Integrated mutational landscape analysis of uterine leiomyosarcomas.

Uterine leiomyosarcomas (uLMS) are aggressive tumors arising from the smooth muscle layer of the uterus. We analyzed 83 uLMS sample genetics, including 56 from Yale and 27 from The Cancer Genome Atlas (TCGA). Among them, a total of 55 Yale samples including two patient-derived xenografts (PDXs) and 27 TCGA samples have whole-exome sequencing (WES) data; 10 Yale and 27 TCGA samples have RNA-sequencing (RNA-Seq) data; and 11 Yale and 10 TCGA samples have whole-genome sequencing (WGS) data. We found recurrent somatic mutations in TP53, MED12, and PTEN genes. Top somatic mutated genes included TP53, ATRX, PTEN, and MEN1 genes. Somatic copy number variation (CNV) analysis identified 8 copy-number gains, including 5p15.33 (TERT), 8q24.21 (C-MYC), and 17p11.2 (MYOCD, MAP2K4) amplifications and 29 copy-number losses. Fusions involving tumor suppressors or oncogenes were deetected, with most fusions disrupting RB1, TP53, and ATRX/DAXX, and one fusion (ACTG2-ALK) being potentially targetable. WGS results demonstrated that 76% (16 of 21) of the samples harbored chromoplexy and/or chromothripsis. Clinically actionable mutational signatures of homologous-recombination DNA-repair deficiency (HRD) and microsatellite instability (MSI) were identified in 25% (12 of 48) and 2% (1 of 48) of fresh frozen uLMS, respectively. Finally, we found olaparib (PARPi; P = 0.002), GS-626510 (C-MYC/BETi; P < 0.000001 and P = 0.0005), and copanlisib (PIK3CAi; P = 0.0001) monotherapy to significantly inhibit uLMS-PDXs harboring derangements in C-MYC and PTEN/PIK3CA/AKT genes (LEY11) and/or HRD signatures (LEY16) compared to vehicle-treated mice. These findings define the genetic landscape of uLMS and suggest that a subset of uLMS may benefit from existing PARP-, PIK3CA-, and C-MYC/BET-targeted drugs.

Do Cultures From Percutaneously Drained Intra-abdominal Abscesses Change Treatment? A Retrospective Review.

