Increased incidence of childhood lymphoma in children with a history of small for gestational age at birth.

OBJECTIVE: The aim of this study was to evaluate whether children that were born small for gestational age (SGA) have an increased risk for childhood neoplasm. STUDY DESIGN: A population-based cohort analysis comparing the risk for long-term childhood neoplasms (benign and malignant) in children that were born SGA vs. those that were appropriate for gestational age (AGA), between the years1991-2014. Childhood neoplasms were predefined based on ICD-9 codes, as recorded in the hospital medical files. Kaplan-Meier survival curves were constructed to compare cumulative oncological morbidity in both groups over time. Cox proportional hazards model was used to control for confounders. RESULTS: During the study period 231,973 infants met the inclusion criteria; out of those 10,998 were born with a diagnosis of SGA. Children that were SGA at birth had higher incidence of lymphoma (OR 2.50, 95% CI 1.06-5.82; p value = 0.036). In addition, cumulative incidence over time of total childhood lymphoma was significantly higher in SGA children (Log Rank = 0.030). In a Cox regression model controlling for other perinatal confounders; SGA at birth remained independently associated with an increased risk for childhood lymphoma (adjusted HR 2.41, 95% CI 1.03-5.56, p value = 0.043). CONCLUSION: Being delivered SGA is associated with an increased long-term risk for childhood malignancy and specifically lymphoma.

Multiple lines of chemotherapy for patients with high-grade ovarian cancer: Predictors for response and effect on survival.

Guidelines for the treatment of tubo-ovarian cancer patients beyond third line are lacking. We aimed to evaluate the effect of response in each line on patient's outcome as well as identify variables that predict response for additional line of chemotherapy. A cohort study was performed including all patients with advanced high-grade ovarian cancer. Survival analysis was performed using Kaplan-Meier curves and log-rank tests. Odds ratios and hazard ratios were calculated using multilevel, mixed-effects logistic regression and Cox regression, adjusting for repeated measures within individual patients. Two-hundred thirty-eight patients were included and underwent up to 10 lines of chemotherapy. The median progression-free survival was 15.6 and overall survival (OS) was 55.6 months. Response rates dropped with each additional line and by line 5, most patients (61%) became refractory and only 16% had any type of response (complete 4% or partial 12%). By line 2, whether a patient had partial disease (PR), stable disease (SD) or progressive disease (PD) did not have an effect on the OS. From line 2, whether a patient had PR, SD or PD did not have an effect on chemotherapy-free interval. Number of previous lines and time from previous line were the only variables that significantly correlated with both outcome of patients and response to the next line. In conclusion, time interval from the previous line of chemotherapy is the major clinical factor that predicts beneficial effect of another line of treatment in patients with ovarian cancer.

Carboplatin plus paclitaxel weekly dose-dense chemotherapy for high-grade ovarian cancer: A re-evaluation.

INTRODUCTION: We compared oncologic and clinical outcomes in patients with advanced ovarian cancer who received dose-dense weekly paclitaxel with 3-weekly carboplatin with those who received standard 3-weekly chemotherapy. MATERIAL AND METHODS: Comparison of all consecutive patients with advanced (International Federation of Gynecology and Obstetrics stages III-IV) ovarian cancer who received a dose-dense protocol between 2010 and 2016 with an immediate historical cohort of consecutive patients who received standard chemotherapy. Patients who received less than three cycles of treatment were excluded. RESULTS: In all, 246 patients were included in the study, of whom 128 received the dose-dense protocol and 118 were treated with the standard Q3-week protocol. Patients in the dose-dense group had significantly better progression-free survival than those receiving the standard protocol (median progression-free survival 22 vs 15 months; log rank = 0.026). The overall survival of patients in the dose-dense group was also better than that of the patients in the standard protocol group; however, this difference was not statistically significant (median overall survival 66 vs 54 months; log rank = 0.185). The dose-dense protocol remained significantly associated with favorable survival outcome in multivariable analysis adjusted for stage, histologic type, cytoreductive results and neoadjuvant chemotherapy. The use of the dose-dense protocol was associated with higher rates of gastrointestinal, dermatologic, neurologic and hematologic side effects. CONCLUSION: Despite the limitations associated with the comparison to a historical cohort, a dose-dense chemotherapy protocol resulted in a significantly improved progression-free survival and the overall survival tended to be better, but this difference did not reach statistical significance compared with the standard chemotherapy protocol, and may be considered as a treatment alternative, albeit with some increased side effects.

