Citations

Abstract Background: Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries and the incidence and mortality of EC continue to rise in the US. When detected early, EC is highly curable, suggesting that early detection strategies could reduce EC mortality. Women who develop EC often have a prolonged history of abnormal bleeding, offering a window for identifying many at-risk women prior to the development of advanced cancer. To evaluate risk prediction, novel sampling and early detection strategies in women at increased risk of EC, we established a prospective cohort of women with abnormal bleeding that is followed for endometrial hyperplasia and cancer endpoints. Methods: We consecutively enrolled women ≥45 years old presenting to the Mayo Clinic for evaluation of abnormal uterine bleeding (AUB), postmenopausal bleeding (PMB), thickened endometrial stripe (ES) on imaging, or Lynch Syndrome (LS). From all women, an intravaginal tampon and an endometrial brushing via Tao brush were collected before endometrial biopsy. Epidemiological EC risk factor data, clinical data, and endometrial biopsy histology results were abstracted from medical records. Absolute risk of endometrial hyperplasia and EC were calculated overall and in strata based on clinical symptoms and risk factors. Results: Among the first 1,000 women enrolled into the study, 712 (71%) were overweight or obese, 534 (53%) were postmenopausal, and 214 (22%) were current hormone replacement therapy (HRT) users. Endometrial biopsy and, if indicated, subsequent hysterectomy, detected 39 ECs, 16 atypical hyperplasias, and 28 hyperplasias without atypia at baseline evaluation. Among 534 postmenopausal women, 453 (85%) reported any type of bleeding, with spotting (39%) and light bleeding (27%) being more common than heavy bleeding (14%). Among perimenopausal women with AUB (n=452), the absolute risk of EC at baseline was 0.9% and among women with PMB, the absolute risk of EC at baseline was 7.5%. Among women with PMB, EC risk was modified by HRT use (risk of 2.6% in women on HRT and 8.2% in women not on HRT, respectively), obesity (risk of 5.3%, 8.1% and 9.5% for women with normal, overweight, and obese BMI, respectively), and type of bleeding (risk of 9.7%, 4.9%, and 8.2% in women with spotting, light or heavy bleeding, respectively). Discussion: While risk of endometrial cancer in perimenopausal women with AUB is low, approximately 8% of women presenting for clinical work up of PMB have underlying EC. Clinical presentation and risk factors modify the absolute risk of EC and may inform clinical management. Additional recruitment and prospective follow-up is underway to improve estimates of short- and long-term EC risk in women with PMB. With its collection of tampon and Tao brush samples, the study will provide a unique resource to evaluate molecular markers of EC and EC risk in elevated-risk women. Citation Format: Nicolas A. Wentzensen, Megan Clarke, Viji Shridhar, Maureen Lemens, Matthew Hopkins, Lisa Ahlberg, Shannon Laughlin-Tommaso, Karl Podratz, Mark Sherman, Jamie Bakkum-Gamez. A prospective study of endometrial cancer detection in women presenting for evaluation of abnormal peri- and postmenopausal bleeding [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2203.

AbstractBackgroundAcute appendicitis is a common pediatric surgical emergency; however, there are few grading systems to assign disease severity. The American Association for the Surgery of Trauma (AAST) recently developed a grading system for a variety of emergency surgical conditions, including appendicitis. The severity of acute appendicitis in younger patients in KwaZulu‐Natal (South Africa) is unknown. We aimed to describe the disease severity in this patient population using the AAST grading system hypothesizing that the AAST grade would correlate with morbidity, management type, and duration of stay.MaterialsSingle institutional review of patients <18 years old with a final diagnosis of acute appendicitis during 2010–2016 in KwaZulu‐Natal, South Africa, was performed. Demographics, physiologic and symptom data, procedural details, postoperative complications, and Clavien–Dindo classification were abstracted. AAST grades were generated based on intraoperative findings. Summary, univariate, and nominal logistic regression analyses were performed to compare AAST grade and outcomes.ResultsA total of 401 patients were identified with median [IQR] age of 11 [5–13], 65% male. Appendectomy was performed in all patients; 2.4% laparoscopic, 37.6% limited incision, and 60% midline laparotomy. Complications occurred in 41.6%, most commonly unplanned relaparotomy (22.4%), surgical site infection (8.9%), pneumonia (7.2%), and acute renal failure (2.9%). Complication rate and median length of stay increased with greater AAST grade (all p < 0.001). AAST grade was independently associated with increased risk of complications.ConclusionPediatric appendicitis is a morbid disease in a developing middle‐income country. The AAST grading system is generalizable and accurately corresponds with management strategies as well as key clinical outcomes.Level of evidenceRetrospective study, Level IV.Study typeRetrospective single institutional study.