BACKGROUND: Routinely obtaining intraoperative cultures for abdominal infections is not a currently recommended evidence-based practice. Yet, cultures are frequently sent from these infections when they are managed by image-guided percutaneous drains. OBJECTIVE: This study aimed to determine the utility of cultures from percutaneously drained intra-abdominal abscesses. DESIGN: Retrospective medical record review. SETTING: Single university-affiliated institution. PATIENTS: Inpatients with an intra-abdominal abscess secondary to diverticulitis or appendicitis between 2013 and 2021 managed with image-guided percutaneous drain, excluding those with active chemotherapy, HIV, or solid organ transplant, were included in the study. MAIN OUTCOME MEASURES: Frequency culture data from percutaneous drains changed antimicrobial therapy. RESULTS: There were 221 patients who met the inclusion criteria. Of these, 56% were admitted for diverticulitis and 44% for appendicitis. Patients were 54% female and had a median age of 62 years (range, 18-93), and 14% were active smokers. The median length of hospitalization was 8 days (range, 1-78) and the median antibiotics course was 8 days (range, 1-22). Culture data from percutaneous drains altered antimicrobial therapy in 8% of patients (16/211). A culture was obtained from 95% of drains, with 78% of cultures with growth. Cultures grew multiple bacteria in 66% and mixed variety without speciation in 13%. The most common pathogen was the Bacteroides family at 33% of all bacteria. The most common empiric antibiotic regimens were ceftriaxone used in 33% of patients and metronidazole used in 40% of patients. Female sex ( p = 0.027) and presence of bacteria with any antibiotic resistance ( p < 0.01) were associated with higher likelihood of cultures influencing antimicrobial therapy. LIMITATIONS: Retrospective and single institution's microbiome. CONCLUSIONS: Microbiology data from image-guided percutaneous drains of abdominal abscesses altered antimicrobial therapy in 8% of patients, which is lower than reported in previously published literature on cultures obtained surgically. Given this low rate, similar to the recommendation regarding cultures obtained intraoperatively, routinely culturing material from drains placed in abdominal abscesses is not recommended. See Video Abstract at http://links.lww.com/DCR/C64 . LOS CULTIVOS DE ABSCESOS INTRA ABDOMINALES DRENADOS PERCUTNEAMENTE CAMBIAN EL TRATAMIENTO UNA REVISIN RETROSPECTIVA: ANTECEDENTES:La obtención rutinaria de cultivos intra-operatorios para infecciones abdominales no es una práctica basada en evidencia actualmente recomendada. Sin embargo, con frecuencia se envían cultivos de estas infecciones cuando se manejan con drenajes percutáneos guiados por imágenes.OBJETIVO:Determinar la utilidad de los cultivos de abscesos intra-abdominales drenados percutáneamente.DISEÑO:Revisión retrospectiva de gráficos.ESCENARIO:Institución única afiliada a la universidad.PACIENTES:Pacientes hospitalizados con absceso intra-abdominal secundario a diverticulitis o apendicitis entre 2013 y 2021 manejados con drenaje percutáneo guiado por imagen, excluyendo aquellos con quimioterapia activa, VIH o trasplante de órgano sólido.PRINCIPALES MEDIDAS DE RESULTADO:Los datos de cultivo de frecuencia de los drenajes percutáneos cambiaron la terapia antimicrobiana.RESULTADOS:Hubo 221 pacientes que cumplieron con los criterios de inclusión. De estos, el 56% ingresaron por diverticulitis y el 44% por apendicitis. El 54% de los pacientes eran mujeres, tenían una edad media de 62 años (18-93) y el 14% eran fumadores activos. La duración de hospitalización media fue de 8 días (rango, 1-78) y la mediana del curso de antibióticos fue de 8 días (rango, 1-22). Los datos de cultivo de drenajes percutáneos alteraron la terapia antimicrobiana en el 7% (16/221) de los pacientes. Se obtuvo cultivo del 95% de los drenajes, con un 79% de cultivos con crecimiento. Los cultivos produjeron múltiples bacterias en el 63% y variedad mixta sin especiación en el 13%. El patógeno más común fue la familia Bacteroides con un 33% de todas las bacterias. El régimen de antibiótico empírico más común fue ceftriaxona y metronidazol, utilizados en el 33% y el 40% de los pacientes, respectivamente. El sexo femenino ( p = 0,027) y la presencia de bacterias con alguna resistencia a los antibióticos ( p < 0,01) se asociaron con una mayor probabilidad de que los cultivos influyeran en la terapia antimicrobiana.LIMITACIONES:Microbioma retrospectivo y de una sola institución.CONCLUSIONES:Los datos microbiológicos de los drenajes percutáneos guiados por imágenes de los abscesos abdominales alteraron la terapia antimicrobiana en el 7% de los pacientes, que es inferior a la literatura publicada previamente sobre cultivos obtenidos quirúrgicamente. Dada esta baja tasa, similar a la recomendación sobre cultivos obtenidos intraoperatoriamente, no se recomienda el cultivo rutinario de material de drenajes colocados en abscesos abdominales. Consulte Video Resumen en http://links.lww.com/DCR/C64 . (Traducción-Dr. Mauricio Santamaria.

An Evaluation of Sex-Based Differences in Surrogate Consent for Older Adults Undergoing Surgical Intervention.

