ArCH: improving the performance of clonal hematopoiesis variant calling and interpretation.

MOTIVATION: The acquisition of somatic mutations in hematopoietic stem and progenitor stem cells with resultant clonal expansion, termed clonal hematopoiesis (CH), is associated with increased risk of hematologic malignancies and other adverse outcomes. CH is generally present at low allelic fractions, but clonal expansion and acquisition of additional mutations leads to hematologic cancers in a small proportion of individuals. With high depth and high sensitivity sequencing, CH can be detected in most adults and its clonal trajectory mapped over time. However, accurate CH variant calling is challenging due to the difficulty in distinguishing low frequency CH mutations from sequencing artifacts. The lack of well-validated bioinformatic pipelines for CH calling may contribute to lack of reproducibility in studies of CH. RESULTS: Here, we developed ArCH, an Artifact filtering Clonal Hematopoiesis variant calling pipeline for detecting single nucleotide variants and short insertions/deletions by combining the output of four variant calling tools and filtering based on variant characteristics and sequencing error rate estimation. ArCH is an end-to-end cloud-based pipeline optimized to accept a variety of inputs with customizable parameters adaptable to multiple sequencing technologies, research questions, and datasets. Using deep targeted sequencing data generated from six acute myeloid leukemia patient tumor: normal dilutions, 31 blood samples with orthogonal validation, and 26 blood samples with technical replicates, we show that ArCH improves the sensitivity and positive predictive value of CH variant detection at low allele frequencies compared to standard application of commonly used variant calling approaches. AVAILABILITY AND IMPLEMENTATION: The code for this workflow is available at: https://github.com/kbolton-lab/ArCH.

ARIA II: a randomized controlled trial of near-infrared Angiography during RectosIgmoid resection and Anastomosis in women with ovarian cancer.

BACKGROUND: Ovarian cancer with extensive metastatic disease involving pelvic structures often requires rectosigmoid resection for complete gross resection; however, it is associated with increased surgical morbidity. There are limited data, and none in ovarian cancer, on near-infrared assessment of perfusion in rectosigmoid resections with anastomosis. PRIMARY OBJECTIVE: To compare the rate of pelvic complications (pelvic abscesses, anastomotic leaks, and infections) within 30 days of surgery with and without near-infrared assessment of perfusion at time of rectosigmoid resection and re-anastomosis in patients undergoing cytoreductive surgery for ovarian cancer. STUDY HYPOTHESIS: We hypothesize the use of near-infrared technology (intravenous indocyanine green and endoscopic near-infrared fluorescence imaging), compared with standard intra-operative assessment, to evaluate anastomotic perfusion at time of rectosigmoid resection and re-anastomosis will result in lower rates of post-operative pelvic complications. TRIAL DESIGN: This is a planned multicenter randomized controlled trial. Patients who undergo rectosigmoid resection as part of their ovarian cytoreductive surgery will be randomized 1:1 to standard assessment of anastomosis with the surgeon's usual technique (control arm) or assessment with near-infrared angiography using indocyanine green and endoscopic fluorescence imaging (experimental arm). Randomization will occur after rectosigmoid resection has been completed and the surgeon declares their plan to create a diverting ostomy. Randomization will be stratified by plan for diverting ostomy. MAJOR INCLUSION/EXCLUSION CRITERIA: Main inclusion criteria include patients with primary or recurrent ovarian, fallopian tube, or primary peritoneal cancer who are scheduled for cytoreductive surgery with suspected need for low-anterior rectosigmoid resection. PRIMARY ENDPOINT: Rate of 30-day post-operative pelvic complications. SAMPLE SIZE: 310 (155 per arm) ESTIMATED DATES FOR COMPLETING ACCRUAL AND PRESENTING RESULTS: Q2 2027 and Q4 2027, respectively. TRIAL REGISTRATION: NCT04878094.

Morbidity after secondary cytoreductive surgery with or without hyperthermic intraperitoneal chemotherapy for ovarian cancer: An analysis of a randomized phase II trial.

