Sentinel lymph node mapping in endometrial cancer: Current evidence and practice.

Surgical staging with total hysterectomy, bilateral salpingo-oophorectomy, and lymph node assessment is the standard of care for patients with clinical early-stage endometrial cancer. Traditionally, complete pelvic and para-aortic lymphadenectomy (LND) was performed to assess for nodal metastases; however, numerous prospective studies have demonstrated that sentinel lymph node biopsy has similar diagnostic accuracy, and is an acceptable alternative to complete LND. This has led to a paradigm shift in endometrial cancer staging.

Diagnostic accuracy of frozen section and patterns of nodal spread in high grade endometrial cancer: A secondary outcome of the SENTOR prospective cohort study.

OBJECTIVES: The study aimed to define the accuracy of intraoperative frozen section (FS) for the detection of metastases in sentinel lymph node biopsy (SLNB) and describe the pattern of lymph node (LN) spread and relation to molecular classifiers in patients with high-grade endometrial cancer (EC). METHODS: We performed a secondary outcome of clinicopathologic data from the Sentinel Lymph Node Biopsy versus Lymphadenectomy for Intermediate- and High-Grade Endometrial Cancer Staging (SENTOR) prospective cohort study evaluating SLNB in patients with clinical stage I high-grade EC (ClinicalTrials.gov ID: NCT01886066). The primary outcome was the sensitivity of FS of the sentinel lymph node (SLN) specimen, compared to a standardized ultrastaging protocol. Secondary outcomes included the pattern and characteristics of LN spread. RESULTS: There were 126 patients with high-grade EC with a median age of 66 years (range:44-86) and a median Body Mass Index (BMI) of 26.9 kg/m2 (range:17.6-49.3). FS was performed on surgical specimens from 212 hemipelves; SLNs were identified in 202 specimens (95.7%) and fatty tissue alone was identified in 10 specimens (4.7%). Of the 202 hemipelves in which SLNs were identified, 24 were positive for metastatic disease on final pathology. Initial FS correctly identified only 12, yielding a sensitivity of 50% (12/24, 95% CI 29.6-70.4) and a negative predictive value of 94% (178/190, 95% CI 89-96.5). A total of 24 patients (19%) had LN metastases: 16 (13%) had isolated pelvic metastases, 7 (6%) had both pelvic and para-aortic metastases and 1 (0.8%) had an isolated para-aortic metastasis. CONCLUSIONS: Intraoperative FS of SLNs in high-grade EC patients has poor sensitivity. Since isolated para-aortic metastases are rare, para-aortic lymphadenectomy may be omitted in patients in which SLNs were successfully mapped to the pelvis.

Small Cell and Other Rare Histologic Types of Cervical Cancer.

PURPOSE OF REVIEW: The goal of this paper was to summarize the recent evidence on rare subtypes of cervical cancer including small-cell carcinoma of the cervix (SCCC), gastric-type adenocarcinoma, and carcinosarcoma. RECENT FINDINGS: All three cervical cancer subtypes are aggressive with poor treatment response and high recurrence rates. Molecular studies have identified various actionable mutations in both SCCC (PIK3CA, MYC, TP53, PTEN, ARID1A, KRAS, BRCA2) and gastric-type adenocarcinoma (KRAS, ARID1A, PTEN). While there are a limited number of case reports demonstrating a favorable response for recurrent SCCC to immune checkpoint inhibitors, a larger case series failed to show benefit. The checkpoint inhibitors role in gastric-type adenocarcinoma and carcinosarcoma is yet to be determined. Ninety-one percent of SCCC cases show PARP expression, suggesting a possible role for PARP inhibitors; however, this has yet to be examined in future clinical trials. More studies are needed, with a focus on targeted therapies. The role of PARP inhibitors in SCCC is potentially promising, but significant collaboration between centers/groups will be required to achieve this.

Impact of neoadjuvant chemotherapy on somatic mutation status in high-grade serous ovarian carcinoma.