INTRODUCTION: Differences between female and male patients have been identified in many facets of medicine. We sought to understand whether differences in frequency of surrogate consent for operation exist between older female and male patients. MATERIALS AND METHODS: A descriptive study was designed using data from the hospitals participating in the American College of Surgeons National Surgical Quality Improvement Program. Patients age 65 y and older who underwent operation between 2014 and 2018 were included. RESULTS: Of 51,618 patients identified, 3405 (6.6%) had surrogate consent for surgery. Overall, 7.7% of females had surrogate consent compared to 5.3% of males (P < 0.001). Stratified analysis based on age categories showed no difference in surrogate consent between female and male patients aged 65-74 yy (2.3% versus 2.6%, P = 0.16), but higher rates of surrogate consent in females than males among patients aged 75-84 y old (7.3% versus 5.6%, P < 0.001) and age ≥85 y (29.7% versus 20.8%, P < 0.001). A similar relationship was seen between sex and preoperative cognitive status. There was no difference in preoperative cognitive impairment in female and male patients age 65-74 y (4.4% versus 4.6%, P = 0.58), but higher rates of preoperative cognitive impairment were seen in females than males for those age 75-84 (9.5% versus 7.4%, P < 0.001) and aged ≥85 y (29.4% versus 21.3%, P < 0.001). Matching for age and cognitive impairment, there was no significant difference between rate of surrogate consent in males and females. CONCLUSIONS: Female patients are more likely than males to undergo surgery with surrogate consent. This difference is not based on patient sex alone - females undergoing operation are older than their male counterparts and more likely to be cognitively impaired.

A phase 2 evaluation of pembrolizumab for recurrent Lynch-like versus sporadic endometrial cancers with microsatellite instability.

BACKGROUND: Microsatellite instability-high (MSI-H)/mismatch repair deficiency (dMMR) is a biomarker for responses to immune checkpoint inhibitors (ICIs). Whether mechanisms underlying microsatellite instability alter responses to ICIs is unclear. This article reports data from a prospective phase 2 pilot study of pembrolizumab in patients with recurrent MSI-H endometrial cancer (EC) analyzed by whole exome sequencing (WES) and potential mechanisms of primary/secondary ICI resistance (NCT02899793). METHODS: Patients with measurable MSI-H/dMMR EC confirmed by polymerase chain reaction/immunohistochemistry were evaluated by WES and received 200 mg of pembrolizumab every 3 weeks for ≤2 years. The primary end point was the objective response rate (ORR). Secondary end points included progression-free survival (PFS) and overall survival (OS). RESULTS: Twenty-five patients (24 evaluable) were treated. Six patients (25%) harbored Lynch/Lynch-like tumors, whereas 18 (75%) had sporadic EC. The tumor mutation burden was higher in Lynch-like tumors (median, 2939 mutations/megabase [Mut/Mb]; interquartile range [IQR], 867-5108 Mut/Mb) than sporadic tumors (median, 604 Mut/Mb; IQR, 411-798 Mut/Mb; P = .0076). The ORR was 100% in Lynch/Lynch-like patients but only 44% in sporadic patients (P = .024). The 3-year PFS and OS proportions were 100% versus 30% (P = .017) and 100% versus 43% (P = .043), respectively. CONCLUSIONS: This study suggests prognostic significance of Lynch-like cancers versus sporadic MSI-H/dMMR ECs for ORR, PFS, and OS when patients are treated with pembrolizumab. Larger confirmatory studies in ECs and other MSI-H/dMMR tumors are necessary. Defective antigen processing/presentation and deranged induction in interferon responses serve as mechanisms of resistance in sporadic MSI-H ECs. Oligoprogression in MSI-H/dMMR patients appears salvageable with surgical resection and/or local treatment and the continuation of pembrolizumab off study. Clinical studies evaluating separate MSI-H/dMMR EC subtypes treated with ICIs are warranted.

DHES0815A, a novel antibody-drug conjugate targeting HER2/neu, is highly active against uterine serous carcinomas in vitro and in vivo.

