell carcinoma, adenosquamous carcinoma, and adenocarcinoma of the cervix. When staged by 2018 FIGO staging, outcomes appeared to be similar to more common types of cervical cancer for early-stage cases. However, recurrence in 60% of advanced-stage cases may indicate worse outcomes. Although limited by sample size, the high proportion of stage IIIC cases in this cohort may indicate an overall higher stage at presentation or perhaps a propensity for lymph node metastasis. The patient with a complete and durable response after treatment with pembrolizumab highlights the importance of assessing for biomarkers that may identify candidates for immunotherapy or other newer treatment modalities. Objectives: Glassy cell carcinoma of the cervix (GCCC) is a rare histologic subset of adenosquamous carcinoma of the cervix, historically considered to demonstrate aggressive clinical behavior. Given its rarity, there is a lack of standardized guidelines. We performed a retrospective review of cases incorporating updated 2018 FIGO staging to evaluate variation in treatment patterns and oncologic outcomes. Methods: This retrospective review was performed at a comprehensive cancer center from 2012 to 2020. Cases were identified through keyword search for “glassy cell” among cervical cancer patients identified by ICD code. The electronic medical record was utilized to obtain demographic, clinical, and pathologic data. Descriptive statistics and Kaplan-Meier survival analyses were performed. Results: We identified 14 cases of GCCC diagnosed between 2012 and 2020. The median age at diagnosis was 34 years, and the median BMI was 29.91. Patients were all re-staged according to the 2018 FIGO staging system for uniformity. Cases were grouped as early-stage (stage I, n=9) and advanced-stage (stage IIIC, n=5). All nine early-stage cases underwent type III radical hysterectomy (3-MIS, 6-open). Adjuvant external beam radiation with sensitizing cisplatin was given for cases meeting Sedlis criteria (4/9, 44%). The remaining 5/9 cases received no adjuvant therapy. All five advanced stage cases received definitive chemoradiation. After a median follow-up of 47 months, the recurrence rate was 0% (0/9) for early-stage and 60% (3/5) for advanced-stage cases. The median time to recurrence was four months. Chemotherapy was given for 2/3 recurrent cases as second-line treatment. Those same two cases were tested for PD-L1. Both had CPS scores >1 and received pembrolizumab subsequently, one of which had a complete response and was without evidence of disease 21 months later. The 3-year PFS was 100% for early-stage and 40% for advanced-stage. The 3-year OS was 100% for early-stage and 60% for advanced-stage. Kaplan-Meier PFS and OS curves are shown in Figure 1. Conclusions: Among patients with early-stage GCCC, the most common treatment modality was radical hysterectomy with the use of adjuvant radiation for those meeting Sedlis criteria. Overall, treatment decision-making largely mirrored NCCN guidelines for squamous cell carcinoma, adenosquamous carcinoma, and adenocarcinoma of the cervix. When staged by 2018 FIGO staging, outcomes appeared to be similar to more common types of cervical cancer for early-stage cases. However, recurrence in 60% of advanced-stage cases may indicate worse outcomes. Although limited by sample size, the high proportion of stage IIIC cases in this cohort may indicate an overall higher stage at presentation or perhaps a propensity for lymph node metastasis. The patient with a complete and durable response after treatment with pembrolizumab highlights the importance of assessing for biomarkers that may identify candidates for immunotherapy or other newer treatment modalities.

