Citations

Abstract Menorrhagia is a common clinical problem among reproductive age women and annually 5% of reproductive age women seek medical attention, usually with gynecologists and other primary care physicians, for this symptom. Since underlying bleeding disorders are common in women presenting with menorrhagia, and referral for comprehensive hemostatic testing of substantial numbers of women with otherwise unexplained menorrhagia is problematic from the public health and cost perspective, a short, easy-to-administer screening tool comprised of 8 questions for identifying women with menorrhagia for hemostatic evaluation was previously developed (Am J Ob Gyn2008;198:e1–163e8). In the present study, the validity of the screening tool was evaluated in a multi-site, prospectively recruited cohort of women with menorrhagia. 232 women with menorrhagia age 18 and older with a pictorial blood assessment chart (PBAC) score > 100 were recruited from 5 US centers as potential subjects for a prospective cross-over study for evaluation of intranasal DDAVP versus tranexamic acid. All subjects underwent comprehensive laboratory testing for bleeding disorders, including VWF, platelet aggregation/ATP release, and factor assays. Study participants were administered a questionnaire which included the 8 screening tool questions in 4 categories, including history of duration and severity of menorrhagia, anemia treatment, excessive bleeding with hemostatic challenges, and family diagnosis of bleeding disorder. A screening tool was considered positive if there was a positive response for any of the questions in the four categories. Sensitivity of the screening tool with 95% confidence interval was calculated for bleeding disorders and also separately for low VWF (ristocetin cofactor < 50%), and platelet function defects.217 women with menorrhagia including 78% white and 16% black women with complete data were evaluated. In this population, a positive screening tool had a sensitivity of 89% (95% CI, 83–93) for bleeding disorders, 89% for platelet function defects (95% CI, 82–94), and 73% for low VWF (95% CI, 39–94). The sensitivity for bleeding disorders was 87% (95% CI, 79–92) among white women and 94% (95% CI, 79–99) among black women. Adding a PBAC score > 185 increased the sensitivity of the screening tool for bleeding disorders to 95% (95% CI, 90–98). Using a multi-site US population of adult women with menorrhagia, this study confirms the benefit of a short screening tool to assist primary care physicians in the selection of women with menorrhagia to refer for comprehensive hemostatic testing and evaluation. population of adult women with menorrhagia, this study confirms the benefit of a short screening tool to assist primary care physicians in the selection of women with menorrhagia to refer for comprehensive hemostatic testing and evaluation.

Abstract Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. A high proportion of metastatic events to the central nervous system (CNS), a known chemotherapy sanctuary site, was previously observed among the small number of relapses in patients achieving a pCR (Symmans et al 2017), raising the possibility that these CNS events may be independent of response in the breast. I-SPY2 is an adaptively randomized, phase II, platform trial that evaluates new drugs and combinations in the neoadjuvant setting for women with high-risk primary breast cancer. In this study, we evaluated the type and sites of recurrences by RCB classes in the I-SPY 2 TRIAL. Methods: I-SPY 2 patients enrolled prior to 11/2016 across 9 experimental and control arms, with available RCB and event-free survival (EFS) data were included in this analysis. The median follow-up is 3.8 years. We summarized the EFS event type, further sub-dividing the distant recurrence events by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We estimated the overall and site-specific distant recurrence incidence in each RCB class at 3 years using a competing risk (Fine-Gray) model. In addition, we assessed the association between RCB and distant recurrence free survival including all distant recurrences (DRFS), as well as excluding the CNS-only recurrences (non-CNS DRFS) using a Cox model. Our statistics do not adjust for multiplicities beyond variables evaluated in this study. Results: Among 938 subjects, there were 180 EFS events, including 28 (16%) local recurrences (without distant recurrence and/or death) and 152 DRFS events. Among the DRFS events, 25 patients died without a distant recurrence. 127 experienced distant recurrences, including 22 (17.3%) with CNS-only, 16 (12.6%) with CNS and other sites, 87 (68.5%) with non-CNS distant recurrence; 2 (1.6%) patients had missing recurrence site information. Incidence of CNS-only recurrences are low and are similar across RCB classes (pCR/RCB-0 (n=338): 1%, RCB-I (n=129): 3%, RCB-II (n=328): 2%, RCB-III (n=143): 2% at 3 years). In contrast, the incidence of non-CNS recurrences increase with increasing RCB (RCB-0: 2%, RCB-I: 4%, RCB-II: 11%, RCB-III: 19% at 3 years). DRFS of RCB-I patients do not significantly differ from those achieving a pCR/RCB-0 (DRFS at 3 years: 92% vs. 95%, hazard ratio: 1.77 (0.87-3.63)); the small numerical difference is further reduced when the CNS-only recurrences are excluded (non-CNS DRFS at 3 years: 95% vs. 96%, hazard ratio: 1.48 (0.61-3.58)). CNS recurrences among DRFS events are proportionally higher within the pCR (5/16 (31%)) and RCB-I (5/12 (42%)) than in the RCB-II (8/57 (14%)) and RCB-III (4/42 (9%)) groups largely because of the relative low frequency of non-CNS recurrence events. Conclusions: In our high-risk I-SPY 2 cohort, CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings, if confirmed, support the use of RCB to identify patients with excellent outcomes beyond those achieving a pCR; and suggest that inclusion of CNS only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcome. Citation Format: Christina Yau, Angela DeMichele, W. Fraser Symmans, Lajos Pusztai, Douglas Yee, Amy S. Clark, Christos Hatzis, Jeffrey B. Matthews, Jodi Carter, Yunn-Yi Chen, Kimberly Cole, Laila Khazai, Molly Klein, Dina Kokh, Gregor Krings, Sunati Sahoo, Kathy S. Albain, A. Jo Chien, Kirsten K. Edmiston, Anthony D. Elias, Erin D. Ellis, David M. Euhus, Heather S. Han, Claudine Isaacs, Qamar J. Khan, Julie E. Lang, Janice Lu, Jane L. Meisel, Zaha Mitri, Rita Nanda, Donald W. Northfelt, Tara Sanft, Erica Stringer-Reasor, Rebecca K. Viscusi, Anne M. Wallace, Rachel Yung, Nola M. Hylton, Judy C. Boughey, Michelle E. Melisko, Jane Perlmutter, Hope S. Rugo, Richard Schwab, Laura J. van' t Veer, Donald A. Berry, Laura J. Esserman. Site of recurrence after neoadjuvant therapy: Clues to biology and impact on endpoints [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-20-02.