OBJECTIVE: To assess postoperative complications after secondary cytoreductive surgery (SCS) with or without hyperthermic intraperitoneal chemotherapy (HIPEC), we conducted an exploratory analysis of patients with platinum-sensitive recurrent ovarian cancer enrolled in a randomized phase II trial. METHODS: Complications occurring within 30 days of surgery were graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0; only hemoglobin and platelet levels were assessed. Patients were grouped by CTCAE grade ≥ 3 and < 3 complications. RESULTS: Among 83 eligible patients, 33 (40%) had grade ≥ 3 complications and 50 (60%) had grade < 3 complications; anemia and abdominal infections were the most common. There were no perioperative mortalities. Time to initiation of postoperative chemotherapy for patients with grade ≥ 3 and grade < 3 events was 34 days (range, 18-60) and 31 days (range, 21-43), respectively (P = .017). Median progression-free survival (PFS) did not significantly differ between patients with grade ≥ 3 and grade < 3 complications (11.2 months [95% CI: 9.3-14.4] vs 14.9 months [95% CI: 11.3-16.5], respectively; P = .186), nor did median overall survival (OS) (46.9 months [95% CI: 34-NE] vs 68.2 months [95% CI: 52.1-NE], respectively; P = .053). CONCLUSION: Postoperative complications following SCS with or without HIPEC were associated with slight delays in chemotherapy initiation but did not significantly impact oncologic outcomes.

Association of bowel preparation with surgical-site infection in gynecologic oncology surgery: Post-hoc analysis of a randomized controlled trial.

OBJECTIVE: To determine the relationship between bowel preparation and surgical-site infection (SSI) incidence following colorectal resection during gynecologic oncology surgery. METHODS: This post-hoc analysis used data from a randomized controlled trial of patients enrolled from 03/01/2016-08/20/2019 with presumed gynecologic malignancy investigating negative-pressure wound therapy among those requiring laparotomy. Patients were treated preoperatively without bowel preparation, oral antibiotic bowel preparation (OABP), or OABP plus mechanical bowel preparation (MBP) per surgeon preference. Univariate and multivariable analyses with stepwise model selection for SSI were performed for confirmed gynecologic malignancies requiring colorectal resection. RESULTS: Of 161 cases, 15 (9%) had no preparation, 39 (24%) OABP only, and 107 (66%) OABP+MBP. The overall SSI rate was 19% (n = 31)-53% (n = 8/15) in the no preparation, 21% (n = 8/39) in the OABP alone, and 14% (n = 15/107) in the OABP+MBP groups (P = 0.003). The difference between OABP and OABP+MBP was non-significant (P = 0.44). The median length of stay was 9 (range, 6-12), 6 (range, 5-8), and 7 days (range, 6-10), respectively (P = 0.045). The overall complication rate (34%; n = 54) did not significantly vary by preparation type (P = 0.23). On univariate logistic regression analysis, OABP (OR, 0.23; 95% CI: 0.06-0.80) and OABP+MBP (OR, 0.14; 95% CI: 0.04-0.45) were associated with decreased SSI risk compared to no preparation (P = 0.004). On multivariate analysis, both methods of preparation retained a significant impact on SSI rates (P = 0.004). CONCLUSION: Bowel preparation is associated with reduced SSI incidence and is beneficial for patients undergoing gynecologic oncology surgery with anticipated colorectal resection. Further investigation is needed to determine whether OABP alone is sufficient.

Is there a role for hyperthermic intraperitoneal chemotherapy in ovarian cancer?