OBJECTIVE: Uterine serous carcinoma (USC) is an aggressive histologic variant of endometrial cancer which portends a poor prognosis. DHES0815A is a novel antibody-drug-conjugate (ADC) which binds specifically to HER2 overexpressing tumors at a distinct epitope from that bound by trastuzumab and pertuzumab after which it delivers the toxic payload, PBD-MA, a DNA mono-alkylating agent. The objective of this study was to evaluate the preclinical activity of DHES0815A against primary USC cell lines and xenografts. METHODS: Twelve primary USC cell lines were assessed by immunohistochemistry (IHC) for HER2 protein expression and for C-erbB2 gene amplification using fluorescent in situ hybridization (FISH) analysis. Cell viability and bystander killing in USC cell lines after exposure to DHES0815A, the non-targeted ADC, and the unconjugated antibody (i.e. MHES0488A) were evaluated using flow cytometry-based-assays. In vivo activity of DHES0815A was tested against HER2/neu overexpressing USC xenografts. RESULTS: High HER2/neu protein expression was seen in 25% (3/12) of the primary USC cell lines. USC cell lines overexpressing HER2/neu were significantly more sensitive to DHES0815A when compared to the non-targeted control ADC (p < 0.001). DHES0815A did not induce significant bystander killing of HER2/neu negative tumors when admixed with HER2/neu positive tumors. DHES0815A caused growth-inhibition and increased survival in USC HER2/neu overexpressing xenografts when compared to controls (p < 0.01). CONCLUSIONS: DHES0815A is both highly selective and toxic to USC tumors overexpressing HER2/neu both in vitro and in vivo. HER2-directed ADCs, alone or in combination with other HER2/neu targeted agents may represent a novel treatment option for patients with tumors harboring HER2/neu overexpression refractory to trastuzumab and traditional chemotherapy.

Robotic Low Anterior Resection and Partial Bladder Resection for Management of Locoregional Endometrial Cancer Recurrence.

OBJECTIVE: To demonstrate a robotic tumor debulking for management of locoregional endometrial cancer recurrence. DESIGN: Case report. SETTING: Tertiary referral center in New Haven, CT. INTERVENTIONS: A 70-year-old patient with a history of stage IB endometrioid endometrial cancer presented with rectal bleeding 3 years after the completion of treatment. A mass involving the distal sigmoid colon/upper rectum and bilateral distal periureteral masses were visualized on imaging. There was no distant metastatic disease. Colonoscopic biopsies were consistent with endometrial cancer recurrence. Because the patient was symptomatic with rectal bleeding and had no distant metastasis, it was recommended that she undergo surgical resection for management of this locoregional recurrence. The patient was placed in reverse Trendelenburg position with a rightward tilt to mobilize the splenic flexure. Once the cephalad aspect of the descending colon mobilization was completed, the patient was placed in Trendelenburg lithotomy position to expose the pelvis. A robot was docked at this point and the pelvic avascular spaces were delineated. A medial-to-lateral approach was used in mobilization of the sigmoid colon mesentery. The left ureter was identified and the sigmoid branches of inferior mesenteric artery were sealed. The descending/sigmoid colon junction was stapled. After complete mobilization of the sigmoid colon, the tumor-free upper rectum was delineated and stapled. Attention was then turned to the distal peri-ureteral masses. The 2-cm mass on the right, which was densely adherent to the distal right ureter, was completely resected after extensive ureterolysis. The resection of the 4-cm mass on the left which involved both the distal left ureter and the bladder dome required an intentional cystotomy and a partial cystectomy to attain negative margins (Supplemental Figure 1). The procedure was continued with the bowel anastomosis. The anvil was introduced through the vagina and was placed into the proximal limb through an antimesenteric incision. An end-to-end tension-free anastomosis was performed and adequate vascularization was confirmed with intravenous indocyanine green. CONCLUSION: Robotic low anterior resection and partial bladder resection were performed without any complications with negative margins. Robotic tumor debulking should be considered in appropriate patients when managing locoregional recurrence of endometrial cancer [1,2].

Derangements in HUWE1/c-MYC pathway confer sensitivity to the BET bromodomain inhibitor GS-626510 in uterine cervical carcinoma.