Pregnant women with obesity (body mass index, BMI ≥ 30 kg/m2) are more likely to experience prolonged labor and their risk of cesarean is double, compared with those of normal weight (BMI < 25 kg/m2). Oxytocin and prostaglandin F (PGF) are important mediators of myometrial contractility, and COX-2 is downstream of oxytocin signaling and crucial for production of prostaglandins. Our objective was to compare myometrial gene and protein expression of oxytocin and PGF receptors and their downstream signaling in obese and normal weight pregnant women at term. Singleton pregnant women undergoing scheduled cesarean delivery at term were enrolled in a prospective cohort study. Those in labor, with chorioamnionitis or abnormal placentation, or who were exposed to uterotonic agents or magnesium prior to delivery, were excluded. At the time of delivery, a 2x4 cm myometrial strip was obtained from the lower uterine segment and homogenized. RNA and protein extracted were used to assay gene and protein expression of oxytocin receptor (OXTR), COX-2, and PGF alpha receptor (PGFR) using qRT-PCR and western blotting. Data are reported as median [IQR] and compared between obese and normal weight women based on pre-pregnancy BMI using the Mann-Whitney U statistical test. 26 women were enrolled in this study: 6 (23%) had normal pre-pregnancy BMI (median 22 kg/m2, IQR 20-24), and 20 (77%) obese (median BMI 40 kg/m2, IQR 32-49). Myometrial OXTR and COX-2 gene expression were not different between obese and normal-weight women (Figure 1), with a trend towards decreased PGFR gene expression in obese women (p = 0.18). Normalized myometrial protein concentration of OXTR and COX-2 were not statistically different. Myometrial OXTR expression did not differ between obese and normal-weight women, suggesting that oxytocin underdosing rather than dysfunctional receptor may be associated with labor dysfunction in obese women. Alternatively, decreased myometrial PGFR gene expression could be a potential mechanism that contributes to impaired contractility in obese women during labor.

Objectives: The College of American Pathologists recommends < 60 min of ischemia time (IT) for breast cancer specimens to preserve biomarker expression. Our institution implemented a quality improvement initiative in 2019 to limit IT for the uterus to < 60 min for patients undergoing surgery for endometrial cancer (EC) in order to optimize immunohistochemistry (IHC) detection of HER2, ER, PR, and Mismatch Repair (MMR) proteins. We sought to determine patient and surgical factors that influence IT and analyze the association between prolonged IT (≥ 60 min) and biomarker expression in EC specimens. Methods: This is a retrospective review of patients who had a hysterectomy for EC in a comprehensive cancer center from June 2019 to February 2021. Clinical, surgical, and pathologic data were abstracted from medical records. IT was defined as the time between uterine vessel ligation to tissue fixation in formalin. We compared demographic and clinical-pathologic features for patients whose uterine specimens had IT of < 60 min to those with prolonged IT (≥ 60 min). IHC results for HER2, ER, PR, and MMR proteins were also compared between the two groups. Categorical data were compared using Chisquare or Fisher's exact test. Results: Two hundred ninety-nine patients underwent hysterectomy for EC with documented IT during the study period. Most patients had endometrioid histology preoperatively (68%), had FIGO stage IA (64%), and underwent minimally invasive surgery (97%). The average length of surgery was 144 min and the average IT was 41 min. Prolonged IT occurred in 37 (12.4%) cases. Demographic factors associated with prolonged IT included age < 50 (p=0.047) and African American race (p<0.001). Uterine weight (p<0.001), need for minilaparotomy (p<0.001), additional procedures performed (p=0.006), and length of surgery (p<0.001) were associated with prolonged IT (Table 1). Day of the week, time of day, trainee involvement, and surgeon were not associated with ischemia time. IHC for HER2, ER, and PR was performed on 10%, 11%, and 10% of specimens, respectively, whereas IHC for MMR proteins was performed in 98% of cases. Though not statistically significant, there was a trend noted toward negative ER expression on IHC in specimens with prolonged IT (p=0.056). There was no association between IT and expression of HER2 (p=0.508), PR (p=0.25), and MMR proteins (p=0.143-1). Conclusions: Approximately 12% of EC specimens had ischemia time > 60 min. Patient factors (age < 50, race) and surgical factors (need for mini-laparotomy, additional procedures, and length of