PURPOSE OF REVIEW: Our objective is to provide a history, rationale, and review of the use of hyperthermic intraperitoneal chemotherapy (HIPEC) in the treatment of ovarian cancer. RECENT FINDINGS: In the last decade, there has been an increase in the literature regarding HIPEC in the treatment of ovarian cancer. The rationale for HIPEC extends from earlier trials demonstrating improved survival using intraperitoneal chemotherapy. HIPEC provides a one-time opportunity for intraperitoneal chemotherapy at the time of cytoreduction and with the addition of hyperthermia. Cisplatin HIPEC has been demonstrated to have a survival benefit when used in the interval cytoreductive setting. In terms of safety, nephroprotection remains a key concern when administering HIPEC. Sodium thiosulfate provides nephroprotection and should be considered when performing HIPEC. Various institutions have created multidisciplinary protocols for administering HIPEC, which include operating room staff, nursing, anesthesia, pharmacy, and surgical teams. SUMMARY: HIPEC has a role in the treatment paradigm of ovarian cancer. Currently, HIPEC is approved in the interval cytoreductive surgery setting. Further trials are needed to understand the appropriate timing, chemotherapeutic agents, and protocolization of HIPEC.

Impact of obesity and white adipose tissue inflammation on the omental microenvironment in endometrial cancer.

BACKGROUND: A complex relationship between adipose tissue and malignancy, involving an inflammatory response, has been reported. The goal of this work was to assess the prevalence of white adipose tissue (WAT) inflammation in patients with endometrial cancer (EC), and the association with circulating inflammation markers. Furthermore, the aim was to characterize the pathways activated in and the cell type composition of adipose tissue in patients with EC. METHODS: Adipose tissue and blood samples were prospectively collected from 101 patients with EC at initial surgery. WAT inflammation was determined based on adipocytes surrounded by macrophages forming crown-like structures. Circulating levels of metabolic syndrome-associated and inflammatory markers were quantified. RNA-sequencing was performed on adipose samples (n = 55); differential gene expression, pathway, and cellular decomposition analyses were performed using state-of-the-art bioinformatics methods. RESULTS: WAT inflammation was identified in 46 (45.5%) of 101 EC patients. Dyslipidemia, hypertension, and diabetes mellitus were significantly associated with WAT inflammation (p < .05). WAT inflammation was associated with greater body mass index (p < .001) and higher circulating levels of leptin, high-sensitivity C-reactive protein, and interleukin-6, as well as lower levels of adiponectin and sex hormone-binding globulin (p < .05). Transcriptomic analysis demonstrated increased levels of proinflammatory and pro-neoplastic-related gene expression in inflamed omental adipose tissue. CONCLUSIONS: WAT inflammation is associated with metabolic syndrome, obesity, and inflammatory markers, as well as increased expression of proinflammatory and proneoplastic genes.

Hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin induces distinct transcriptomic changes in ovarian tumor and normal tissues.

OBJECTIVE: To determine the effect of hyperthermic intraperitoneal chemotherapy (HIPEC) with carboplatin on the transcriptomic profiles of normal and ovarian cancer (OC) tissues. METHODS: Normal and tumor samples from four OCs were prospectively collected pre- and immediately post-HIPEC treatment and subjected to RNA-sequencing. Differential gene expression, gene ontology enrichment and pathway analyses were performed. Heat shock protein and immune-response protein expression was assessed using protein arrays and western blotting. RESULTS: RNA-sequencing revealed 4231 and 322 genes significantly differentially expressed between pre- and post-treatment normal and OC tissues, respectively (both adjusted p-value <0.05). Gene enrichment analyses demonstrated that the most significantly upregulated genes in normal tissues played a role in immune as well as heat shock response (both adjusted p < 0.001). In contrast, HIPEC induced an increased expression of primarily heat shock response and protein folding-related genes in tumor tissues (both adjusted p < 0.001). HIPEC-induced heat shock protein (HSP) expression changes, including in HSP90, HSP40, HSP60, and HSP70, were also observed at the protein level in both normal and tumor tissues. CONCLUSIONS: HIPEC with carboplatin resulted in an upregulation of heat shock-related genes in both normal and tumor tissue, with an additional immune response gene induction in normal and protein folding in tumor tissue. The findings of our exploratory study provide evidence to suggest that HIPEC administration may suffice to induce gene expression changes in residual tumor cells and raises a biological basis for the consideration of combinatorial treatments with HSP inhibitors.

Clonal relationship and directionality of progression of synchronous endometrial and ovarian carcinomas in patients with DNA mismatch repair-deficiency associated syndromes.