OBJECTIVE: Whole-exome-sequencing (WES) studies reported c-MYC gene-amplification and HUWE1 gene deletion/mutations in a significant number of cervical-cancer-patients (CC) suggesting HUWE1/c-MYC pathway as potential therapeutic target. We investigated HUWE1/c-MYC expression in fresh-frozen-CC and the activity of the novel BET inhibitor GS-626510 (Gilead-Science-Inc) against primary WES CC-cultures and CC-xenografts. METHODS: HUWE1 and c-MYC expression were evaluated by qRT-PCR in 23 CC including 12 fresh-frozen-tumor-tissues and 11 primary-cell-lines. c-Myc expression was also evaluated by Western-Blot (WB) and fluorescence-in-situ-hybridization (FISH) in all 11 fully sequenced primary-CC-cell-lines. Primary tumors were evaluated for sensitivity to GS-626510 in-vitro using proliferation and viability-assays. siRNA experiments were used to evaluate the effect of HUWE1 silencing on primary-CC-cell-line growth and sensitivity to GS-626510. Finally, the in-vivo activity of GS-626510 was studied in CC-CVX8-mouse-xenografts. RESULTS: Fresh-frozen-CC and primary-CC-cell-lines overexpressed c-MYC when compared to normal tissues (p = .01). FISH demonstrated amplification of c-MYC in 9/11 (82%) of the primary-CC-cell-lines. Cell-lines with derangements in HUWE1/c-MYC pathway were highly sensitive to GS-626510, with a dose-response decrease in cell proliferation and viability. siRNA silencing of HUWE1 significantly increased c-MYC expression and CC cell-proliferation and enhanced the in-vitro sensitivity to GS-626510. Twice-daily oral doses of GS-626510 were well tolerated in-vivo and highly effective in decreasing tumor-growth (p = .004) and increasing survival (p = .004) of CC-CVX8 xenografts. CONCLUSIONS: Downregulation/inactivation of HUWE1 may increase c-MYC expression and proliferation in primary-CC-cell-lines. GS-626510 may represent a novel, potentially highly effective therapeutic agent against CC overexpressing c-MYC and/or harboring HUWE1 mutations. Clinical studies with BET inhibitor in CC-patients harboring radiation/chemotherapy-resistant disease are warranted.

Academic tweeting in #ObGyn. Where do we stand?

Objective To describe the scenario of academic tweeting and utilization of Twitter by editorial board members of the leading journal in obstetrics and gynecology. Methods The Twitter presence of an editorial board members of obstetrics and gynecology journal with an impact factor greater than 4 was determined. Details of their Twitter activity, year of graduation from medical school and gender were analyzed. Median SparkScore™, an online influence measure, of journals was compared to the highest impact factor journals in medicine (New England Journal of Medicine, The Lancet, The British Medical Journal and Journal of the American Medical Association). Results In the six highest impact factor journals in obstetrics and gynecology, 92 of 240 (38.3%) editorial board members had an active Twitter account. The Twitter presence of editorial members of Obstetrics and Gynecology was statistically less when compared to all other journals (P < 0.01). The median number of tweets in the last 24 h and 7 days were 0. Median SparkScore™ for the highest impact factor obstetrics and gynecology journals (24) were lower compared to the highest impact journals in medicine (66) (P = 0.03). Conclusion Editorial board members of the six highest impact factor journals in obstetrics and gynecology are not capitalizing on the dynamic nature of Twitter and its instant convenient access from our smartphones to further academia, when compared to specialties in medicine. There is a need for increased adoption of Twitter among physician leaders in the specialty.

Why Are There So Few Women Medical School Deans? Debunking the Myth That Shorter Tenures Drive Disparities.

PURPOSE: Gender disparities among the senior echelons of academic medicine are striking and persistent. The role of medical school dean has been particularly immune to gender diversity, and limited prior research identified women's shorter decanal tenures as a potential driver. The authors assessed gender differences in tenure length of deanships in the current era to elucidate this finding. METHOD: From October 2020 to June 2021, the authors collected information about medical school deanships that were held from January 1, 2006, to June 30, 2020. All schools were members of the Association of American Medical Colleges (AAMC). The authors collected data from online public records and augmented their findings via direct outreach to medical schools. They used time-to-event analyses before and after adjustment for interim vs permanent status of the initial appointment, school ownership (public/private), and school size to assess for gender differences in length of deanship tenure during the study period. The unit of analysis was deanships, and the primary outcome was length of deanships measured in years. RESULTS: Authors included data on 528 deanships. Women held 91 (17%) of these terms. Men held the majority of permanent deanships (n = 352 [85%]). A greater percentage of the deanships held by women were interim only (n = 27 [30%]) compared with men (n = 85 [20%]). In unadjusted and adjusted analyses, there were no significant gender differences in length of deanship tenures. CONCLUSIONS: Analysis of appointments of AAMC-member medical school deans from 2006 to 2020 revealed that women have remained in their deanships as long as their male counterparts. The myth about women deans' shorter longevity should no longer be promulgated. Academic medicine should consider novel solutions to addressing women's persistent underrepresentation in the dean role, including employing the gender proportionality principle used in the business and legal communities.