Condensation: A Retrospective Cohort Study to Investigate the Association Between Maternal Pre-pregnancy Obesity and Childhood Respiratory Disease.

OBJECTIVE: We sought to explore whether maternal pre-pregnancy obesity is an independent risk factor for offspring respiratory morbidity during childhood. METHODS: A population-based retrospective cohort analysis comparing childhood respiratory morbidity incidence in offspring to mothers with pre-pregnancy obesity (BMI ≥ 30 kg/m2) and those who had lower BMI was conducted. Respiratory diagnoses were pre-defined based on ICD-9 codes. The study population comprises of all deliveries that took place at the Soroka University Medical Center (SUMC), the sole tertiary hospital in the Negev (Southern Israel), between the years 1991-2014. A Kaplan-Meier survival curve was used for cumulative respiratory morbidity incidences over time and a Cox proportional hazards model was constructed to control for confounders. RESULTS: During the study period, 242,342 infants met the inclusion criteria; out of which 3290 were born to mothers with a diagnosis of pre-pregnancy obesity. Offspring to mothers with pre-pregnancy obesity had a significant higher risk for obstructive sleep apnea (OR 1.43, 95% CI 1.002-2.046) as well as a higher total risk for hospitalizations due to childhood respiratory morbidity (OR 1.21, 95% CI 1.041-1.398). The cumulative respiratory morbidity incidence over time was significantly higher in the maternal pre-pregnancy obesity group (p = 0.044). Controlling for maternal age, gestational diabetes mellitus, hypertensive disorders and gestational age, pre-pregnancy obesity remained an independent risk factor for offspring respiratory morbidity (adjusted HR = 1.175, 95% CI 1.018-1.357). CONCLUSION: Maternal pre-pregnancy obesity may create an environment leading to an increased risk for long-term offspring respiratory morbidity, and specifically obstructive sleep apnea.

Maternal Smoking during Pregnancy and the Risk for Childhood Infectious Diseases in the Offspring: A Population-Based Cohort Study.

OBJECTIVE: Infectious diseases account for up to 43% of childhood hospitalizations. Given the magnitude of infection-related hospitalizations, we aimed to evaluate the effect of maternal smoking during pregnancy on the risk for long-term childhood infectious morbidity. STUDY DESIGN: This is a population-based cohort analysis comparing the long-term risk for infectious diseases, in children born to mothers who smoked during pregnancy versus those who did not. Infectious diseases were predefined based on International Classification of Diseases, Ninth Revision codes. Deliveries occurred between the years 1991 and 2014. RESULTS: A total of 246,854 newborns met the inclusion criteria; 2,986 (1.2%) were born to mothers who smoked during pregnancy. Offspring of smokers had significantly higher risk for several infectious diseases during childhood (upper respiratory tract, otitis, viral infections, and bronchitis) as well as increased risk for total infection-related hospitalizations (odds ratio = 1.5, 95% confidence interval [CI]: 1.3-1.7; p = 0.001). Cumulative incidence of infection-related hospitalizations was significantly higher in offspring of smokers (log-rank test, p = 0.001). Controlling for maternal age, diabetes, hypertensive disorders, and gestational age at index delivery, smoking remained an independent risk factor for infectious diseases during childhood (adjusted hazard ratio = 1.5, 95% CI: 1.3-1.6; p = 0.001). CONCLUSION: Intrauterine exposure to maternal smoking may create an environment leading to an increased future risk for long-term pediatric infectious morbidity of the offspring.

Pre-pregnancy obesity and childhood malignancies: A population-based cohort study.