Sporadic synchronous endometrial (ECs) and ovarian cancers (OCs), although clinically considered to be independent primaries, have been shown to be clonally related and likely constitute metastases from each other. We sought to define whether synchronous ECs/OCs in patients with DNA mismatch repair (MMR)-deficiency syndromes would be clonally related. We subjected synchronous ECs/OCs from four patients (LS3-LS6) with clinically confirmed Lynch syndrome (LS) and one patient with constitutional mismatch repair-deficiency syndrome (CMMRD) to massively parallel sequencing targeting 468 cancer-related genes. Somatic mutations, copy number alterations (CNAs), clonal relatedness and clonal decomposition analyses were performed using previously described bioinformatics methods. All synchronous ECs/OCs analyzed were considered independent primaries based on clinicopathologic criteria. Sequencing analysis revealed that the ECs/OCs of three cases (LS2-CMMRD, L3, L4) harbored similar repertoires of somatic mutations and CNAs and were clonally related. In these three cases, a subset of subclonal mutations in the EC became clonal in the OC, suggesting that the EC was likely the substrate from which the OC developed. LS5's EC/OC had distinct mutational profiles but shared specific CNAs. In contrast, LS6's EC/OC harbored distinct somatic mutations and lacked CNAs, consistent with each tumor constituting an independent primary lesion. In LS5 and LS6, PTEN mutations and PTEN loss of protein expression were found to be restricted to the EC. Finally, re-analysis of sequencing data of sporadic synchronous ECs/OCs supported the observations made in the current study that the directionality of progression is likely from the endometrium to the ovary. In conclusion, contrary to sporadic synchronous ECs/OCs, which are almost invariably clonally related, ECs/OCs simultaneously involving the uterus and ovary in LS patients may represent distinct primary tumors. A subset of MMR-deficiency syndrome-related synchronous ECs/OCs, however, may originate from a single primary tumor at variance with their clinical diagnosis, with the endometrium being the likeliest site of origin.

Non-exenterative surgical management of recurrent endometrial carcinoma.

OBJECTIVE: To examine the role of non-exenterative secondary cytoreductive surgery (SCS) compared with non-surgical treatments and identify predictors of improved survival for patients with recurrent endometrial cancer (EC). METHODS: All patients undergoing primary surgical management for EC 1/1/2009-12/31/2017 who subsequently developed recurrence were retrospectively identified. Survival was determined from date of diagnosis of first recurrence to last follow-up and estimated using Kaplan-Meier method. Differences in survival were analyzed using Log-rank and Wald tests, based on Cox Proportional Hazards model. RESULTS: Among 376 patients with recurrent EC, median time to recurrence was 14.3 months (range, 0.2-102.2), post-recurrence median survival 29 months, median follow-up 29.2 months (range, 0-116). Sixty-one patients (16.2%) received SCS, 257 (68.4%) medical management (MM) (chemotherapy and/or radiation therapy), 32 (8.5%) hormonal therapy, 26 (6.9%) no further therapy. Patients selected for SCS were younger, had more endometrioid histology, more stage I disease at initial diagnosis, no residual disease after primary surgery, longer interval to first recurrence or progression, and the longest OS (57.6 months) (95% CI, 33.3-not reached). On multivariate analysis SCS was an independent predictor of improved survival. Among the 61 SCS patients, age < 70 at time of initial diagnosis, and endometrioid histology, were associated with improved post-relapse survival univariately (p = 0.008, 0.03, respectively). CONCLUSIONS: While MM was the most common treatment for first recurrence of EC, patients selected for surgery demonstrated the greatest survival benefit even after controlling for tumor size, site, histology, stage, time to recurrence. Careful patient selection and favorable tumor factors likely play a major role in improved outcomes. Surgical management should be considered whenever feasible in medically eligible patients, with additional consideration given to our suggested criteria.

The impact of near-infrared angiography and proctoscopy after rectosigmoid resection and anastomosis performed during surgeries for gynecologic malignancies.

