Diagnosis and Management of Cervical Squamous Intraepithelial Lesions in Pregnancy and Postpartum.

Perinatal care provides important health care opportunities for many individuals at risk for cervical cancer. Pregnancy does not alter cervical cancer screening regimens. ASCCP risk-based management has a colposcopy threshold of a 4% immediate risk of cervical intraepithelial neoplasia (CIN) 3 or cancer, but the actual risk can be considerably higher based on current and past screening results. Improving cervical cancer outcomes with diagnosis during pregnancy rather than postpartum and facilitating further evaluation and treatment postpartum for lesser lesions are the perinatal management goals. Although colposcopy indications are unchanged in pregnancy, some individuals with lower risk of CIN 2-3 and reliable access to postpartum evaluation may defer colposcopy until after delivery. Cervical intraepithelial neoplasia diagnosed in pregnancy tends to be stable, with frequent regression postpartum, though this is not universal. Colposcopic inspection during pregnancy can be challenging. Although biopsies in pregnancy are subjectively associated with increased bleeding, they do not increase complications. Endocervical curettage and expedited treatment are unacceptable. Treatment of CIN 2-3 in pregnancy is not recommended. Excisional biopsies in pregnancy are reserved for suspicion of malignancy that cannot be confirmed by colposcopic biopsy and when excisional biopsy results would alter oncologic or pregnancy care. Surveillance of high-grade lesions in pregnancy uses human papillomavirus-based testing, cytology, and colposcopy, with biopsy of worsening lesions every 12-24 weeks from diagnosis until postpartum evaluation. Mode of delivery does not definitively affect persistence of CIN postpartum. Postpartum care may involve a full colposcopic evaluation or expedited excisional procedure if indicated.

The impact of fetal surgical procedures on perinatal anxiety and depression.

BACKGROUND: Perinatal mental illness presents a significant health burden to both patients and families. Many factors are hypothesized to increase the incidence of perinatal depression and anxiety in the fetal surgical population, including uncertain fetal prognosis and inherent risks of surgery and preterm delivery. OBJECTIVE: This study aimed to determine the incidence and disease course of postpartum depression and anxiety in the fetal surgery population. STUDY DESIGN: A retrospective medical record review study was conducted of fetal surgery patients delivering between November 2016 and November 2021 at an academic level IV perinatal healthcare center. Demographics and surgical, obstetrical, and psychiatric diagnoses were abstracted. Standard descriptive analyses were performed. RESULTS: Eligible patients were identified (N=119). Fetal surgery was performed at a mean gestational age of 22.8 weeks (standard deviation, 4.11). Laser ablation of placental anastomoses (n=51) and in utero myelomeningocele repair (n=22) were the most common procedures. Of 119 patients, 34 (28.6%) were diagnosed with preexisting depression or anxiety, with 19 (55.9%) and 17 (50.0%) on baseline medication for depression or anxiety, respectively, before surgery. Of 85 patients, 23 (27.1%) without a history of anxiety or depression had new identification of one or both after delivery. Of note, 2 patients experienced suicidal ideation after delivery. Of the 119 patients, 8 (6.7%) and 12 (10.1%) initiated a new psychiatric medication during or after pregnancy, respectively, and 19 (16.0%) received a therapy referral. Among patients with baseline anxiety or depression, 20 of 34 patients (58.8%) experienced an exacerbation after delivery, 9 of 34 patients (26.5%) were referred for therapy, 9 of 34 patients (26.5%) were changing dose or medication for anxiety, and 11 of 34 patients (32.4%) were changing dose or medication for depression. Of the 119 patients, 24 (20.2%) experienced new or worsening depression or anxiety after the standard 6-week postpartum visit. CONCLUSION: Among patients undergoing fetal surgery, a high incidence of postpartum depression and anxiety was identified, with most patients with prepregnancy anxiety or depression experiencing exacerbation after delivery. The timeframe to clinical presentation with depression or anxiety symptoms may be delayed beyond the traditional 6-week postpartum period and into the first postpartum year. This observation could be attributed to de novo postpartum exacerbation or a lack of standardized treatment approaches earlier in the disease course or antepartum period. Understanding effective longitudinal supportive interventions is an essential next step.

Assessing the capacity of methylated DNA markers of cervical squamous cell carcinoma to discriminate oropharyngeal squamous cell carcinoma in human papillomavirus mediated disease.