Clinicopathologic characteristics and oncologic outcomes in adenosarcoma of gynecologic sites.

OBJECTIVE: To examine clinicopathologic characteristics and oncologic outcomes of patients diagnosed with Mullerian adenosarcoma and to evaluate ovarian preservation as a practical management option in early-stage disease. METHODS: A retrospective review was performed of 31 patients treated for uterine, ovarian, or cervical adenosarcoma at our institution between 1/2000-3/2020. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier estimates, the log-rank test, and Cox proportional hazards regression. RESULTS: Median age was 51 years (IQR: 41-68). Primary sites included uterine corpus (n = 23, 74.2%), uterine cervix (n = 7, 22.6%), and ovary (n = 1, 3.2%). Surgical management primarily consisted of total hysterectomy +/- bilateral adnexectomy +/- lymph node dissection. Fifteen (48.1%) patients underwent lymph node dissection; no patients had positive nodes. Ovaries were preserved in 6 (19.4%). Twenty-two (71.0%) patients received no adjuvant therapy, 4 (12.9%) received chemotherapy, 1 (3.2%) received chemoradiation, and 3 (9.7%) received hormonal therapy. Sarcomatous overgrowth (p = 0.04), high grade histology (p = 0.002), and greater depth of myometrial invasion (p = 0.001) were associated with decreased RFS. None of the 6 patients with ovarian preservation had recurrences. At last follow up, 21 patients (67.7%) had no evidence of disease, 7 (22.6%) were deceased due to disease, and 3 (9.7%) were deceased due to non-cancerous reasons. CONCLUSIONS: Uterine adenosarcoma appears to have a relatively good prognosis, especially in the absence of risk factors, such as sarcomatous overgrowth, high grade histology, and deep myometrial invasion. Ovarian preservation may be a feasible management option with non-inferior outcomes for premenopausal women with early-stage disease. Future studies including larger patient cohorts are needed for this rare disease.

Surrogate consent for surgery among older adult patients.

BACKGROUND: Surrogate consent for surgery is sought when a patient lacks capacity to consent for their own operation. The purpose of this study is to describe older adults who underwent surgical interventions with surrogate consent. METHODS: A descriptive analysis was performed using data from the American College of Surgeons National Surgical Quality Improvement Program Geriatric Surgery Pilot collected from 2014 to 2018. All patients included were ≥65 years old and underwent a surgical procedure. Demographic and preoperative health characteristics were evaluated to examine differences between those with and without surrogate consent. RESULTS: In total, 51,618 patients were included in this study, and 6.6% underwent an operation with surrogate consent. Surrogate consent was more common among older patients (median age 83 vs 73, P < .001), female patients (7.7% vs 5.3%, P < .001), patients undergoing emergency as opposed to elective procedures (21.9% vs 1.6%, P < .001), patients with cognitive impairment (50.5% vs 2.4%, P < .001), and patients who were dependent on others for activities of daily living (41.9% vs 4.1%, P < .001). Nearly half of patients with a diagnosis of cognitive impairment signed their own consent. CONCLUSION: Surrogate consent was more common among patients who were older, female, had a higher comorbidity burden, and had preoperative disability. Nearly half of patients with documented cognitive impairment signed their own consent. These results indicate that further research is needed to understand how surgeons determine which patients require surrogate consent.

Robotic radical trachelectomy with an abdominally placed vaginal cerclage for containment of early stage cervical cancer.

•Uterine manipulator elimination may minimize cervical tumor fractionation.•Tumor containment with a vaginal purse-string suture may minimize tumor dissemination.•Further studies of the efficacy of such MIS surgical modifications are warranted.