OBJECTIVES: Reducing anastomotic leak rates after rectosigmoid resection and anastomosis is a priority in patients undergoing gynecologic oncology surgery. Therefore, we investigated the implications of performing near-infrared angiography (NIR) via proctoscopy to assess anastomotic perfusion at the time of rectosigmoid resection and anastomosis. METHODS: We identified all patients who underwent rectosigmoid resection and anastomosis for a gynecologic malignancy between January 1, 2013 and December 31, 2018. NIR proctoscopy was assessed via the PINPOINT Endoscopic Imaging System (Stryker). RESULTS: A total of 410 patients were identified, among whom NIR was utilized in 133 (32.4%). There were no statistically significant differences in age, race, BMI, type of malignancy, surgery, histology, FIGO stage, hypertension, diabetes, or preoperative chemotherapy between NIR and non-NIR groups. All cases of rectosigmoid resection underwent stapled anastomosis. The anastomotic leak rate was 2/133 (1.5%) in the NIR cohort compared with 13/277 (4.7%) in the non-NIR cohort (p = 0.16). Diverting ostomy was performed in 9/133 (6.8%) NIR and 53/277 (19.9%) non-NIR patients (p < 0.001). Postoperative abscesses occurred in 8/133 (6.0%) NIR and 44/277 (15.9%) non-NIR patients (p = 0.004). The NIR cohort had significantly fewer post-operative interventional procedures (12/133, 9.0% NIR vs. 55/277, 19.9% non-NIR, p = 0.006) and significantly fewer 30-day readmissions (14/133, 10.5% NIR vs. 61/277, 22% non-NIR, p = 0.004). CONCLUSIONS: NIR proctoscopy is a safe tool for assessing anastomotic rectal perfusion after rectosigmoid resection and anastomosis, with a low anastomotic leak rate of 1.5%. Its potential usefulness should be evaluated in randomized trials in patients undergoing gynecologic cancer surgery.

Current and novel mapping substances in gynecologic cancer care.

Many tracers have been introduced into current medical practice with the purpose of improving lymphatic mapping techniques, anatomic visualization, and organ/tissue perfusion assessment. Among them, three tracers have dominated the field: indocyanine green, technetium-99m radiocolloid (Tc99m), and blue dye. Tc99m and blue dye are used individually or in combination; however, given particular challenges with these tracers, such as the need for a preoperative procedure by nuclear medicine and cost, other options have been sought. Indocyanine green has proven to be a promising alternative for certain procedures, as it is easy to use and has quick uptake. Its use in the management of gynecologic cancers was first described for sentinel lymph node mapping in cervical cancer, and later for endometrial and vulvar cancers. This review provides an in-depth look at these mapping substances, their uses, and the potential for new discoveries.

Surgical site infection reduction bundle in patients with gynecologic cancer undergoing colon surgery.

OBJECTIVE: Surgical site infections (SSIs) can lead to substantial morbidity, prolonged hospitalization, increased costs, and death in patients undergoing colorectal procedures. We sought to investigate the effect of using an SSI reduction bundle on the rate of SSIs in gynecologic cancer patients undergoing colon surgery. METHODS: We identified all gynecologic cancer patients who underwent colon resection at our institution from 2014 to 2016, during which time a service-wide SSI reduction bundle was introduced. The intervention included preoperative oral antibiotics with optional mechanical bowel preparation, skin preparation with antibacterial solution, and the use of a separate surgical closing tray. SSI rates were assessed within 30days post-surgery. RESULTS: Of 233 identified patients, 115 had undergone colon surgery prior to (PRE) and 118 after (POST) the implementation of the intervention. A low anterior resection was the most common colon surgery in both cohorts. The incidence of SSI within 30days of surgery was 43/115 (37%) in the PRE and 14/118 (12%) in the POST cohorts (p≤0.001). Wound dehiscence was noted in 30/115 (26%) and 2/118 (2%) patients, respectively (p≤0.001). In patients whose operation took longer than 360min, 30-day SSI rates were 37% (28/76) and 12% (8/67), respectively (p≤0.001). In patients with an estimated blood loss >500cm3, SSI rates were 44% (27/62) and 15% (10/67), respectively (p≤0.001). CONCLUSIONS: The implementation of an SSI reduction bundle was associated with a significant reduction in 30-day SSIs in these patients. The intervention remained effective in patients undergoing longer operations and in those with increased blood loss.

