Is sentinel lymph node assessment useful in patients with a preoperative diagnosis of endometrial intraepithelial neoplasia?

OBJECTIVE: To determine the prevalence of underlying high-intermediate (high-IM) and high-risk endometrial cancer (EC) in patients with preoperative diagnosis of Endometrial intraepithelial neoplasia (EIN) and to assess the impact of the information retrieved from the sentinel lymph node (SLN) on adjuvant therapy. METHODS: Retrospective cohort study of women undergoing hysterectomy, optional bilateral salpingo-oophorectomy (BSO) and lymph nodes assessment for EIN between December 2007 and August 2021. RESULTS: One hundred and sixty two (162) eligible patients were included, of whom 101 (62.3%) had a final diagnosis of EIN, while 61 (37.7%) were ultimately diagnosed with carcinoma. Out of 15 patients with high-IM to high-risk disease (9.25% of all EIN), 12 had grade 2-3 EC including 8 with >50% myometrial invasion, 2 with serous subtype, 1 with cervical invasion and 2 with pelvic lymph nodes involvement. Of the 3 patients with grade 1 EC, one patient had disease involving the adnexa and 2 patients had tumor invading >50% of the myometrium and with lymphovascular space invasion (LVSI). Ten patients received vaginal brachytherapy after surgery, 3 patients with extrauterine spread were treated with systemic chemotherapy followed by vaginal brachytherapy and pelvic external-beam radiotherapy and 2 patients with early-stage serous carcinoma received chemotherapy followed by vaginal brachytherapy. CONCLUSIONS: Information from SLN, even when negative, can be helpful in the management of patients with EC after preoperative EIN, as some patients are found to have high-IM to high-risk disease on final pathology. These patients would require either re-staging surgery or adjuvant external beam radiotherapy, both could be avoided by proper staging.

Surgical and oncological outcomes of sentinel lymph node sampling in elderly patients with intermediate to high-risk endometrial carcinoma.

OBJECTIVE: We aimed to evaluate the surgical and oncological outcomes of elderly patients with intermediate to high-risk endometrial cancer undergoing staging with sentinel lymph node (SLN) sampling and pelvic lymphadenectomy. METHODS: We conducted a retrospective study of elderly (>65-year-old) patients diagnosed with endometrial cancer between December 2007 and August 2017. These patients had been treated at a single center in Montreal, Canada. We compared the surgical and oncological outcomes of three cohorts undergoing surgical staging in non-overlapping eras: 1) lymphadenectomy, 2) lymphadenectomy and SLN sampling, 3) SLN sampling alone. Using life tables, Kaplan-Meier survival curves and log-rank tests, we analyzed 2-year progression-free survival, overall survival, and disease-specific survival. RESULTS: Our study included 278 patients with a median age of 73 years (range; 65-91): 84 (30.2%) underwent lymphadenectomy, 120 (43.2%) underwent SLN sampling with lymphadenectomy, and 74 (26.6%) had SLN sampling alone. The SLN sampling alone group had shorter operative times with a median duration of 199 minutes (range, 75-393) compared with 231 (range, 125-403) and 229 (range, 151-440) minutes in the SLN sampling with lymphadenectomy and lymphadenectomy cohorts; respectively (p<0.001). The SLN sampling alone group also had lower estimated blood loss with a median loss of 20 mL (range, 5-150) vs 25 mL (range, 5-800) and 40 mL (range, 5-400) in the SLN sampling with lymphadenectomy and lymphadenectomy cohorts, respectively (p=0.002). The 2 year overall survival and progression-free survival were not significantly different between the three groups (p=0.45, p=0.51, respectively). On multivariable analysis after adjusting for age, American Society of Anesthesiologists (ASA) score, stage, grade, and lymphovascular space invasion, adding SLN sampling was associated with better overall survival, (HR 0.2, CI [0.1 to 0.6], p=0.006) and progression-free survival (HR 0.5, CI [0.1 to 1.0], p=0.05). CONCLUSION: Sentinel lymph node-based surgical staging is feasible and associated with better surgical outcomes and comparable oncological outcomes in elderly patients with intermediate and high-risk endometrial cancer.

Association Between Hyperbaric Bupivacaine Dose and Maternal Hypotension: Retrospective Database Study of 8226 Women Undergoing Cesarean Delivery Under Spinal Anesthesia.