OBJECTIVE: Exploring the effect of maternal obesity during pregnancy on the long-term health of offspring is of great importance. The aim of this study was to evaluate the association between maternal pre-pregnancy obesity and future risk of childhood malignancies. STUDY DESIGN: A population-based cohort analysis comparing the risk for long-term childhood malignancies (up to the age of 18 years) in children born (1991-2014) to mothers with and without pre-pregnancy obesity (body mass index > 30) was conducted in July 2017. Childhood malignancies were predefined based on ICD-9 codes, as recorded in the hospital medical files. Children with congenital malformations and multiple gestations were excluded from the analysis. The Kaplan-Meier survival curve was constructed to compare cumulative oncological morbidity in both groups over time. The Cox proportional hazards model was used to control for confounders. RESULTS: During the study period, 241 273 infants met the inclusion criteria; 3268 were born to mothers with pre-pregnancy obesity. Children of obese women had significantly increased risk for several childhood malignancies (including brain tumors) as well as increased risk for total hospitalizations with malignancy diagnoses, even after controlling for several confounders (adjusted HR 1.90, 95% CI 1.07-3.37, P = 0.028). Cumulative incidence of oncological morbidity was also significantly increased over time in the studied group (log-rank P = 0.023). CONCLUSION: Maternal pre-pregnancy obesity is significantly associated with an increased long-term risk for general childhood malignancies, and specifically brain tumors in the offspring. These results are important when counseling mothers regarding potential future risks and recommended lifestyle modifications.

CA-125 reduction during neoadjuvant chemotherapy is associated with success of cytoreductive surgery and outcome of patients with advanced high-grade ovarian cancer.

INTRODUCTION: The objective was to assess whether an early response to neoadjuvant chemotherapy in women with advanced ovarian cancer may predict short- and long-term clinical outcome. MATERIAL AND METHODS: This is a retrospective study of all women with stage III-IV tubo-ovarian cancer treated with neoadjuvant chemotherapy at a single center in Montreal between 2003 and 2014. Logistic regression models were used to evaluate the association between cancer antigen 125 (CA-125) levels during neoadjuvant chemotherapy and debulking success. Cox proportional hazard models were used to estimate hazard ratios and their respective 95% CI for death and recurrence. Harrell's concordance indices were calculated to evaluate which variables best predicted the chemotherapy-free interval and overall survival in our population. RESULTS: In all, 105 women were included. Following the first, second, and third cycles of neoadjuvant chemotherapy, CA-125 levels had a median reduction of 43.2%, 85.4%, and 92.9%, respectively, compared with CA-125 levels at diagnosis. As early as the second cycle, CA-125 was associated with overall survival (hazard ratio 1.03, 95% CI 1.01-1.05, per 50 U/mL increment). By the third cycle, CA-125 did not only predict overall survival (hazard ratio 1.04, 95% CI 1.01-1.08), but it predicted overall survival better than the success of debulking surgery (Harrell's concordance index 0.646 vs 0.616). Both absolute CA-125 levels and relative reduction in CA-125 levels after 2 and 3 cycles predicted the chance to achieve complete debulking (P < .05). CONCLUSIONS: Reduction of CA-125 levels during neoadjuvant chemotherapy provides an early predictive tool that strongly correlates with successful cytoreductive surgery and long-term clinical outcome in women with advanced high-grade serous and endometrioid ovarian cancer.

Similar Overall Survival Using Neoadjuvant Chemotherapy or Primary Debulking Surgery in Patients Aged Over 75 Years with High-Grade Ovarian Cancer.

OBJECTIVE: To perform a hypothesis-generating evaluation of patient outcomes following neoadjuvant chemotherapy (NACT) compared with those following primary debulking surgery (PDS) in patients over age 75 with high-grade ovarian cancer. METHODS: This was a retrospective cohort study of consecutive patients aged 75 years and older, with high-grade ovarian cancer. Data were analyzed in SPSS 25.0 using descriptive statistics to characterize groups based on primary treatment modality, Kaplan-Meier survival curves to estimate overall and progression-free survival, and Cox proportional hazards to analyze confounders. RESULTS: Of 429 patients with stages III and IV high-grade ovarian cancer (endometrioid and serous), 71 were aged older than 75 years and met our criteria for inclusion; 58 were treated with NACT while 13 underwent primary debulking. Sixteen patients did not undergo interval debulking following NACT. There were no significant differences in demographic characteristics between the groups. Following NACT, more patients were completely debulked-36.2% versus 21% (P = 0.000)-and had a shorter length of stay (5 vs. 7 d; P = 0.018). Overall survival was similar between the NACT and PDS groups (58.7 vs. 59.7 mo; LR -0.836; P = 0.361) despite lower progression-free survival in the NACT group (25.9 vs. 47.1 mo; P = 0.042; LR 4.31). Both progression-free and overall survival were significantly higher when patients undergoing NACT achieved complete debulking (21.7 and 102.3 mo, respectively) compared with suboptimal debulking (12.03 and 14.2 mo, respectively). CONCLUSION: In this select group older patients with stage III and IV high-grade ovarian cancers, neoadjuvant chemotherapy may be considered without compromising outcomes and contributes to complete debulking.