BACKGROUND: Patients treated with neoadjuvant chemotherapy (NACT) for advanced high-grade serous ovarian carcinoma (HGSC) have a higher rate and shorter time to platinum-resistant recurrence compared to patients treated with primary cytoreductive surgery (PCS) and adjuvant chemotherapy. The purpose of this study is to determine the impact of NACT on somatic mutation status in platinum-sensitive and resistant HGSC. Patients with advanced HGSC who had a documented response to platinum-based NACT, a banked blood sample, and a banked tumor sample before and after NACT were identified. Whole exome and/or targeted deep sequencing was performed in matched normal and pre/post-NACT tumor samples from 3 platinum-resistant and 2 platinum-sensitive patients to identify somatic non-synonymous mutations at each time point. RESULTS: When comparing exonic non-synonymous mutations in pre-NACT and post-NACT samples from the same patient, an average of 41% (1-68%) of genes were mutated at both time points. There were no trends detected in the mutational burden following exposure to NACT in platinum-resistant vs. platinum-sensitive cases. The majority of mutated genes were unique to each case. We identified several genes that were commonly mutated in pre-NACT samples specific to platinum-resistant (CSPG4, SLC35G5, TUBA3D) or sensitive (CYP2D6, NUTM1, DNAH5) cases. Four mutated genes emerged exclusively in the platinum-resistant cases (ADGRV1, MUC17, MUC20, PAK2) following NACT. CONCLUSIONS: Patients with advanced HGSC present with significant intra-tumor heterogeneity. NACT significantly impacts the somatic mutation status irrespective of the time to recurrence. The mutated genes detected in chemo-naive pre-NACT tumor samples from either resistant or sensitive cases could potentially have a role in the prediction of chemotherapy response in patients scheduled to receive NACT; larger studies are required to further validate these genes.

Sentinel Lymph Node Mapping in High-Grade Endometrial Cancer.

Sentinel lymph node (SLN) mapping is becoming an acceptable alternative to full lymphadenectomy for evaluating lymphatic spread in clinical stage I endometrial cancer (EC). While the assessment of pelvic and para-aortic lymph nodes is part of the surgical staging of EC, there is a long-standing debate over the therapeutic value of full lymphadenectomy in this setting. Although lymphadenectomy offers critical information on lymphatic spread and prognosis, most patients will not derive oncologic benefit from this procedure as the majority of patients do not have lymph node involvement. SLN mapping offers prognostic information while simultaneously avoiding the morbidity associated with an extensive and often unnecessary lymphadenectomy. A key factor in the decision making when planning for EC surgery is the histologic subtype. Since the risk of lymphatic spread is less than 5% in low-grade EC, these patients might not benefit from lymph node assessment. Nonetheless, in high-grade EC, the risk for lymph node metastases is much higher (20-30%); therefore, it is crucial to determine the spread of disease both for determining prognosis and for tailoring the appropriate adjuvant treatment. Studies on the accuracy of SLN mapping in high-grade EC have shown a detection rate of over 90%. The available evidence supports adopting the SLN approach as an accurate method for surgical staging. However, there is a paucity of prospective data on the long-term oncologic outcome for patients undergoing SLN mapping in high-grade EC, and more trials are warranted to answer this question.

Sentinel lymph node biopsy in high-grade endometrial cancer: a systematic review and meta-analysis of performance characteristics.

OBJECTIVE: A sentinel lymph node biopsy is widely accepted as the standard of care for surgical staging in low-grade endometrial cancer, but its value in high-grade endometrial cancer remains controversial. The aim of this systematic review and meta-analysis was to evaluate the performance characteristics of sentinel lymph node biopsy in patients with endometrial cancer with high-grade histology (registered in the International Prospective Register of Systematic Reviews with identifying number CRD42020160280). DATA SOURCES: We systematically searched the MEDLINE, Epub Ahead of Print, MEDLINE In-Process & Other Non-Indexed Citations, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Embase databases all through the OvidSP platform. The search was performed between January 1, 2000, and January 26, 2021. ClinicalTrials.gov was searched to identify ongoing registered clinical trials. STUDY ELIGIBILITY CRITERIA: We included prospective cohort studies in which sentinel lymph node biopsy were evaluated in clinical stage I patients with high-grade endometrial cancer (grade 3 endometrioid, serous, clear cell, carcinosarcoma, mixed, undifferentiated or dedifferentiated, and high-grade not otherwise specified) with a cervical injection of indocyanine green for sentinel lymph node detection and at least a bilateral pelvic lymphadenectomy as a reference standard. If the data were not reported specifically for patients with high-grade histology, the authors were contacted for aggregate data. METHODS: We pooled the detection rates and measures of diagnostic accuracy using a generalized linear mixed-effects model with a logit and assessed the risk of bias using the Quality Assessment of Diagnostic Accuracy Studies 2 tool. RESULTS: We identified 16 eligible studies of which the authors for 9 of the studies provided data on 429 patients with high-grade endometrial cancer specifically. The study-level median age was 66 years (range, 44-82.5 years) and the study-level median body mass index was 28.6 kg/m2 (range, 19.4-43.7 kg/m2). The pooled detection rates were 91% per patient (95% confidence interval, 85%-95%; I2=59%) and 64% bilaterally (95% confidence interval, 53%-73%; I2=69%). The overall node positivity rate was 26% (95% confidence interval, 19%-34%; I2=44%). Of the 87 patients with positive node results, a sentinel lymph node biopsy correctly identified 80, yielding a pooled sensitivity of 92% per patient (95% confidence interval, 84%-96%; I2=0%), a false negative rate of 8% (95% confidence interval, 4%-16%; I2=0%), and a negative predictive value of 97% (95% confidence interval, 95%-99%; I2=0%). CONCLUSION: Sentinel lymph node biopsy accurately detect lymph node metastases in patients with high-grade endometrial cancer with a false negative rate comparable with that observed in low-grade endometrial cancer, melanoma, vulvar cancer, and breast cancer. These findings suggest that sentinel lymph node biopsy can replace complete lymphadenectomies as the standard of care for surgical staging in patients with high-grade endometrial cancer.