BACKGROUND: Low-dose (≤8 mg) hyperbaric bupivacaine for spinal anesthesia during cesarean delivery results in reduced efficacy, yet as a secondary outcome was associated with reduced frequency of spinal-induced hypotension. Our primary aim was to investigate the relationship between hyperbaric bupivacaine dose and the occurrence of spinal-induced hypotension for cesarean delivery. METHODS: Retrospective study of cesarean delivery under spinal or combined spinal anesthesia with hyperbaric bupivacaine in 1 academic institution (2 centers-tertiary and district) from 2012 to 2018. Data were retrieved from the anesthesia information management systems (Metavision, iMDsoft, Tel Aviv, Israel) and the hospital information system, including potential confounding factors, maternal age and weight, hypertensive disease of pregnancy, single/multiple gestation, gestational age, vasopressor administration, planned/urgent surgery, position during anesthesia placement (sitting/lateral), and anesthesiologist seniority. Spinal-induced hypotension was defined as systolic blood pressure that either dropped >20% from baseline or <100 mm Hg. The primary outcome of interest was the incidence of spinal-induced hypotension according to hyperbaric bupivacaine dose. Logistic regression was used to characterize the association between the dose of hyberbaric bupivacaine and spinal-induced hypotension after adjusting for confounding factors. RESULTS: A total of 8226 women were identified. The hyperbaric bupivacaine dose administered was <9 mg for 2395 (29.1%), 9-9.5 mg for 1031 (12.5%), 10 mg for 4155 (50.5%), and >10 mg for 645 (7.8%). We used a cutoff (<10 vs ≥10 mg) to assess for the primary outcome, using multivariable logistic regression. The incidence of at least 1 spinal-induced hypotension episode was higher in patients who received ≥10 mg hyperbaric bupivacaine, 75.8% vs 62.9% for doses below 10 mg, P < .0001; however, even women with lower doses had hypotension. Hyperbaric bupivacaine dose <10 mg was associated with a lower incidence of spinal hypotension, adjusted odds ratio (OR) of 0.774, 95% confidence interval (CI), 0.669-0.897, and P = .0006, adjusted for confounding factors.Umbilical cord pH was available for 2684 (32.6%) cases. There were significantly more neonates with pH < 7.2, among women who received hyperbaric bupivacaine ≥10 mg (10.1%) versus women who received <10 mg (6.8%), P = .0032; however, in the adjusted model, hyperbaric bupivacaine dose ≥10 mg was not associated with pH < 7.2 and an OR of 0.955 (95% CI, 0.631-1.446, P = .829). CONCLUSIONS: Our major finding was that hypotension occurred at all doses of hyperbaric bupivacaine, yet occurrence of spinal hypotension was significantly associated with doses ≥10 mg after adjustment for potential confounders.

The effect of spinal hypotension and anesthesia-to-delivery time interval on neonatal outcomes in planned cesarean delivery.

BACKGROUND: Maternal hypotension after spinal anesthesia, and time from anesthesia to delivery, are potentially modifiable risk factors for neonatal acidosis. OBJECTIVE: This study aimed to examine the relationship between the time from spinal anesthesia to delivery and spinal hypotension in planned cesarean deliveries and their effect on neonatal outcome, primarily neonatal acidosis. STUDY DESIGN: We performed a retrospective analysis of women with singleton pregnancy undergoing spinal anesthesia for planned cesarean delivery between 37 0/7 and 41 6/7 weeks' gestation using electronic medical records. The occurrence of spinal hypotension and anesthesia-to-incision and incision-to-delivery intervals (minutes) were the primarily studied variables. In addition, spinal hypotension index was developed to account for the duration and magnitude of maternal hypotension. The 90th percentile for the spinal hypotension index defined the sustained spinal hypotension group. The primary outcome was neonatal acidosis (pH of ≤7.1 or base deficit of ≥12.0). The odds ratios were calculated using univariate and multivariate logistic regression models. The multivariate analysis included sporadic spinal hypotension or sustained spinal hypotension, use of vasopressor treatment, and anesthesia-to-incision and incision-to-delivery intervals. RESULTS: We included 3150 women in the study. Notably, 43.4% experienced at least 1 event of spinal hypotension (sporadic) and 14.8% experienced sustained spinal hypotension. Neonatal acidosis occurred in 3.4% cases of sporadic spinal hypotension (odds ratio, 1.83; 95% confidence interval, 2.27-2.87) and in 5.8% cases of sustained hypotension (odds ratio, 3.00; 95% confidence interval, 1.87-4.80). Both anesthesia-to-incision and incision-to-delivery intervals were significantly associated with neonatal acidosis as follows: at 90th percentile cutoff, the odds ratios for neonatal acidosis were 3.82 (95% confidence interval, 2.03-7.19) and 2.94 (95% confidence interval, 1.70-5.10), respectively. The use of ephedrine (odds ratio, 2.42; 95% confidence interval, 1.35-4.32) but not phenylephrine (odds ratio, 0.76; 95% confidence interval, 0.34-1.72) treatment was also associated with more cases of neonatal acidosis. The woman's age, gestational age, neonatal birthweight, fetal presentation, and the number of previous cesarean deliveries were not associated with neonatal acidosis. In multivariate analysis, anesthesia-to-incision and incision-to-delivery intervals, use of vasopressor treatment, and sustained spinal hypotension were independently associated with neonatal acidosis. After adjustment, the risk for neonatal acidosis did not increase in women who experienced sporadic spinal hypotension only. Neither neonatal acidosis nor the primary research variables were associated with neonatal complications such as transient tachypnea of the newborn, respiratory distress, or admission to the neonatal unit. CONCLUSION: Neonatal acidosis in planned cesarean delivery was common. However, serious perinatal consequences were rare. The adverse effects of sustained spinal hypotension and prolonged anesthesia-to-incision and incision-to-delivery intervals on neonatal acid-base balance were additive. This supports the adoption of prevention strategies for spinal hypotension, which is widely evidenced based on the obstetrical anesthesia literature, but still not universally used. Whether the reduction in intraoperative time intervals would benefit the neonate should be determined by future prospective studies.