OBJECTIVE: Early identification of human papillomavirus associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC) is challenging and novel biomarkers are needed. We hypothesized that a panel of methylated DNA markers (MDMs) found in HPV(+) cervical squamous cell carcinoma (CSCC) will have similar discrimination in HPV(+)OPSCC tissues. MATERIALS AND METHODS: Formalin-fixed, paraffin-embedded tissues were obtained from patients with primary HPV(+)OPSCC or HPV(+)CSCC; control tissues included normal oropharynx palatine tonsil (NOP) and cervix (NCS). Using a methylation-specific polymerase chain reaction, 21 previously validated cervical MDMs were evaluated on tissue-extracted DNA. Discrimination between case and control cervical and oropharynx tissue was assessed using area under the curve (AUC). RESULTS: 34 HPV(+)OPSCC, 36 HPV(+)CSCC, 26 NOP, and 24 NCS patients met inclusion criteria. Within HPV(+)CSCC, 18/21 (86%) of MDMs achieved an AUC ≥ 0.9 and all MDMs exhibited better than chance classifications relative to control cervical tissue (all p < 0.001). In contrast, within HPV(+)OPSCC only 5/21 (24%) MDMs achieved an AUC ≥ 0.90 but 19/21 (90%) exhibited better than chance classifications relative to control tonsil tissue (all p < 0.001). Overall, 13/21 MDMs had statistically significant lower AUCs in the oropharyngeal cohort compared to the cervical cohort, and only 1 MDM exhibited a statistically significant increase in AUC. CONCLUSIONS: Previously validated MDMs exhibited robust performance in independent HPV(+)CSCC patients. However, most of these MDMs exhibited higher discrimination for HPV(+)CSCC than for HPV(+)OPSCC. This suggests that each SCC subtype requires a unique set of MDMs for optimal discrimination. Future studies are necessary to establish an MDM panel for HPV(+)OPSCC.

Impact of comorbidities and extent of lymphadenectomy on quality of life in endometrial cancer patients treated with minimally invasive surgery in the era of sentinel lymph nodes.

OBJECTIVE: To identify predictors of quality of life (QoL) among patients who undergo surgical staging with sentinel lymph node (SLN) biopsy or lymphadenectomy for endometrial cancer. METHODS: Patients who underwent minimally invasive surgery for primary endometrial cancer at the Mayo Clinic from October 2013 to June 2016 were mailed a 30-item QoL in Cancer survey (QLQ-C30) and a validated 13-item lower extremity lymphedema screening questionnaire. Patients who answered <50% of the items or had a pre-operative history of lymphedema were excluded. Multivariable linear regression models were fit to evaluate predictors of QoL using inverse-probability of treatment weighting to adjust for differences at the time of the surgery between the lymphadenectomy and SLN groups. RESULTS: The 221 patients included in the analysis were stratified into two groups: patients who underwent (1) bilateral lymphadenectomy as 'backup' after SLN mapping (lymphadenectomy group; n=101) or (2) SLN removal with or without side-specific lymphadenectomy (SLN group; n=120). On multivariable analysis, obesity, lower extremity lymphedema, and kidney disease had significant (p<0.05) and clinically meaningful negative impacts on global QoL. Declines in average adjusted global QoL scores were marked (19.7 points lower) in patients with BMI ≥40 kg/m2 and lower extremity lymphedema compared with non-obese patients without lower extremity lymphedema. In contrast, there was only a 2.9 point difference in the adjusted average global QoL score between the SLN and lymphadenectomy groups. CONCLUSIONS: Lower extremity lymphedema coupled with obesity predicts poorer QoL in patients who undergo surgical staging for endometrial cancer. In this population, reduction of lower extremity lymphedema by performing SLN instead of lymphadenectomy and earlier targeted interventions may improve patients' QoL. Future research focusing on targeted interventions is needed.

Epigenomics may begin to explain in vitro differential response to hypomethylating agents in MMR-D hypermethylated endometrial cancer.