A risk score for prediction of venous thromboembolism in gynecologic cancer: The Thrombogyn score.

BACKGROUND: Gynecologic cancers are associated with high rates of venous thromboembolism (VTE), which is exacerbated by pelvic surgery and chemotherapy. OBJECTIVES: The aim of this study was to develop and validate a risk score for VTE in patients with gynecologic cancer and to test the predictive ability of the score following addition of procoagulant biomarker data. PATIENTS AND METHODS: Clinical and laboratory variables were used to develop a risk score for the prediction of VTE in patients with gynecological cancer (n = 616), which was validated in a separate cohort of patients (n = 406). Endogenous thrombin potential and D-dimer levels were determined in a subset (n = 290) of patients and used to produce an extended score in the validation cohort. RESULTS: Multivariable regression analysis identified BMI >30, hemoglobin <11.5 g/dL and chemotherapy as independent predictors of VTE, which formed the Thrombogyn score. Following competing risk regression analysis, subdistribution hazard ratios (SHRs), adjusted for cancer stage, were 8.16 (95% confidence interval [CI], 1.69-43.77) in the high-risk group (score = 2-3) and 4.12 (95% CI, 0.85-20.15) in the intermediate-risk group (score = 1) compared with the low-risk group (score = 0). SHRs for the validation cohort were 6.26 (95% CI, 1.24-31.39) and 3.00 (95% CI, 0.67-13.32), respectively. Cumulative incidence of VTE in the validation cohort high-risk group was 10.34% (95% CI, 6.51-16.41) per women-years compared with 1.06% (95% CI, 0.26-4.26) in the low-risk group. Using the extended Thrombogyn score, adjusted SHRs were 16.83 (95% CI, 4.20-67.37) in the high-risk group with a cumulative incidence of 21.15% (95% CI, 10.32-45.24). External validation of the score is required. CONCLUSIONS: The Thrombogyn score identifies patients with gynecologic cancer at high and low risk of VTE. Addition of biomarker data improves the predictive power of the score.

Patients' experience and compliance with extended low molecular weight heparin prophylaxis post-surgery for gynecological cancer: a prospective observational study.

OBJECTIVE: Gynaecological cancer patients have a high risk of developing venous thromboembolism (VTE). There is limited information on patient experience and compliance with an extended low molecular weight heparin prophylaxis in this setting. The aim of this study was to assess patient compliance, satisfaction and experience with the extended low molecular weight heparin prophylaxis after major surgery for gynaecological cancer. METHODS: This was a prospective observational study conducted in a large tertiary center for gynaecological cancer between July 2017-March 2018. Consecutive patients undergoing surgery for gynaecological cancer who received low molecular weight heparin prophylaxis for four weeks following surgery were recruited. All participants received a log book to record all injections, side effects, and questionnaire to be completed at the end of the study. RESULTS: A total of 106 patients completed and returned the VTE prophylaxis logbook and questionnaire. Sixty-six (62%) patients received low molecular weight heparin for 28 days, twenty-five (24%) for 26-27 days, and 15 (14%) for less than 26 days. The median number of days of therapy was 28 days (range; 12-28 days). Reasons for missed or stopped injections included: forgetfulness(n=12), medical procedures (n=6), pain (n=5), incorrect prescription (n=4), patient choice (n=3), cost (n=2), physician request (n=2), non-availability of person administering the injections (n=1) or unknown (n=5). Sixty-one (58%) patients self-administered the injections. Patients who had the injection performed by a third person were twice as likely to experience pain compared to patients who self-administered (OR 2.81, p=0.003). Eighty-nine (84%) patients self-reported side effects during low molecular weight heparin prophylaxis including: bruising (75%), pain after injections (49%), itchiness (9%), swelling (9%) or other (8%). Although 83 (78%) patients were satisfied with injections, 91 (86%) admitted they would much prefer a tablet form. CONCLUSIONS: Compliance with standard recommended regimen of 28-days prophylaxis was completed by 62% of patients. Majority of patients (86%) reported a preference for a tablet form, if one was available.