surgery) were associated with prolonged ischemia time. We suspect this is primarily due to uterine size and surgical complexity, which are not modifiable. The potential impact of IT on IHC detection of HER2, ER, PR, and MMR merits further investigation. Objectives: The College of American Pathologists recommends < 60 min of ischemia time (IT) for breast cancer specimens to preserve biomarker expression. Our institution implemented a quality improvement initiative in 2019 to limit IT for the uterus to < 60 min for patients undergoing surgery for endometrial cancer (EC) in order to optimize immunohistochemistry (IHC) detection of HER2, ER, PR, and Mismatch Repair (MMR) proteins. We sought to determine patient and surgical factors that influence IT and analyze the association between prolonged IT (≥ 60 min) and biomarker expression in EC specimens. Methods: This is a retrospective review of patients who had a hysterectomy for EC in a comprehensive cancer center from June 2019 to February 2021. Clinical, surgical, and pathologic data were abstracted from medical records. IT was defined as the time between uterine vessel ligation to tissue fixation in formalin. We compared demographic and clinical-pathologic features for patients whose uterine specimens had IT of < 60 min to those with prolonged IT (≥ 60 min). IHC results for HER2, ER, PR, and MMR proteins were also compared between the two groups. Categorical data were compared using Chisquare or Fisher's exact test. Results: Two hundred ninety-nine patients underwent hysterectomy for EC with documented IT during the study period. Most patients had endometrioid histology preoperatively (68%), had FIGO stage IA (64%), and underwent minimally invasive surgery (97%). The average length of surgery was 144 min and the average IT was 41 min. Prolonged IT occurred in 37 (12.4%) cases. Demographic factors associated with prolonged IT included age < 50 (p=0.047) and African American race (p<0.001). Uterine weight (p<0.001), need for minilaparotomy (p<0.001), additional procedures performed (p=0.006), and length of surgery (p<0.001) were associated with prolonged IT (Table 1). Day of the week, time of day, trainee involvement, and surgeon were not associated with ischemia time. IHC for HER2, ER, and PR was performed on 10%, 11%, and 10% of specimens, respectively, whereas IHC for MMR proteins was performed in 98% of cases. Though not statistically significant, there was a trend noted toward negative ER expression on IHC in specimens with prolonged IT (p=0.056). There was no association between IT and expression of HER2 (p=0.508), PR (p=0.25), and MMR proteins (p=0.143-1). Conclusions: Approximately 12% of EC specimens had ischemia time > 60 min. Patient factors (age < 50, race) and surgical factors (need for mini-laparotomy, additional procedures, and length of surgery) were associated with prolonged ischemia time. We suspect this is primarily due to uterine size and surgical complexity, which are not modifiable. The potential impact of IT on IHC detection of HER2, ER, PR, and MMR merits further investigation.

Maternal stress during pregnancy is widespread and is associated with poor offspring outcomes, including long-term mental health issues. Prenatal stress-induced fetal neuroinflammation is thought to underlie aberrant neurodevelopment and to derive from a disruption in intrauterine immune homeostasis, though the exact origins are incompletely defined. We aimed to identify divergent immune and microbial metagenome profiles of stressed gestating mice that may trigger detrimental inflammatory signaling at the maternal–fetal interface. In response to stress, maternal glucocorticoid circuit activation corresponded with indicators of systemic immunosuppression. At the maternal–fetal interface, density of placental mononuclear leukocytes decreased with stress, yet maternal whole blood leukocyte analysis indicated monocytosis and classical M1 phenotypic shifts. Genome-resolved microbial metagenomic analyses revealed reductions in genes, microbial strains, and metabolic pathways in stressed dams that are primarily associated with pro-inflammatory function. In particular, disrupted Parasutterella excrementihominis appears to be integral to inflammatory and metabolic dysregulation during prenatal stress. Overall, these perturbations in maternal immunological and microbial regulation during pregnancy may displace immune equilibrium at the maternal–fetal interface. Notably, the absence of and reduction in overt maternal inflammation during stress indicates that the signaling patterns driving fetal outcomes in this context are more nuanced and complex than originally anticipated.