This work examines differences in chromatin accessibility, methylation, and response to DNA hypomethylating agents between mismatch repair-deficient and non-mismatch repair-deficient endometrial cancer. Next-generation sequencing of a stage 1B, grade 2 endometrioid endometrial cancer tumor revealed microsatellite instability and a variant of unknown significance in POLE along with global and MLH1 hypermethylation. Inhibition of viability by decitabine in the study and comparison tumors was minimal, as shown by an inhibitory effect of 0 and 17.9, respectively. Conversely, the inhibitory effect of azacitidine on the study tumor was more pronounced, at 72.8 versus 41.2. In vitro, mismatch repair-deficient endometrial cancer with MLH1 hypermethylation respond better to DNA methyltransferase inhibition by azacytidine (DNA/RNA inhibition), than to decitabine (DNA-only inhibition). Additional large studies are needed to substantiate our findings.

Focal-occult placenta accreta: a clandestine source of maternal morbidity.

BACKGROUND: Focal-occult placenta accreta spectrum is known to cause adverse obstetrical morbidity outcomes, however, direct comparisons with previa-associated placenta accreta spectrum morbidity are lacking. OBJECTIVE: We sought to compare the baseline characteristics, surgical and obstetrical morbidity, and subsequent pregnancy outcomes of patients with focal-occult placenta accreta spectrum with those of patients with previa-associated accreta. STUDY DESIGN: A retrospective review was conducted of all pathologically confirmed placenta accreta spectrum cases from 2018 to 2022 at a tertiary care center. The baseline characteristics, surgical, obstetrical, and subsequent pregnancy outcomes were recorded. Cases of focal-occult placenta accreta spectrum was compared with cases of previa-associated placenta accreta spectrum across a range of morbidity characteristics including hemorrhagic factors, interventions, postdelivery reoperations, infections, and intensive care unit admission. Statistical comparison was performed using Kruskal-Wallis or chi-square tests, and a P value of <.05 was considered significant. RESULTS: A total of 74 cases were identified with 43 focal-occult and 31 previa-associated placenta accreta spectrum cases. Of those, 25.6% of the patients with focal-occult placenta accreta spectrum and 100% of the patients with previa-associated placenta accreta spectrum underwent a hysterectomy. One case of focal-occult placenta accreta spectrum and 29 cases of previa-associated placenta accreta spectrum were diagnosed antenatally. Patients with focal-occult placenta accreta spectrum did not differ from those with previa-associated placenta accreta spectrum in mean maternal age (33.0 vs 33.1 years), body mass index, or the incidence of previous dilation and curettage procedures (16.3% vs 25.8%). Patients with focal-occult placenta accreta spectrum were significantly more likely to have a lower mean parity (1.5 vs 3.6 gestations), higher gestational age at delivery (36.1 vs 33.9 weeks' gestation), and were less likely to have had a previous cesarean delivery (12/43, 27.9% vs 30/31, 96.8%). In addition, patients with focal-occult placenta accreta spectrum had less previous cesarean deliveries (mean, 0.5 vs 2.3), were more likely to have undergone in vitro fertilization (20.9% vs 3.2%), and less likely to have anterior placentation. When contrasting the clinical outcomes of patients with focal-occult placenta accreta spectrum with those with previa-associated placenta accreta spectrum, the postpartum hemorrhage rates (71.0% vs 67.4%), mean quantitative blood loss (2099 mL; range, 500-9516 mL vs 2119 mL; range 350-12,220 mL), mean units of red blood cells transfused (1.4 vs 1.7), massive transfusion rate (9.3% vs 3.2%), and intensive care unit admission rates (11.6% vs 6.5%) were not significantly different, but there was a nonsignificant trend toward higher morbidity among patients with focal-occult accreta. Patients with focal-occult accreta had a higher incidence of reoperations or return to the operating room (30.2 vs 6.5%; P=.01). When comparing focal-occult with previa-associated placenta accreta spectrum, the composite outcomes, including hemorrhagic morbidity (77.4% vs 74.4%), any maternal morbidity (83.9% vs 76.7%), and severe maternal morbidity (64.5% vs 65.1%), were not significantly different between the groups. Nine focal-occult placenta accreta spectrum patients had a subsequent pregnancy, and 3 of those had recurrent placenta accreta spectrum. CONCLUSION: Focal-occult placenta accreta spectrum presents with fewer identifiable risk factors than placenta previa-associated placenta accreta spectrum but may be associated with an in vitro fertilization pregnancy. Patients with focal-occult placenta accreta spectrum was observed to have a higher incidence of reoperation when compared with patients previa-associated placenta accreta spectrum, and no other statistically significant differences in morbidity outcomes were observed. The absence of differences in morbidity outcomes may be attributable to a lack of antenatal detection of focal-occult accreta and merits further investigation.