Feasibility of Robotic-Assisted Laparoendoscopic Single-Site Surgery in the Gynecologic Oncology Setting.

STUDY OBJECTIVE: To assess the feasibility of incorporating robotic laparoendoscopic single-site (R-LESS) surgery into gynecologic oncology care. DESIGN: Retrospective study (Canadian Task Force classification II-3). SETTING: Academic university hospital. PATIENTS: Patients undergoing R-LESS hysterectomy for gynecologic malignancies, preinvasive disease, or risk reduction performed by a single gynecologic oncologist between 2014 and 2016. INTERVENTIONS: We incorporated R-LESS as part of standard surgical management for highly selected patients undergoing hysterectomy for common gynecologic oncology indications. MEASUREMENTS AND MAIN RESULTS: We identified 30 patients undergoing R-LESS hysterectomy meeting study criteria over a 2-year period. Indications for surgery included uterine cancer (n = 13), preinvasive cervical or uterine disease (n = 9), cervical cancer (n = 3), and hereditary gynecologic cancer risk (n = 5). Median patient age was 52 years (range, 35-77), and body mass index was 26 kg/m2 (range, 19-34). Median uterine size was 8 cm (range, 5.5-11). Eighteen patients had prior abdominal surgery (60%). Twenty-seven patients underwent R-LESS extrafascial hysterectomy, 11 of whom underwent only robotic-assisted total laparoscopic hysterectomy ± bilateral salpingo-oophorectomy with a median operative time of 140 minutes (range, 115-179). Procedures performed concurrently for the remainder included pelvic sentinel lymph node mapping (n = 14) and pelvic lymphadenectomy (n = 2), with respective median operative times of 175 (range, 150-230) and 233 minutes. One patient with endometrial cancer was converted to multiport robotic surgery to complete a pelvic and para-aortic lymphadenectomy due to high-risk disease on frozen section. Three patients underwent R-LESS radical hysterectomy, bilateral salpingo-oophorectomy, sentinel lymph node mapping, and pelvic lymphadenectomy with a median operative time of 412 minutes (range, 336-451). No perioperative complications were encountered, and all patients were discharged within 24 hours of surgery. CONCLUSION: In highly selected patients, R-LESS extrafascial and radical hysterectomy is associated with acceptable operative times and perioperative outcomes. With additional experience, surgeons may offer this approach to patients undergoing increasingly complex procedures, even in the gynecologic oncology setting.

Comparing Single-Site and Multiport Robotic Hysterectomy with Sentinel Lymph Node Mapping for Endometrial Cancer: Surgical Outcomes and Cost Analysis.

STUDY OBJECTIVE: To compare operative times, surgical outcomes, and costs of robotic laparoendoscopic single-site (R-LESS) vs multiport robotic (MPR) total laparoscopic hysterectomy (TLH) with sentinel lymph node (SLN) mapping for low-risk endometrial cancer. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Academic university hospital. PATIENTS: Patients with a biopsy-proven diagnosis of complex atypical hyperplasia (CAH) or low-grade (1 or 2) endometrial cancer with body mass index <30 kg/m2 and undergoing robotic TLH and SLN mapping between 2012 and 2016 were included. INTERVENTIONS: Surgical outcomes and cost data were collected retrospectively and analyzed based on the surgical approach with R-LESS vs MPR assistance. MEASUREMENTS AND MAIN RESULTS: Twenty-seven patients who met the inclusion criteria were identified, including 14 patients who underwent R-LESS TLH with SLN mapping and 13 patients who underwent MPR TLH with SLN mapping. Median uterine weight was comparable in the 2 cohorts (111.3 g vs 83.8 g; p = .33). Operative and console times were equivalent with the R-LESS and MPR approaches (median, 175 minutes vs 184 minutes, p = .61 and 136 vs 140 minutes, p = .12, respectively). Median estimated blood loss was 50 mL in both cohorts. Successful bilateral SLN mapping occurred in 85.7% of the R-LESS procedures and 76.9% of MPR procedures. No intraoperative or 30-day complications were encountered, and all patients were discharged within 23 hours of surgery. MPR was associated with additional disposable instrument and drape costs of $460 to $660 compared with R-LESS, depending on the surgeon's instrument selection. Average total hospital charges were lower for R-LESS procedures ($13,410 vs $15,952; p < .05). CONCLUSION: In highly selected patients with CAH or low-grade endometrial cancer undergoing TLH and SLN mapping, R-LESS appears to result in equivalent perioperative outcomes as a MPR approach while offering a more cost-effective option. Further research is needed to determine the benefits of R-LESS procedures in the gynecologic oncology setting.