AbstractBackgroundThe American Association for the Surgery of Trauma (AAST) anatomic severity grading system for adhesive small bowel obstruction (ASBO) has demonstrated to be a valid tool in North American patient populations. Using a multi‐national patient cohort, we retrospectively assessed the validity the AAST ASBO grading system and estimated disease severity in a global population in order to correlate with several key clinical outcomes.MethodsMulticenter retrospective review during 2012–2016 from four centers, Minnesota USA, Bologna Italy, Pietermaritzburg South Africa, and Bucharest Romania, was performed. Adult patients (age ≥ 18) with ASBO were identified. Baseline demographics, physiologic parameters, laboratory results, operative and imaging details, outcomes were collected. AAST ASBO grades were assigned by independent reviewers. Univariate and multivariable analyses with odds ratio (OR) and 95% confidence intervals (CIs) were performed.ResultsThere were 789 patients with a median [IQR] age of 58 [40–75] years; 47% were female. The AAST ASBO grades were I (n = 180, 23%), II (n = 443, 56%), III (n = 87, 11%), and IV (n = 79, 10%). Successful non‐operative management was 58%. Conversion rate from laparoscopy to laparotomy was 33%. Overall mortality and complication and temporary abdominal closure rates were 2, 46, and 4.7%, respectively. On regression, independent predictors for mortality included grade III (OR 4.4 95%CI 1.1–7.3), grade IV (OR 7.4 95%CI 1.7–9.4), pneumonia (OR 5.6 95%CI 1.4–11.3), and failing non‐operative management (OR 2.4 95%CI 1.3–6.7).ConclusionThe AAST EGS grade can be assigned with ease at any surgical facility using operative or imaging findings. The AAST ASBO severity grading system has predictive validity for important clinical outcomes and allows for standardization across institutions, providers, and future research. Disease severity and outcomes varied between countries.Level of evidence IIIStudy type Retrospective multi‐institutional cohort study.

Study Design: Systematic review. Objectives: We conducted a systematic review of the literature to answer the following questions regarding the use of steroid therapy in metastatic spinal cord compression (MSCC): 1. In cases of MSCC, what is the effect of steroid administration before definitive radiotherapy or surgery on ambulatory status, bowel and bladder function and survival? 2. What steroid dosing regimens are associated with the best outcomes concerning neurological symptoms and complication prevention in cases of MSCC? Summary of Background Data: Currently, there is significant variation in the initial bolus dose, daily maintenance dose and duration of treatment when steroids are used as a bridge to definitive therapy for MSCC. Methods: A literature search following PRISMA guidelines was conducted in June 2016, using Medline via Ovid SP, Medline via PubMed, Embase, Biosis Previews and the Cochrane Library. Search terms used in each database varied slightly to optimize results. All generic steroid formulations were included along with spinal cord compression or myelopathy combined with metastatic or malignant tumors. Papers discussing acute traumatic causes of spinal cord compression were excluded, as were papers discussing cord compression from nonmetastatic tumors or epidural lipomatosis. Subjects were limited to adult humans undergoing definitive treatment with radiotherapy or surgery. Results: Of the 309 papers retrieved, 66 full text studies were reviewed and 6 papers were found to address the stated questions. Conclusions: There is a paucity of high quality literature evaluating the use of steroids in MSCC. On the basis of the evidence available an initial 10 mg intravenous bolus of dexamethasone followed by 16 mg PO QD has been associated with fewer complications compared with 100 mg bolus and 96 mg QD. Weaning of steroids should occur rapidly after definitive treatment. Risk of gastric bleeding or perforation can be managed with the routine use of proton-pump inhibitors. Level of Evidence: Level IIIa.