Overall survival after surgical staging by lymph node dissection versus sentinel lymph node biopsy in endometrial cancer: a national cancer database study.

OBJECTIVE: Substituting lymphadenectomy with sentinel lymph node biopsy for staging purposes in endometrial cancer has raised concerns about incomplete nodal resection and detrimental oncological outcomes. Therefore, this study aimed to investigate the association between the type of lymph node assessment and overall survival in endometrial cancer accounting for node status and histology. METHODS: Women with stage I-III endometrial cancer who underwent hysterectomy and lymph node assessment from January 2012 to December 2015 were identified in the National Cancer Database. Patients who underwent neoadjuvant therapy, had previous cancer, and whose follow-up was less than 90 days were excluded. Multivariable Cox proportional hazards regression analyses were performed to assess factors associated with overall survival. RESULTS: Of 68 614 patients, 64 796 (94.4%) underwent lymphadenectomy, 1777 (2.6%) underwent sentinel node biopsy only, and 2041 (3.0%) underwent both procedures. On multivariable analysis, neither sentinel lymph node biopsy alone nor sentinel node biopsy followed by lymphadenectomy was associated with significantly different overall survival compared with lymphadenectomy alone (HR 0.92, 95% CI 0.73 to 1.17, and HR 0.91, 95% CI 0.77 to 1.08, respectively). When stratified by lymph node status, sentinel node biopsy alone or followed by lymphadenectomy was not associated with different overall survival, both in patients with negative (HR 0.95, 95% CI 0.73 to 1.24, and HR 1.04, 95% CI 0.85 to 1.27, respectively) or positive (HR 0.91, 95% CI 0.54 to 1.52, and HR 0.77, 95% CI 0.57 to 1.04, respectively) lymph nodes. These findings held true when sentinel node biopsy alone and sentinel node biopsy plus lymphadenectomy groups were merged, and on stratification by histotype (type one vs type 2) or inclusion of only complete lymphadenectomy (at least 10 pelvic nodes and at least one para-aortic node removed). In all analyses, age, Charlson-Deyo score, black race, AJCC pathological T stage, grade, lymphovascular invasion, brachytherapy, and adjuvant chemotherapy were independently associated with overall survival. DISCUSSION: No difference in overall survival was found in patients with endometrial cancer who underwent sentinel node biopsy alone, sentinel node biopsy followed by lymphadenectomy, or lymphadenectomy alone. This observation remained regardless of node status, histotype, and lymphadenectomy extent.

Oncologic outcomes of endometrial cancer in patients with low-volume metastasis in the sentinel lymph nodes: An international multi-institutional study.

OBJECTIVE: To assess oncologic outcomes in endometrial cancer patients with low-volume metastasis (LVM) in the sentinel lymph nodes (SLNs). METHODS: Patients with endometrial cancer and SLN-LVM (≤2 mm) from December 3, 2009, to December 31, 2018, were retrospectively identified from 22 centers worldwide. Patients with International Federation of Gynecology and Obstetrics (FIGO) stage IV, adnexal involvement, or unknown adjuvant therapy (ATx) were excluded. RESULTS: Of 247 patients included, 132 had isolated tumor cell (ITC) and 115 had micrometastasis (MM). Overall 4-year recurrence-free survival (RFS) was 77.6% (95% CI, 70.2%-85.9%); median follow-up for patients without recurrence was 29.6 (interquartile range, 19.2-41.5) months. At multivariate analysis, Non-endometrioid (NE) (HR, 5.00; 95% CI, 2.50-9.99; P < .001), lymphovascular space invasion (LVSI) (HR, 3.26; 95% CI, 1.45-7.31; P = .004), and uterine serosal invasion (USI) (HR, 3.70; 95% CI, 1.44-9.54; P = .007) were independent predictors of recurrence. Among 47 endometrioid ITC patients without ATx, 4-year RFS was 82.6% (95% CI, 70.1%-97.2). Considering 18 ITC patients with endometrioid grade 1 disease, without LVSI, USI, or ATx, only 1 had recurrence (median follow-up, 24.8 months). CONCLUSIONS: In patients with SLN-LVM, NE, LVSI, and USI were independent risk factors for recurrence. Patients with any risk factor had poor prognosis, even when receiving ATx. Patients with ITC and grade 1 endometrioid disease (no LVSI/USI) had favorable prognosis, even without ATx. Further analysis (with more patients and longer follow-up) is needed to assess whether ATx can be withheld in this low-risk subgroup.