Receptor for advanced glycation endproducts (RAGE) is a key regulator of oval cell activation and inflammation-associated liver carcinogenesis in mice.

UNLABELLED: The receptor for advanced glycation endproducts (RAGE) is a multiligand receptor and member of the immunoglobulin superfamily. RAGE is mainly involved in tissue damage and chronic inflammatory disorders, sustaining the inflammatory response upon engagement with damage-associated molecular pattern molecules (DAMPs) such as S100 proteins and high-mobility group box 1 (HMGB1). Enhanced expression of RAGE and its ligands has been demonstrated in distinct tumors and several studies support its crucial role in tumor progression and metastasis by still unknown mechanisms. Here we show that RAGE supports hepatocellular carcinoma (HCC) formation in the Mdr2(-/-) mouse model, a prototype model of inflammation-driven HCC formation, which mimics the human pathology. Mdr2(-/-) Rage(-/-) (dKO) mice developed smaller and fewer HCCs than Mdr2(-/-) mice. Interestingly, although in preneoplastic Mdr2(-/-) livers RAGE ablation did not affect the onset of inflammation, premalignant dKO livers showed reduced liver damage and fibrosis, in association with decreased oval cell activation. Oval cells expressed high RAGE levels and displayed reduced proliferation upon RAGE silencing. Moreover, stimulation of oval cells with HMGB1 promoted an ERK1/2-Cyclin D1-dependent oval cell proliferation in vitro. Finally, genetic and pharmacologic blockade of RAGE signaling impaired oval cell activation in an independent mouse model of oval cell activation, the choline deficient ethionine-supplemented dietary regime. CONCLUSION: Our data identified a novel function of RAGE in regulating oval cell activation and tumor development in inflammation-associated liver carcinogenesis.

Surgery Advances in Gynecologic Tumors: The Evolution and Outcomes of Robotic Surgery for Gynecologic Cancers in a Tertiary Center.

The integration of innovation into routine clinical practice is faced with many challenges. In 2007, we received the mandate to evaluate how the introduction of a robotic program in gynecologic oncology affected patient-centered care by studying its impact on clinical outcomes and hospital resource utilization. Here we summarize the history and experience of developing a robotic surgery program for gynecologic cancers over 16 years. Analysis of the data indicates that robotic surgery improved perioperative patient clinical parameters, decreased blood loss, complications, and hospital stay, maintained the oncologic outcome, and is cost-effective, resulting in it becoming the dominant surgical approach in gynecologic oncology in a tertiary cancer care institution.

The continuum of a prolonged labor and a second stage cesarean delivery.

OBJECTIVE: To investigate the association of the timing of primary cesarean delivery with the progress of labor and the operative delivery rate at the subsequent successful trial of labor. METHODS: A retrospective study of women with a primary cesarean and subsequent term cephalic vaginal delivery in two medical centers. Cesarean deliveries were classified as planned, intrapartum first stage or intrapartum second stage. The second stage duration and the operative delivery rate, adjusted to epidural analgesia and oxytocin use, were compared between the groups. χ2 and Kruskal-Wallis tests were used for analysis of categorical and continuous variables, respectively. RESULTS: The study population included 1166 women. The second stage of labor was longer when the previous cesarean delivery occurred during the second stage compared to planned or first stage (1.7 h vs 1.3 h vs 1.3 h, p = 0.005). The proportion of operative deliveries was greater among women with previous cesarean in the second stage of labor (39.6%), compared to planned (26.9%) or first stage (28.8%), p = 0.006. CONCLUSION: Cesarean delivery at the second stage of labor is associated with a longer second stage and an increased operative delivery rate at the subsequent vaginal birth. Our findings attest to the delicate passenger-passage relations that can exist in some parent-couples.

Adult hepatocytes are generated by self-duplication rather than stem cell differentiation.

The liver is thought to utilize facultative stem cells, also known as "oval cells" or "atypical ductal cells" (ADCs), for regeneration following various types of injury. However, this notion has been based largely on in vitro studies and transplantation models; where lineage tracing has been used, results have been conflicting and effect sizes have been small. Here, we used genetic and nucleoside analog-based tools to mark and track the origin and contribution of various cell populations to liver regeneration in vivo following several ADC-inducing insults. We report that, contrary to prevailing stem-cell-based models of regeneration, virtually all new hepatocytes come from preexisting hepatocytes.