Abstract Background:Late recurrence (emergence from dormancy) is characteristic of ER+ breast cancers. Despite adjuvant endocrine therapy, many breast cancers recur decades after their initial diagnosis and treatment. Why this occurs is poorly understood. Methods: We studied 2 independent datasets of endocrine treated, ER+ breast cancers with up to 20 years follow-up. The 1st comprised matched samples from the primary tumor pretreatment at diagnosis and the first recurrence after or during adjuvant endocrine therapy (all FFPE). The 2nd dataset comprised pretreatment biopsies only (all snap frozen). For both datasets, high quality RNA was amplified, labelled, and subjected to transcriptome analysis using the Affymetrix technology (U133 Plus 2.0). Low quality data were identified using 'simpleaffy' and 'ffpe', and removed; all tools were from the R package unless otherwise noted. Remaining data were normalized using 'frma'. Genes differentially expressed between early (≤3 years) and late (≥ 5 years) were selected using limma. Unsupervised hierarchical clustering and PCA explored the structure of the data. A similar molecular analysis was done on the 2nd dataset. A classification scheme that robustly separated early from late recurrences was validated in an independent public dataset of comparable patients, array platform, and frozen tissues. We also explored features in pretreatment samples that predetermined response duration. Results: Genes that separated pretreatment specimens by recurrence time did not separate posttreatment specimens. Specimens did not cluster in patient pairs or by site of recurrence. 8245 genes were differentially expressed between early and late recurrences in the FFPE samples, while 2400 genes were significantly different in the same comparison in the frozen samples. Initial pathway analysis was done on each dataset independently using IPA (Ingenuity® Systems, www.ingenuity.com). 70 canonical pathways were identified in common between the two datasets (pretreatment). We then looked for genes regulated in both datasets (ignores FFPE and frozen tissue as source). There were 279 genes in common that differentially regulated in the same direction (upregulated; downregulated). IPA analysis of these genes identified 49 canonical pathways. We also explored the differentially expressed gene sets using 'GSEA' (www.software.broadinstitute.org/gsea/index.jsp). Pathways consistently associated with early vs. late recurrence include integrin signaling, the unfolded protein response, endoplasmic reticulum stress, actin-based motility, and estrogen biosynthesis. Conclusion: Analysis of pretreatment tumors can predict early recurrences from those that will remain dormant and recur much later. Recurrent tumors exhibit a remodeled molecular landscape that likely reflects the effects of treatments and/or a recreation of a niche with potentially common features at the site of recurrence. Changes in molecular signaling associated with duration of recurrence are consistent with our experimental model studies in vitro implicating UPR signaling as a major integrator of response to endocrine therapy and duration of survival. Additional data sets are being arrayed and more detailed molecular signaling studies are in progress. Citation Format: Clarke R, Dixon MJ, Jin L, Turnbull A, Hu R, Zwart A, Wang Y, Xuan J, Sengupta S, Renshaw L, Sims A, Liu MC. Molecular features of dormancy in ER+ breast cancers [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-10.