Personalized tumor-specific DNA junctions to detect circulating tumor in patients with endometrial cancer.

INTRODUCTION: There are no reliable blood biomarkers for monitoring endometrial cancer patients in the current clinical practice. Circulating tumor DNA (ctDNA) is emerging as a promising non-invasive method to measure tumor burden, define prognosis and monitor disease status in many solid cancers. In this pilot study, we investigated if unique tumor-specific DNA junctions can be used to detect ctDNA levels in patients with endometrial cancer. METHODS: Chromosomal rearrangements in primary tumors of eleven patients with high-grade or advanced stage endometrial cancer were determined by whole-genome Mate-Pair sequencing. Identified unique tumor-specific junctions were evaluated in pre- and six-week post-surgery patient plasma using individualized quantitative polymerase chain reaction (qPCR) assays. The relationship between clinicopathological features and detection of ctDNA was investigated. RESULTS: CtDNA was detected in 60% (6/10) of cases pre-surgery and in 27% (3/11) post-surgery. The detection of ctDNA pre-surgery was consistent with clinical indicators of aggressive disease such as advanced stage (80% - 4/5), lymphatic spread of disease (100% - 3/3), serous histology (80% - 4/5), deep myometrial invasion (100% - 3/3), lympho-vascular space invasion (75% - 3/4). All patients in which ctDNA was detected post-surgically had type II endometrial cancer. DISCUSSION: This pilot study demonstrates the feasibility of using personalized tumor-specific junction panels for detecting ctDNA in the plasma of endometrial cancer patients. Larger studies and longer follow-up are needed to validate the potential association between pre-surgical ctDNA detection and the presence of cancers with aggressive pathologic tumor characteristics or advanced stage observed in this study.

Controversies in the Management of Early-stage Serous Endometrial Cancer.

BACKGROUND/AIM: Early-stage uterine serous carcinoma (USC) has one of the highest recurrence rates and mortality among early-stage uterine epithelial cancers. Research into the clinical management of USC has begun to progress, guided by surgical and pathological advances. This article summarizes the available literature regarding diagnosis, management, and possible future uses of molecular analysis of women with early-stage USC. MATERIALS AND METHODS: PubMed was searched for all pertinent English language research articles published from January 1, 2006 through March 1, 2020 which included a study population of women diagnosed with stage 1 USC. Due to the scarcity of prospective or large-scale data, studies were not limited by design or numbers of patients. Studies performed at earlier dates were incorporated to provide context. RESULTS: A total of 86 studies were included in the review. Multiple well-designed studies have confirmed the safety of a minimally invasive surgical approach for surgical management of USC. The role of sentinel node biopsy has been validated with both prospective and retrospective multi-center data. Stage I USC is associated with a highly variable risk of recurrence, even following completion of adjuvant chemoradiation. This aggressive phenotype has been linked to high numbers of somatic copy number alterations, tumor protein 53, and phosphatidylinositol 3 kinase mutations, which have been shown to be predictive of prognosis. CONCLUSION: Early-stage USC demonstrates a lack of predictable recurrence patterns, with reports noting distant recurrence in patients with disease confined to polyps. Unless no residual tumor is found on hysterectomy, chemotherapy and radiotherapy should be discussed and individualized by stage and treatment goals.

Reduced lymphedema after sentinel lymph node biopsy versus lymphadenectomy for endometrial cancer.