Tubal ligation during cesarean delivery and future risk for ovarian cancer: a population-based cohort study.

OBJECTIVE: Data regarding the effect of post-partum bilateral tubal ligation (BTL) on future risk for ovarian cancer (OC) is lacking. In the current study, we aimed to evaluate the effect of BTL during cesarean delivery (CD) on the long-term risk for OC. STUDY DESIGN: A population-based cohort analysis of women above the age of 35 that underwent CD in their last delivery, comparing the long-term risk for OC between patients that had a Pomeroy excisional BTL and those that did not. OC diagnosis was pre-defined based on ICD-9 codes. Procedures occurred between the years 1991-2017. Kaplan-Meier survival curve was used to compare the cumulative incidence of OC over time and Cox proportional hazards model was constructed to control for confounders. RESULTS: During the study period 13,124 women met the inclusion criteria; 9438 (71.9%) of which had only CD and 3686 (28.1%) underwent CD with BTL. Despite the significantly higher incidence of maternal factors that might increase the long-term risk for OC in the BTL group (advanced maternal age, obesity, hypertensive diseases during pregnancy and diabetes mellitus), the cumulative incidence of OC cases was not significantly different between the two groups (Log-rank test p = 0.199). Likewise, when performing a Cox regression model controlling for maternal age, obesity, hypertensive diseases and diabetes, OC risk was not significantly different between the groups (adjusted HR 2.36, 95% CI 0.73-7.62; p = 0.149). CONCLUSION: Despite an increased incidence of known risk factors for OC, patients that underwent BTL during CD did not have increased long-term risk for OC.

Sequential therapeutic targeting of ovarian Cancer harboring dysfunctional BRCA1.

BACKGROUND: Poly (ADP-ribose) polymerase inhibitors (PARPi) have become the first targeted therapies available in the treatment of patients with high-grade serous ovarian cancer (HGSOC). We recently described a significant reduction in PARP1 protein levels in vitro and in vivo in patients treated with standard carboplatinum-paclitaxel chemotherapy, raising the question whether the sequence of treatment used today with chemotherapy followed by PARPi is optimal. In this study, we aim to evaluate if the sequence of PARPi followed by chemotherapy could be more beneficial. METHODS: BRCA1-mutated (UWB1.287, SNU-251), epigenetically-silenced (OVCAR8), and wild-type (SKOV3, A2780PAR & A2780CR) ovarian cancer cell lines were exposed to clinically relevant doses of PARPi followed by different doses of standard chemotherapy and compared to the inverse treatment. The therapeutic efficacy was assessed using colony formation assays. Flow cytometry was used to evaluate cell apoptosis rate and the changes in cell cycle. Finally, apoptotic and cell cycle protein expression was immunodetected using western blot. RESULTS: Exposure to PARPi prior to standard chemotherapy sensitized BRCA1-mutated or epigenetically-silenced BRCA1 cell lines to lower doses of chemotherapy. Similar results were observed in BRCA1 wild-type and cell lines in which BRCA1 functionality was restored. Moreover, this treatment increased the apoptotic rate in these cell lines. CONCLUSION: Pre-treatment with PARPi followed by standard chemotherapy in vitro is more efficient in growth inhibition and induction of apoptosis compared to the administration of standard chemotherapy followed by PARPi.

Risk factors for lymph nodes involvement in obese women with endometrial carcinomas.