Fetal scalp stimulation (FSS) versus fetal blood sampling (FBS) for women with abnormal fetal heart rate monitoring in labor: a prospective cohort study.

OBJECTIVE: To evaluate the performance of fetal scalp stimulation (FSS) compared to fetal blood sampling (FBS) as a second line test of fetal wellbeing in labor. STUDY DESIGN: A prospective cohort study was conducted including 298 fetal blood sampling procedures performed due to abnormal fetal cardiotocography (CTG). Two independent observers interpreted the CTG following stimulation. The FSS test was classified as normal when an elicited acceleration and/or provoked fetal heart rate variability was recorded. The FBS was classified as normal (pH ≥7.25), borderline (pH 7.21-7.24), and abnormal (pH ≤7.20). RESULTS: Of the 298 procedures, 249 (84%) had a normal scalp pH result, 199 (67%) had an acceleration in response to FSS and 255 (86%) had an acceleration or normal variability in response to FSS. All 11 of the neonates classified as normal by FSS, but abnormal by FBS were born with normal Apgar scores and cord pH results. The consistency between FSS and FBS was "fair" (kappa 0.28) while the consistency between either test and cord arterial pH was "poor". CONCLUSIONS: This study suggests that FSS has the potential to be a reliable alternative to FBS. The findings require evaluation in a well-designed randomized controlled trial.

Day care versus inpatient management of nausea and vomiting of pregnancy: cost utility analysis of a randomised controlled trial.

OBJECTIVE: To assess the comparative cost effectiveness of day care over inpatient management of nausea and vomiting of pregnancy (NVP). STUDY DESIGN: A cost utility analysis was performed using a decision analytical model in which a Markov model was constructed. The Markov model was primarily populated with data from a recently published randomised controlled trial. Which included pregnant women presenting to Cork University Maternity Hospital, a tertiary referral maternity hospital, seeking treatment for NVP. Costs and outcomes were estimated from the perspective of the Irish health service (HSE) and patients. A probabilistic sensitivity analysis, using a Monte Carlo simulation, was also performed. A Bayesian Value of Information analysis was used to estimate the value of collecting additional information. RESULTS: When both the healthcare provider and patient's perspective was considered, day care management of NVP remained less costly (mean €985; 95% C.I. 705-1456 vs. €3837 (2124-8466)) and more effective (9.42; 4.19-12.25 vs. 9.49; 4.32-12.39 quality adjusted life years) compared with inpatient management. The Cost Effectiveness Acceptability Curve indicates the probability that day care management is 70% more cost effective compared to inpatient management at a ceiling ratio of €45,000 per QALY, indicating little decision uncertainty. The Bayesian Value of Information analysis indicates there is value in collecting further information; the Expected Value of Perfect Information (EVPI) is estimated to be €5.4 million. CONCLUSION: Day care management of NVP is cost effective compared to inpatient management.

Day care compared with inpatient management of nausea and vomiting of pregnancy: a randomized controlled trial.

OBJECTIVE: To examine day care treatment of nausea and vomiting of pregnancy compared with the traditional inpatient management of this condition. METHODS: We conducted an open-label, single-center, randomized controlled trial to examine the differences between day care and inpatient management of pregnant women with nausea and vomiting of pregnancy. Primary outcome was total number of inpatient nights related to nausea and vomiting of pregnancy. RESULTS: Ninety-eight women were randomized to initial day care management (n=42) or inpatient management (n=56). Results are calculated from the time of randomization until resolution of nausea and vomiting of pregnancy. Women randomized to inpatient care experienced a median (interquartile range) of 2 (1-4) inpatient days compared with 0 (0-2) inpatient days for women randomized to day care (P<.001). Women randomized to initial treatment as an inpatient had significantly more median total number of inpatient admissions (one [1-2] compared with zero [0-1] admissions; P<.001) compared with women randomized to day care. No significant differences were observed in day care visits (median [interquartile range] one [1-4] compared with two [1-4]; P=.30). Women randomized to inpatient care were as satisfied with their care as those randomized to day care (median [interquartile range]: 67 [57-69] compared with 63 [58-71] Client Satisfaction Questionnaire score; P=.7). CONCLUSION: Day care treatment of nausea and vomiting of pregnancy reduced hospital inpatient stay and was acceptable to patients. CLINICAL TRIAL REGISTRATION: ISRCTN Register, http://www.isrctn.org, ISRCTN05023126. LEVEL OF EVIDENCE: : I.