OBJECTIVE: Endometrial cancer surgical staging includes lymph node assessment which can lead to lower extremity lymphedema. The aim of this study was to estimate prevalence after sentinel lymph node biopsy versus lymphadenectomy. METHODS: Consecutive patients who underwent minimally invasive surgery at the Mayo Clinic, Rochester, Minnesota, USA, between January 2009 and June 2016 for newly diagnosed endometrial cancer were mailed our validated 13 item lower extremity lymphedema screening questionnaire. We also ascertained via questionnaire whether the patient was ever diagnosed with lower extremity lymphedema. RESULTS: Among 378 patients included in the analysis, 127 (33.5%) had sentinel lymph node biopsy with or without side specific lymphadenectomy (sentinel lymph node cohort) and 251 (66.4%) underwent bilateral lymphadenectomy prior to sentinel lymph node biopsy implementation at our institution or as 'backup' after sentinel lymph node mapping (lymphadenectomy cohort). The prevalence of lower extremity lymphedema was 41.5% (157/378), with 69 patients (18.3%) self-reporting a lower extremity lymphedema diagnosis after their endometrial cancer surgery at a median of 54.3 months (interquartile range 31.2-70.1 months), and an additional 88 patients (23.3%) identified by the screening questionnaire. The prevalence of lower extremity lymphedema was significantly higher in the lymphadenectomy cohort compared with the sentinel lymph node group (49.4% (124/251) vs 26.0% (33/127); p<0.001). When the cohorts were restricted to patients surgically managed after the introduction of sentinel lymph node, the prevalence of lower extremity lymphedema was still significantly higher in the lymphadenectomy cohort compared with the sentinel lymph node cohort (39.0% (41/105) vs 26.0% (33/127); p=0.03). In a multivariable analysis adjusted for body mass index, receipt of adjuvant external beam radiation, diabetes, congestive heart failure, and International Federation of Gynecology and Obstetrics grade, the adjusted odds ratio for the association between type of nodal sampling (lymphadenectomy cohort vs sentinel lymph node cohort) and lower extremity lymphedema was 2.75 (95% confidence interval 1.69 to 4.47, p<0.001). CONCLUSIONS: Sentinel lymph node biopsy was associated with a decreased risk of post-treatment lymphedema compared with lymphadenectomy in patients who underwent surgical staging for endometrial carcinoma.

Human Papillomavirus-Associated Anogenital Pathology in Females With HPV-Positive Oropharyngeal Squamous Cell Carcinoma.

We sought to determine the incidence and location of human papillomavirus (HPV)-associated anogenital disease in women with HPV-positive oropharyngeal squamous cell carcinoma (OPSCC) via a retrospective cohort study with prospective contact to update history at Mayo Clinic in Rochester, Minnesota. Females undergoing treatment for nonmetastatic HPV-positive OPSCC from 2011 to 2019 were identified. Clinical history and outcomes were abstracted from medical records. Patients without documented anogenital history were contacted, consented, and administered a survey, and external records were requested and reviewed. Seventeen of 46 patients (37.0%) had a history of anogenital HPV-associated disease, and 16 of 17 (94.1%) required procedures to diagnose or treat HPV lesions. The cervix was the most common site (16/17, 94.1%). Procedures included colposcopy (n = 6), cervical excision (n = 3), cryotherapy (n = 4), and hysterectomy (n = 3). One case of fatal cervical carcinoma was noted, diagnosed 1 year following OPSCC. Three of 17 (17.6%) had HPV-related vulvovaginal disease, and 1 of 17 had anal disease. Patients with a history of HPV-positive OPSCC may be at elevated risk for HPV-associated anogenital disease.

Impact of hysteroscopy on course of disease in high-risk endometrial carcinoma.

OBJECTIVE: Previous studies have investigated the impact of preoperative hysteroscopy on the staging and survival of predominantly grade 1 endometrial cancers. We sought to evaluate the effect of hysteroscopy on the peritoneal spread of tumor cells and disease course in a large series of patients with high-risk endometrial cancer. METHODS: Patients who underwent hysterectomy for grade 3 endometrial carcinoma on final surgical pathology at the Mayo Clinic in Rochester, MN between January 2009 to June 2016 were included, noting hysteroscopy within 6 months from surgery. Intra-peritoneal disease was defined as any positive cytology OR adnexal invasion OR stage IV. The presence of intra-peritoneal disease OR peritoneal recurrence within 2 years from surgery was defined as peritoneal dissemination. Cox proportional hazards models were fit to evaluate associations between hysteroscopy exposure and progression within 5 years following surgery. RESULTS: Among 831 patients, 133 underwent hysteroscopy. There was no difference in age, body mass index, ASA ≥3, or serous histology between patients who did or did not undergo hysteroscopy. Advanced stage disease (III/IV) was less common among patients who underwent hysteroscopy (30.1% vs 43.8%, P=0.003). No difference was observed between those with vs without hysteroscopy in the rate of positive cytology (22.0% vs 29.7%, P=0.09), stage IV (16.5% vs 21.9%, P=0.16), intra-peritoneal disease (28.6% vs 36.1%, P=0.09), or peritoneal dissemination (30.8% vs 39.3%, P=0.06). On stratifying by stage, hysteroscopy did not increase the risk of progression (HR 1.06, 95% CI 0.59 to 1.92 for stage I/II; HR 0.96, 95% CI 0.62 to 1.48 for stage III/IV). CONCLUSION: In this retrospective study of grade 3 endometrial cancer, we did not observe any significant association between pre-operative hysteroscopy and the incidence of positive cytology, peritoneal disease, peritoneal dissemination, or cancer progression.