Abstract Background: Mammography (digital 2D or digital 3D/tomosynthesis) is the cornerstone of current screening strategies for breast cancer, but new approaches are needed to further reduce the proportion of cancers diagnosed at advanced stages and more effectively identify those women in need of additional testing and biopsies. Circulating cell-free nucleic acids (cfNAs) shed from tumors, isolated from peripheral blood, and analyzed with ultra-deep and broad sequencing of cancer-associated genes, have great potential for early cancer detection. The ultimate goal is to develop blood cfNA cancer screening tests for use in conjunction with established risk factors and/or radiographic features for improved cancer detection. Development of these tests requires large, well-annotated cohorts of asymptomatic participants with adequate volumes of prediagnostic blood. The STRIVE Study cohort was recently established to train and validate cfNA-based tests for early detection of breast cancer. Eligibility criteria and trial design: The STRIVE Study is a new prospective, multi-ethnic mammography cohort that will recruit 120,000 subjects from 15+ US breast cancer screening centers (including Mayo Clinic and Sutter Health sites). Eligibility criteria require only that a participant has a scheduled routine screening mammogram at a participating center and has not received a biopsy prior to the research blood draw. Participants are recruited within 28 days of screening mammography (digital or tomosynthesis), consent electronically, provide blood samples, and complete an on-line risk factor questionnaire. Participants will be followed for all cancer diagnoses, cancer recurrences, and death for at least 5 years. Pertinent medical record information, imaging findings (including breast density), and follow-up data will be transferred electronically to a central database throughout the study period. Additional blood samples will be collected from participants with abnormal mammogram results, or who are diagnosed with cancer, to document and better understand the evolution of cfNA signals. Recruitment began in February 2017. Primary Aims: To train and validate a cfNA blood-based test to identify breast cancer overall in a cohort of women undergoing screening mammography. Statistical Methods: The study will be divided into a training phase (1/3 of participants) and an independent clinical validation phase (remaining 2/3 of participants). In the training phase, statistical machine learning techniques will be used to develop algorithms incorporating cfNA signals, clinical characteristics, or radiological features. In the validation phase, the prespecified locked algorithm developed from the training phase will be clinically validated in an independent group of women. Contact information for people with a specific interest in the trial: Additional details regarding the STRIVE Study are available on the ClinicalTrials.gov website (NCT03085888). For site-specific questions, please call 844-366-9738 for the Mayo Clinic and 1-855-578-7483 for Sutter Health. Citation Format: Liu MC, Cummings S, Vachon CM, Kerlikowske K, Couch FJ, Morris EA, Olson JE, Polley EC, Conners AL, Ellis RL, Patel B, Maimone IV S, Zhang N, Hamilton S, Clarke CA, Allen BA, Maddala T, Hartman A-R. Development of cell-free nucleic acid-based tests for early detection of breast cancer: The STRIVE study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr OT3-02-01.

BACKGROUNDThe Spine Oncology Study Group Outcomes Questionnaire (SOSGOQ) was developed as the first spine oncology‐specific health‐related quality of life (HRQOL) measure. This study evaluated the psychometric properties and clinical validity of the SOSGOQ in a diverse cohort of patients with spinal metastases.METHODSAn international, multicenter, prospective observational cohort study including patients with spinal metastases who underwent surgery and/or radiotherapy was conducted by the AOSpine Knowledge Forum Tumor. Demographic, tumor, and treatment data were collected. HRQOL was evaluated using the SOSGOQ and Medical Outcomes Study Questionnaire Short Form 36 Health Survey (SF‐36) at baseline and fixed follow‐up times. Construct validity was assessed using multitrait scaling analyses, confirmatory factor analyses, and correlation with the SF‐36 and NRS pain score. Test‐retest reliability was assessed in a subgroup of patients between 12 weeks after treatment and the retest 4 to 9 days later.RESULTSA total of 238 patients were enrolled at 9 centers across North America; 153 of these patients had HRQOL data available at 12 weeks after treatment. Multitrait scaling analyses and confirmatory factor analyses resulted in a refined version of the SOSGOQ with 4 domains and 4 single items. The revised SOSGOQ (SOSGOQ2.0) demonstrated strong correlations with SF‐36 and the ability to discriminate between clinically distinct patient groups. Reliability of the SOSGOQ2.0 was demonstrated to be good, with an intraclass correlation coefficient ranging from 0.58 to 0.92 for the different domains.CONCLUSIONSThe SOSGOQ2.0 is a reliable and valid measure with which to evaluate HRQOL in patients with spinal metastases. It is recommended to use the SOSGOQ2.0 together with a generic HRQOL outcome measure to comprehensively assess HRQOL and increase sensitivity and specificity. Cancer 2018;124:1828‐38. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.