OBJECTIVE: To assess risk factors for lymph node involvement in patients with endometrial cancer and a body-mass index (BMI) ≥30 kg/m2. MATERIALS AND METHODS: A retrospective analysis was performed of obese patients diagnosed with endometrial carcinoma between 2007 and 2015, treated in a single center in Montreal. Preoperative variables evaluated were age, BMI, parity, and preoperative ASA score, grade, CA-125 and histology. Odds ratios (OR) and hazard ratios (HR) and their respective 95% confidence intervals (95%CI) were calculated using multivariable logistic regression and Cox proportional hazard models. RESULTS: The study included 230 women with BMI ≥30, 223 (97.0%) had complete staging. Pelvic lymph node involvement was detected in 26 patients (11.3%). Sentinel node detection and pelvic lymph node dissection decreased with increasing BMI (adjusted OR 0.86, 95%CI 0.76-0.97 and 0.76, 95%CI 0.59-0.96, respectively, per 1 kg/m2 increment). Pelvic lymph node involvement was inversely correlated with BMI (adjusted OR 0.88, 95%CI 0.79-0.99) and present in 16/85 (18.8%), 6/56 (10.7%), and 4/82 (4.9%) of patients with a BMI of 30.0-34.9, 35.0-39.9, and ≥40.0 kg/m2, respectively. Preoperative CA-125 was associated with lymph node involvement (adjusted OR 2.77, 95%CI 1.62-4.73, per quartile increment). CONCLUSION: Pelvic lymph node dissection might be omitted in selected cases of morbidly obese patients with failed sentinel nodes mapping and a low CA-125.

Triple tracer (blue dye, indocyanine green, and Tc99) compared to double tracer (indocyanine green and Tc99) for sentinel lymph node detection in endometrial cancer: a prospective study with random assignment.

OBJECTIVE: Sentinel lymph node (SLN) mapping is increasingly being used in the treatment of apparent early-stage endometrial cancer. The aim of this study was to evaluate whether three tracers (blue dye, indocyanine green (ICG), and technetium-99 (Tc99)) performed better than two (ICG and Tc99). STUDY DESIGN: Prospective study of all consecutive patients (n=163) diagnosed with clinical early-stage endometrial cancer from 2015 to 2017. All patients were randomly assigned to receive a mixture of ICG and Tc99 with or without blue dye. Subgroup analysis for detection rates was performed for each group (double versus triple tracer). RESULTS: One hundred and fifty-seven patients met the inclusion criteria. Eighty patients received ICG and Tc99 with unilateral and bilateral SLN detection rates of 97.5% and 81.3%, respectively. Seventy-seven patients received all three tracers with unilateral and bilateral detection rates of 93.5% and 80.5%, respectively. Only one patient in the triple tracer group was detected by blue dye alone. No significant differences were noticed in unilateral or bilateral detection rates between the two groups, nor in the detection of lymph node metastasis. CONCLUSION: The addition of blue dye to ICG and Tc99 did not demonstrate any improvement in SLN detection.

Incorporating robotic surgery into the management of ovarian cancer after neoadjuvant chemotherapy.