Retrospective 15-Year Review of Anal Cytology Screening in Women at Mayo Clinic Rochester, Minnesota.

OBJECTIVES: Anal cytology is a modality for anal cancer screening in high-risk women. In this retrospective study, we review risk factors associated with abnormal anal cytology and unsatisfactory anal cytology rates, and correlate findings of cytology with histological results. METHODS: A retrospective cohort study of anal cytology screening in women at Mayo Clinic in Rochester, Minnesota from 2002 to 2018 was conducted. RESULTS: Three hundred fifty-seven women had a total of 592 anal cytologies performed. Three hundred seventeen women had screening anal cytology, whereas 40 women had anal cytology for surveillance given a history of anal intraepithelial neoplasia (AIN) or anal cancer. An unsatisfactory anal cytology result was found in 14.7%. Risk factors, type of follow-up, and correlation with histologic specimens were also reviewed. Histologic finding of AIN 2/3 correlated with abnormal anal cytology 84% of the time in this cohort. CONCLUSIONS: High-risk women should be screened on a periodic basis for anal cancer. Anal cytology is one possible modality that can be used. Further insight into AIN progression, regression, recurrence, and outcome after treatment will help direct future screening recommendations.

Recurrence patterns in patients with abnormal cardiophrenic lymph nodes at ovarian cancer diagnosis.

OBJECTIVES: Metastases in cardiophrenic lymph nodes noted at diagnosis of epithelial ovarian cancer confer a poor prognosis. It is unclear if cardiophrenic nodal metastases portend an atypical pattern of recurrence. We report on patients with radiographically involved cardiophrenic lymph nodes who underwent optimal primary debulking surgery to describe patterns of recurrence and response to chemotherapy. METHODS: Patients undergoing primary debulking surgery for stage IIIC/IV epithelial ovarian carcinoma with residual disease ≤1.0 cm at our institution from 2003 to 2011 with a pre-operative computed tomography (CT) scan were identified. Scans were reviewed by blinded radiologists, who identified abnormal cardiophrenic lymph nodes via a qualitative assessment scale based on size, heterogeneity, and architecture. RESULTS: Of the 250 patients identified, a recurrence site was documented in 22/27 (81.5%) with abnormal pre-operative cardiophrenic lymph nodes (defined by an elevated Qualitative Assessment Scale (QAS) score of ≥4), and in 128/223 (57.4%) without abnormal pre-operative cardiophrenic lymph nodes. Median short axis and long axis lymph node diameters for these patients was 9 (range 6-15) mm and 15 (range 11-22) mm, respectively. Cardiophrenic lymph nodes were resected in one patient. Patients with abnormal cardiophrenic nodes are more likely to have synchronous recurrence in thorax/pelvis and abdomen (50.0% (11/22) vs 25.0% (32/128), p=0.02) and less likely to have isolated recurrence in pelvis or abdomen (40.9% (9/22) vs 68.0% (87/128)). All patients who had a CT scan after six cycles of chemotherapy had improvement (defined as reduction of QAS score) in cardiophrenic lymphadenopathy. CONCLUSIONS: Despite cardiophrenic adenopathy demonstrating a complete radiographic response to chemotherapy, their presence pre-operatively is associated with an increased risk of recurrence in the thorax. Knowledge of this propensity to recur in the thorax is important to ensure all extra-abdominal recurrence sites are diagnosed and managed appropriately.

Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile.