e16569 Background: The National Cancer Institute’s (NCI) Cancer Trials Support Unit (CTSU) provides access to NCI-sponsored trials. To participate in a multi-center trial, sites must first complete the trial’s Protocol Specific Requirements (PSRs); interested sites are listed as “pending” in the CTSU database until all PSRs are completed. The aim of this investigation was to examine site activation delays for a study with multiple start-up steps and evaluate an intervention directed at helping sites more rapidly open it to patient accrual. Methods: NCCTG N0577, an anaplastic glioma trial named CODEL, was identified as a slow accruing trial with many sites listed as pending activation in the CTSU’s database (>85%; n=227 pending). Most N0577 pending sites had 1-2 incomplete PSRs (with 75% requiring only a neurocognitive certification), and we suspected that sites were not aware of these requirements. To accelerate site activation for N0577, we created an intervention using Awareness Theory. First, N0577 was amended to streamline the neurocognitive certification process. We then generated email lists of the 227 pending sites’ PIs (n=21; note: many were PIs of multiple sites) and their respective administrators (n=46), and created tailored email notices by PSR category explaining the necessary steps to complete N0577 activation at their site or to report their site as not planning to participate. Emails were sent to sites via the CTSU. Results: 31 sites (14%) registered activity for N0577 within 3 weeks of the intervention. Of these, 22 changed status to “approved,” 2 were disapproved, 1 withdrew, and 6 made changes but remained pending. This represents a marked increase (+520%) in site activity of the CTSU Regulatory Support Service (RSS) for N0577, compared with the monthly average (5 events/mo) during the preceding 6 months. Accrual is being monitored to observe for any increases and will be reported. Conclusions: Complicated and incomplete PSRs delay site activation of multi-center trials and may impact accrual. Streamlining PSR processes and early monitoring of CTSU site activation with notifications to sites of outstanding PSRs for trials can increase the timeliness of sites opening trials, with the potential to improve accrual.