Preinvasive and Invasive Cervical Adenocarcinoma: Preceding Low-Risk or Negative Pap Result Increases Time to Diagnosis.

OBJECTIVES: The aims of the study were to investigate screening histories of women with adenocarcinoma in situ (AIS) and adenocarcinoma (AdCa) of the cervix and to further evaluate screening for glandular disease. MATERIALS AND METHODS: Screening histories were retrospectively collected for patients with AIS or AdCa at a single large-volume academic institution from 2005 to 2015. Fisher exact and Wilcoxon rank sum tests were used to compare AIS with AdCa patient characteristics, distribution of preceding Pap (i.e., trigger Pap) results, and high-risk human papillomavirus testing. The association between Pap result and time to diagnosis was evaluated. RESULTS: Eighty-seven cases, 50 AIS and 37 AdCa, met study criteria; median age was 31 and 43 years, respectively. Among the AIS cohort, 52.0% had a negative or low-risk trigger Pap result versus 24.3% of those with AdCa (p = .001). The time to diagnosis of AIS ranged from 8.4 to 18.8 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .002). The time to diagnosis of AdCa ranged from 14.6 to 44.7 weeks for those with high- versus low-risk or negative trigger Pap results, respectively (p = .003). Among those with high-risk human papillomavirus testing, 89.7% tested positive at the time of trigger Pap with 100% positivity among those with low-risk or negative trigger Pap results. CONCLUSIONS: Cervical AIS and AdCa affect many young nulliparous women and commonly preceded by low-risk or negative Pap testing. The interval to diagnosis increases with low-risk and negative Pap results, and therefore, further investigation into optimal screening for glandular lesions is needed.

Vaginal lacerations during laparoscopic hysterectomy for endometrial cancer and local recurrence risk.

Objective: Laparoscopic surgery (MIS) offers equivalent oncologic outcomes as compared to open surgery, while causing lesser morbidity and resulting in a faster recovery. Vaginal extraction of specimens may cause vaginal or perineal lacerations (VL). The objective of this retrospective study was to assess local recurrence rates compared between cases with vaginal laceration (VL) or without vaginal lacerations (NL). Methods: We identified patients with endometrial cancer who underwent MIS between 2014 and 2018. We assessed the rate of local recurrence between patients in VL and NL cohorts. The study included all histologic subtypes and stages while benign final pathology, synchronous primaries or cases that required laparotomy for extraction were excluded. Results: 338 MIS cases were evaluable of which 40 cases had a vaginal laceration during specimen extraction. There was no significant difference in age, race, presence of LVSI, stage, grade, histology or use of vaginal brachytherapy between cohorts. Cases with vaginal lacerations were significantly associated with a higher median BMI and larger uterine size. The VL cohort was more likely to have received adjuvant treatment. In early stage disease, more cases had non-endometrioid histology in the VL group and had increased incidence of chemotherapy and radiation use as well. There were no cases of isolated vaginal recurrence (0/40) in the VL group as compared to an incidence of 2 % (7/298) in the NL group with a relative risk of 0.48 (CI: 0.03-8.36, p = 0.62). There were 4 cases of pelvic recurrence (4/40) in the VL group and 2 cases in the NL group (2/298) with a relative risk of 2.13 (CI: 0.46-9.89, p = 0.34). Conclusions: In endometrial cancer cases, we did not observe a significantly increased risk of vaginal or pelvic recurrence after a vaginal laceration at the time of specimen removal.