INTRODUCTION: With the rapid uptake of robotic surgery in surgical oncology, its use in the treatment of epithelial ovarian cancers is being evaluated. Complete cytoreduction represents the goal of surgery either at primary cytoreduction or after neoadjuvant chemotherapy in the setting of interval cytoreduction. In selected patients, the extent of disease would enable minimally invasive surgery. The objective of this study was to evaluate the impact of introducing robotic surgery for interval cytoreduction of selected patients with stage III-IV ovarian cancer. METHODS: All patients who underwent surgery from November 2008 to 2014 (concurrent time period when robotic and open surgery were used simultaneously) after receiving neoadjuvant chemotherapy for advanced ovarian cancer (stage III-IV) were compared with all consecutive patients who underwent cytoreductive surgery by laparotomy after neoadjuvant chemotherapy between January 2006 and November 2008. Inclusion criteria included an interval cytoreductive surgery by laparotomy or robotic assistance for stage III-IV non-mucinous epithelial ovarian, fallopian tube, or primary peritoneal cancer. Exclusion criteria included patients treated concurrently for a non-gynecologic cancer, as well as secondary cytoreductive surgeries and diagnostic surgeries without an attempt at tumor reduction. Overall survival, progression-free survival, and peri-operative outcomes were compared for the entire patient cohort with those with advanced ovarian cancer who received neoadjuvant chemotherapy immediately before and after the introduction of robotic surgery. RESULTS: A total of 91 patients were selected to undergo interval cytoreduction either via robotic surgery (n=57) or laparotomy (n=34) after the administration of neoadjuvant chemotherapy. The median age of the cohort was 65 years (range 24-88), 78% had stage III disease, and the median follow-up time was 37 months (5.6-91.4 months). The median survival was 42.8±3.1 months in the period where both robotic surgery and laparotomy were offered compared with 37.9±9.8 months in the time period preceding when only laparotomy was performed (p=0.6). All patients selected to undergo interval robotic cytoreduction following neoadjuvant chemotherapy had a reduction of cancer antigen 125 by at least 80%, resolution of ascites, and CT findings suggesting the potential to achieve optimal interval cytoreduction. All these patients achieved optimal cytoreduction with <1 cm residual disease, including 82% with no residual disease. The median blood loss was 100 mL (mean 135 mL, range 10-1250 mL), and the median hospital stay was 1 day. CONCLUSION: Robotic interval cytoreductive surgery is feasible in well-selected patients. Future studies should aim to define ideal patients for minimally invasive cytoreductive surgery.

Oncologic and Surgical Outcomes of Robotic Versus Open Radical Hysterectomy for Cervical Cancer.

OBJECTIVE: In view of the recent controversy concerning the use of minimally invasive radical hysterectomy as primary treatment for early stage cervical cancer, this study compared the survival and perioperative outcomes in a cohort of patients who underwent radical hysterectomy either by laparotomy or by robotics. METHODS: This retrospective study compared all consecutive patients with early stage cervical cancer since the beginning of the Division of Gynecologic Oncology at the Jewish General Hospital in 2003, who underwent robotic radical hysterectomy (n = 74) with a cohort of all consecutive patients from the immediate past who underwent open radical hysterectomy (n = 24) for early stage cervical cancer. All patients were treated at the Jewish General Hospital in Montréal (Canadian Task Force Classification II-2). RESULTS: The median follow-up time for the robotic group was 46 months. During that time, 7% and 17% of patients in the robotic group and the laparotomy group had disease recurrence, respectively (P = 0.12). Cox multivariate regression showed no statistically significant effect of surgical approach on overall survival (hazard ratio 1.50, P = 0.63) or on progression-free survival (hazard ratio 0.29, P = 0.07). Patients in the robotic cohort had significantly shorter median hospital stays (1 day vs. 7 days, P < 0.001), and their overall incidence of postoperative complications was lower (13% vs. 50%, P < 0.001). Median estimated blood loss for robotics was also significantly lower (82 mL vs. 528 mL, P < 0.001). CONCLUSION: Based on the data on a limited number of patients in a Canadian context, robotic radical hysterectomy did not lead to worse oncologic outcomes and was associated with improved short-term surgical outcomes. One might consider the evaluation of more personalized surgical decision making.

Distinct homologous recombination gene expression profiles after neoadjuvant chemotherapy associated with clinical outcome in patients with ovarian cancer.

OBJECTIVE: The expression of homologous recombination (HR) genes in high grade ovarian cancer (HGOC) samples from debulking surgeries were correlated to outcomes in patients selected for chemotherapy treatment regimens. STUDY DESIGN: RNA was extracted from 96 fresh frozen tumor samples from debulking surgeries from chemotherapy naïve patients with HGOC (primary derived surgeries (PDS), n = 55) or following neoadjuvant chemotherapy treatment (NACT), n = 41). The samples were selected for high tumor content by a gynecological pathologist, and cancer cell content was further confirmed using a percent tumor content covariate, and mutation score covariate analysis. Gene expression analysis was performed using a tailored NanoString-based Pancancer Pathway Panel. Cox proportional hazard regression models were used to assess the associations between the expression of 19 HR genes and survival. RESULTS: In the PDS group, over-expression of six HR genes (C11orf30, NBN, FANCF, FANCC, FANCB, RAD50) was associated with improved outcome, in contrast to the NACT group where four HR genes (BRCA2, TP53, FANCB, RAD51) were associated with worse outcome. With the adding extent of debulking as a covariate, three HR genes (NBN, FANCF, RAD50), and only one HR gene (RAD51) remained significantly associated with survival in PDS and NACT groups, respectively. CONCLUSION: Distinct HR expression profiles define subgroups associated with overall outcome in patients that are exposed to neoadjuvant chemotherapy and not only chemotherapy-naïve patients.