BACKGROUND: Vaginal diazepam is frequently used to treat pelvic floor tension myalgia and pelvic pain despite limited knowledge of systemic absorption. AIM: To determine the pharmacokinetic and adverse event profile of diazepam vaginal suppositories. METHODS: We used a prospective pharmacokinetic design with repeated assessments of diazepam levels. Eight healthy volunteers were administered a 10-mg compounded vaginal diazepam suppository in the outpatient gynecologic clinic. Serum samples were collected at 0, 45, 90, 120, and 180 minutes; 8, 24, and 72 hours; and 1 week following administration of a 10-mg vaginal suppository. The occurrence of adverse events was assessed using the alternate step and tandem walk tests, the Brief Confusion Assessment Method, and numerical ratings. Plasma concentrations of diazepam and active long-acting metabolites were measured. Pharmacokinetic parameters were calculated by standard noncompartmental methods. RESULTS: The mean peak diazepam concentration (Cmax) of 31.0 ng/mL was detected at a mean time (Tmax) of 3.1 hours after suppository placement. The bioavailability was found to be 70.5%, and the mean terminal elimination half-life was 82 hours. The plasma levels of temazepam and nordiazepam peaked at 0.8 ng/mL at 29 hours and 6.4 ng/mL at 132 hours, respectively. Fatigue was reported by 3 of 8 participants. CLINICAL IMPLICATIONS: Serum plasma concentrations of vaginally administered diazepam are low; however the half-life is prolonged. STRENGTHS & LIMITATIONS: Strengths include use of inclusion and exclusion criteria aimed at mitigating clinical factors that could adversely impact diazepam absorption and metabolism, and the use of an ultrasensitive LC-MS/MS assay. Limitations included the lack of addressing the efficacy of vaginal diazepam in lieu of performing a pure pharmacokinetic study with healthy participants. CONCLUSION: Vaginal administration of diazepam results in lower peak serum plasma concentration, longer time to peak concentration, and lower bioavailability than standard oral use. Providers should be aware that with diazepam's long half-life, accumulating levels would occur with chronic daily doses, and steady-state levels would not be reached for up to 1 week. This profile would favor intermittent use to allow participation in physical therapy and intimacy. Larish AM, Dickson RR, Kudgus RA, et al. Vaginal Diazepam for Nonrelaxing Pelvic Floor Dysfunction: The Pharmacokinetic Profile. J Sex Med 2019;16;763-766.

Primary Gastric Choriocarcinoma Presenting as a Pregnancy of Unknown Location.

BACKGROUND: Pregnancy of unknown location presents a diagnostic challenge, in rare occasions leading to the diagnosis of malignancy. We describe a case of ß-hCG-secreting nongestational primary gastric choriocarcinoma presenting as a pregnancy of unknown location. CASE: A 37-year-old woman, gravida 4 para 3013, presented with several days of vaginal bleeding and rising ß-hCG level without ultrasound localization of pregnancy. The diagnosis of pregnancy of unknown location was made and methotrexate administered at a ß-hCG level of 7,779 milli-international units/mL. A 40% decrease in ß-hCG level was noted between days 4 and 7. One week later, an inappropriate ß-hCG level rise to 10,937 milli-international units/mL was noted, prompting a second dose of methotrexate and computed tomography imaging, leading to the discovery of gastric and liver lesions. Pathology from gastric biopsies revealed nongestational choriocarcinoma. The patient was treated with chemotherapy, with death from cardiac arrest 7 months after diagnosis. CONCLUSION: Malignancies that can secrete ß-hCG include gestational trophoblastic disease, gonadal and extragonadal germ cell tumors, and malignancies with choriocarcinoma differentiation. Although ectopic pregnancy compromises approximately 2% of first-trimester pregnancy, gestational trophoblastic neoplasia and gestational choriocarcinoma can be seen in 1 of 1,500 and 1 of 20,000 pregnancies, respectively. When ß-hCG levels do not fall appropriately in women undergoing medical management for pregnancy of unknown location, ectopic ß-hCG secretion by a malignancy must be considered.

Bilateral ovarian B-lineage lymphoblastic lymphoma with MLL gene rearrangement: a novel case in infancy.

Mixed-lineage leukemia (MLL) gene rearrangements have rarely been reported in pediatric lymphoma despite their high prevalence in pediatric leukemia. We present a case of an infant with bilateral ovarian B-lineage lymphoblastic lymphoma with MLL gene rearrangement. We also briefly summarize the clinicopathologic significance of MLL gene rearrangements, and review the reported cases of pediatric ovarian lymphoma with and without MLL rearrangement.