Comparison of flow diversion and coiling in large unruptured intracranial saccular aneurysms.

BACKGROUND AND PURPOSE: Flow diversion has emerged as an important tool for the management of intracranial aneurysms. The purpose of this study was to compare flow diversion and traditional embolization strategies in terms of safety, efficacy, and clinical outcomes in patients with unruptured, large saccular aneurysms (≥10 mm). METHODS: Forty patients treated with the Pipeline Embolization Device (PED) were matched in a 1:3 fashion with 120 patients treated with coiling based on patient age and aneurysm size. Fusiform and anterior communicating artery aneurysms were eliminated from the analysis. Procedural complications, angiographic results, and clinical outcomes were analyzed and compared. RESULTS: There were no differences between the 2 groups in terms of patient age, sex, aneurysm size, and aneurysm location. The rate of procedure-related complications did not differ between the PED (7.5%) and the coil group (7.5%; P=1). At the latest follow-up, a significantly higher proportion of aneurysms treated with PED (86%) achieved complete obliteration compared with coiled aneurysms (41%; P<0.001). In multivariable analysis, coiling was an independent predictor of nonocclusion. Retreatment was necessary in fewer patients in the PED group (2.8%) than the coil group (37%; P<0.001). A similar proportion of patients attained a favorable outcome (modified Rankin Scale, 0-2) in the PED group (92%) and in the coil group (94%; P=0.8). CONCLUSIONS: The PED provides higher aneurysm occlusion rates than coiling, with no additional morbidity and similar clinical outcomes. These findings suggest that the PED might be a preferred treatment option for large unruptured saccular aneurysms.

Microsatellite Instability-High Endometrial Cancers with MLH1 Promoter Hypermethylation Have Distinct Molecular and Clinical Profiles.

PURPOSE: Microsatellite instability-high (MSI-H) endometrial carcinomas are underpinned by distinct mechanisms of DNA mismatch repair deficiency (MMR-D). We sought to characterize the clinical and genetic features of MSI-H endometrial cancers harboring germline or somatic mutations in MMR genes or MLH1 promoter hypermethylation (MLH1ph). EXPERIMENTAL DESIGN: Of > 1,100 patients with endometrial cancer that underwent clinical tumor-normal sequencing, 184 had MSI-H endometrial cancers due to somatic MMR mutations or MLH1ph, or harbored pathogenic germline MMR mutations. Clinicopathologic features, mutational landscape, and tumor-infiltrating lymphocyte (TIL) scores were compared among MMR-D groups using nonparametric tests. Log-rank tests were used for categorical associations; Kaplan-Meier method and Wald test based on Cox proportional hazards models were employed for continuous variables and survival analyses. RESULTS: Compared with patients with germline (n = 25) and somatic (n = 39) mutations, patients with MLH1ph endometrial cancers (n = 120) were older (P < 0.001), more obese (P = 0.001) and had more advanced disease at diagnosis (P = 0.025). MLH1ph endometrial cancers were enriched for JAK1 somatic mutations as opposed to germline MMR-D endometrial cancers which showed enrichment for pathogenic ERBB2 mutations. MLH1ph endometrial cancers exhibited lower tumor mutational burden and TIL scores compared with endometrial cancers harboring germline or somatic MMR mutations (P < 0.01). MLH1ph endometrial cancer patients had shorter progression-free survival (PFS) on univariate analysis, but in multivariable models, stage at diagnosis remained the only predictor of survival. For stage I/II endometrial cancer, two-year PFS was inferior for patients with MLH1ph endometrial cancers compared with germline and somatic MMR groups (70% vs. 100%, respectively). CONCLUSIONS: MLH1ph endometrial cancers likely constitute a distinct clinicopathologic entity compared with germline and somatic MMR-D ECs with potential treatment implications.