Risk of Thromboembolic Disease With Cost Estimates in Patients Undergoing Robotic Assisted Surgery for Endometrial Cancer and Review of the Literature.

OBJECTIVE: This study sought to evaluate the incidence, risk factors, and estimated cost associated with venous thromboembolism (VTE) following robotic surgery for endometrial cancer. METHODS: The study included all consecutive patients with newly diagnosed endometrial cancer who underwent robotic surgery, excluding patients with a previous history of VTE (3%), those taking long-term warfarin (3%), and patients with conversions to laparotomy (3%). The incidence of postoperative symptomatic VTE within 90 days was analyzed. Direct and indirect medical costs were estimated using a linked billing database for standardized, inflation-adjusted costs. RESULTS: A total of 558 cases were identified. Median BMI was 29 kg/m2 (range, 17-85 kg/m2), median operative time was 227 minutes (range, 75-419 minutes), and median blood loss was 30 mL (range, 3-400 mL). All patients received thromboprophylaxis with intraoperative subcutaneous heparin and sequential pneumatic compression devices. Extended postoperative prophylaxis for 28 days was administered to 88 (17.2%) patients with high-risk factors. A total of eight patients (1.6%) developed symptomatic VTE, and all eight were in the group that did not receive extended prophylaxis. The number needed to treat to prevent one VTE was 52.8, with an absolute risk reduction 1.89% (95% CI 0.59% to 3.19%). The average cost for treatment of a VTE was $7653 (range, $4396-$12 211), equivalent to the cost of treating 21 patients with extended prophylaxis ($356 per patient). CONCLUSION: The incidence of VTE in patients with endometrial cancer who underwent robotic-assisted surgery was low (1.6%), and none of the VTEs occurred in the cohort of high-risk patients who received extended thromboprophylaxis.

Recurrent pregnancy loss and future risk of female malignancies.

PURPOSE: To investigate whether patients with a history of recurrent pregnancy loss (RPL) have an increased risk for future female malignancies. METHODS: A retrospective population-based study compared the incidence of long-term female malignancies in a cohort of women with and without a history of RPL (2 or more consecutive pregnancy losses). Deliveries occurred between the years 1988 and 2013, with a mean follow-up duration of 12 years. Women with known malignancies before the index pregnancy were excluded from the analysis. Female malignancies were divided according to specific type including ovary, breast, uterine and uterine cervix. Kaplan-Meier survival curve was used to estimate the cumulative incidence of malignancies. Cox proportional hazards model was used to determine the adjusted hazard ratios (HR) for female malignancy after controlling for confounders. RESULTS: During the study period, 106,265 patients met the inclusion criteria; 6.6% (n = 7052) of patients had a diagnosis of RPL. During the follow-up period, patients with RPL had a significantly increased risk of being diagnosed with female malignancies as a group, while individually there was an increased risk of breast and uterine cervix cancer. Using a Kaplan-Meier survival curve, patients with a history of RPL had a significantly higher cumulative incidence of female malignancies. Using a Cox proportional hazards model, adjusted for confounders such as smoking, parity, and diabetes mellitus, a history of RPL remained independently associated with female malignancies (adjusted HR 1.4; P = 0.003). CONCLUSIONS: RPL is independently associated with long-term female malignancies. Patients with a history of RPL may benefit from counseling and screening for breast and uterine cervix cancer in particular.

Inhibition of PI3K-AKT-mTOR pathway sensitizes endometrial cancer cell lines to PARP inhibitors.

BACKGROUND: Phosphatase and Tensin homolog (PTEN) is a tumor suppressor gene. Loss of its function is the most frequent genetic alteration in endometrioid endometrial cancers (70-80%) and high grade tumors (90%). We assessed the sensitivity of endometrial cancer cell lines to PARP inhibitors (olaparib and BMN-673) and a PI3K inhibitor (BKM-120), alone or in combination, in the context of their PTEN mutation status. We also highlighted a direct pathway linking PTEN to DNA repair. METHODS: Using endometrial cancer cellular models with known PTEN status, we evaluated their homologous recombination (HR) functionality by RAD51 foci formation assay. The 50% Inhibitory concentration (IC50) of PI3K and PARP inhibitors in these cells was assessed, and western blotting was performed to determine the expression of proteins involved in the PI3K/mTOR pathway. Moreover, we explored the interaction between RAD51 and PI3K/mTOR by immunofluorescence. Next, the combination effect of PI3K and PARP inhibitors on cell proliferation was evaluated by a clonogenic assay. RESULTS: Cells with mutated PTEN showed over-activation of the PI3K/mTOR pathway. These cells were more sensitive to PARP inhibition compared to PTEN wild-type cells. In addition, PI3K inhibitor treatment reduced RAD51 foci formation in PTEN mutated cells, and sensitized these cells to PARP inhibitor. CONCLUSION: Targeting both PARP and PI3K might lead to improved personalized therapeutic approaches in endometrial cancer patients with PTEN mutations. Understanding the complex interaction of PTEN mutations with DNA repair in endometrial cancer will help to better select patients that are likely to respond to some of the new and costly targeted therapies.

Clinical outcome of neoadjuvant chemotherapy for advanced ovarian cancer.

OBJECTIVE: To evaluate clinical outcome in patients selected to receive neoadjuvant chemotherapy (NACT) compared to primary debulking surgery (PDS). METHODS: Retrospective study including all consecutive patients diagnosed and treated for advanced (stages III-IV) ovarian cancers between the years 2003-2015. RESULTS: 263 women were included in the study, of these, 127 patients were selected to receive NACT and 136 were treated with PDS followed by adjuvant chemotherapy. PDS was associated with longer OS in stage IIIc disease (median OS: 60.2 vs. 48.8months; p-value 0.039) compared with NACT. Patients achieved higher rates of complete cytoreduction in the NACT group compared to the PDS group (65.9% vs. 40.2%; p=0.001). Patients attaining complete cytoreduction after PDS had the best survival, (median OS 106months) followed by those with complete cytoreduction after NACT (median OS 71months), followed by those with residual disease after PDS (median OS 55months). Patients with residual disease following interval debulking after NACT had the worst outcome (median OS 36months). Platinum sensitivity following first line and second line chemotherapy was similar whether patients received neoadjuvant chemotherapy or not. CONCLUSION: PDS was associated with improved outcome. NACT appears to improve survival outcome in patients that would have had residual disease after PDS, and attain complete cytoreduction at the time of interval cytoreduction. This treatment option can be used in selected patients that are not candidates for complete cytoreduction at PDS.

Minimizing pain medication use and its associated costs following robotic surgery.

INTRODUCTION: Minimally invasive surgery (MIS) has been associated with diminished postoperative pain and analgesia requirements. The objective of the current study was to evaluate the use of analgesia in the post-operative period following robotic surgery for endometrial cancer. METHODS: All consecutive patients who underwent robotic surgery for the treatment of endometrial cancer were included in this study. The timing, dose, and type of analgesics administered postoperatively were recorded from patients' electronic medical record. Data was compared to a matched historical cohort of patients who underwent laparotomy before the introduction of the robotic program. RESULTS: Only eight patients (2.4%, 5 during the first 25 cases and 3 following mini-laparotomy) received patient-controlled analgesia (PCA) following robotic surgery. Most patients' pain was alleviated by over-the-counter analgesics (acetaminophen, non-steroidal anti-inflammatories). In comparison to laparotomy, patients who underwent robotic surgery required significantly less opioids (71mg vs. 12mg IV morphine, p<0.0001) and non-opioids (4810mg vs. 2151mg acetaminophen, 1892 vs. 377mg ibuprofen, and 1470mg vs. 393mg naproxen; all p<0.0001). CONCLUSION: Patients require less analgesics (opioids and non-opioids) following robotic surgery in comparison to conventional laparotomy, including the elderly and the obese. The diminished pain medication use is associated with some cost savings.