3523 Background: The association of KRAS or BRAFV600E mutations with prognosis in colon cancers has been inconsistent. Since primary tumor site may influence outcome, we analyzed KRAS and BRAFV600E stratified by tumor site in resected stage III colon cancers from a randomized adjuvant trial of mFOLFOX6 + cetuximab chemotherapy (N= 2,686) where no survival difference by treatment was found. Methods: 2,580 tumors were analyzed for mutations in BRAFV600E (exon 15) or KRAS (codons 12, 13), and for deficient DNA mismatch repair (dMMR). Cox models were used, adjusting for mutation status, age, sex, treatment, T-stage, histologic grade, nodal status, tumor site, and MMR. After study initiation, eligibility was restricted to patients (pts) with KRAS wild-type (WT) tumors. At a median follow-up 4.1 yrs, 83% of pts are alive. Results: KRAS and BRAFV600E mutations were detected in 716 (28%) and 346 (14%) tumors, respectively; dMMR was found in 314 (12%). Proximal (to splenic flexure) tumors (50%) were associated with older age and were more likely to be high grade (33 vs 18%), T-stage3,4 (88 vs 82%), mutated for KRAS (33 vs 23%) or BRAFV600E (23 vs 4%), and dMMR (21 vs 3%)[all p <0.02]. Pts with distal vs proximal tumors showed improved disease-free survival (DFS)[ HR 0.7, 95% CI (0.6-0.9); p<0.01 unadjusted for KRAS or BRAF;]. Mutant KRAS [HR=1.5 (1.2-1.7); p<.0001] or mutant BRAF [HR=1.4 (1.1-1.7); p=0.02] were each independently associated with worse DFS. The KRAS and tumor site interaction was significant (unadjusted pinteraction=0.02; adjusted pinteraction=0.07), with poorer DFS among distal tumors having mutant KRAS [HR 1.7 (1.3-2.2); p<.0001]. No interaction was observed for BRAFV600E and tumor site, despite worse DFS for mutant BRAFV600E among proximal tumors [HR 1.3 (1-1.8); p=0.04]. Conclusions: The adverse prognostic impact of KRAS, but not BRAFV600E, mutations was confined to the distal colon. This finding underscores the importance of tumor site in the interpretation of the prognostic impact of KRAS status, and motivates similar analyses in pts with advanced disease.

3564 Background: Lethal-7 (let-7) microRNA has been shown to inhibit colon cancer cell proliferation by inducing KRAS downregulation after binding to specific sites in the 3’- UTR. Recent studies identified a KRAS 3’-UTR polymorphism in the let-7 complimentary site (LCS6) that has been shown to weaken let-7 binding and alter KRAS expression. Carriers of the LCS6 G-allele showed worse survival in metastatic colorectal cancer from prior studies of limited sample size. In the current study, we evaluated the LCS6 variant in 2,834 Stage III colon cancer patients and its association with disease-free survival (DFS), KRAS mutation status, and other clinicopathological features. Methods: In the NCCTG phase III trial (N0147), the LCS6 variant was assayed in germline DNA extracted from whole blood using RT-PCR. Extracted tumor DNA was analyzed for KRAS exon 2 mutations. Chi-squared and two-sample t test were used to compare baseline factors and KRAS mutation status between patients defined by LCS6 variant status. Log-rank tests and multivariate Cox models assessed the unadjusted and adjusted associations between LCS6 status and DFS, respectively. Results: We identified 432 (15.2%) patients heterozygous or homozygous for the LCS6 G-allele and 2402 (84.8%) patients homozygous for the LCS6 T-allele. G-allele carriers were significantly more frequent in Caucasians than other races (Chi-Squared Test, p<0.0001). No associations were found between the LCS6 genotype and T stage, positive lymph node number, tumor differentiation, or primary tumor location (all p>0.2). Moreover, the LCS6 genotype was not associated with DFS (hazard ratio = 0.93, p=0.49) even after combining LCS6 genotype with KRAS mutation status. Conclusions: We report the largest association study investigating the LCS6 polymorphism and colon cancer outcome. There is no significant evidence that the germline LCS6 genotype was associated with DFS in stage III colon cancer patients. Additional studies are needed to determine if LCS6 genotype differs between tumor and germline DNA which may further clarify its prognostic value.

Study Design: Literature review. Objectives: Surgical site infection (SSI) following spine surgery leads to significant patient morbidity, mortality, and increased health care costs. The purpose of this article is to identify risk factors and strategies to prevent SSIs following spine surgery, with particular focus on avoiding infections in posterior cervical surgery. Methods: We performed a literature review and synthesis to identify methods that can be used to prevent the development of SSI following spine surgery. Specific pearls for preventing infection in posterior cervical spine surgery are also presented. Results: SSI prevention can be divided into patient and surgeon factors. Preoperative patient factors include smoking cessation, tight glycemic control, weight loss, and nutrition optimization. Surgeon factors include screening and treatment for pathologic microorganisms, skin preparation using chlorhexidine and alcohol, antimicrobial prophylaxis, hand hygiene, meticulous surgical technique, frequent irrigation, intrawound vancomycin powder, meticulous multilayered closure, and use of closed suction drains. Conclusion: Prevention of SSI following spine surgery is multifactorial and begins with careful patient selection, preoperative optimization, and meticulous attention to numerous surgical factors. With careful attention to various patient and surgeon factors, it is possible to significantly reduce SSI rates following spine surgery.

Abstract High‐dimensional mass cytometry data potentially enable a comprehensive characterization of immune cells. In order to positively affect clinical trials and translational clinical research, this advanced technology needs to demonstrate a high reproducibility of results across multiple sites for both peripheral blood mononuclear cells (PBMC) and whole blood preparations. A dry 30‐marker broad immunophenotyping panel and customized automated analysis software were recently engineered and are commercially available as the Fluidigm® Maxpar® Direct™ Immune Profiling Assay™. In this study, seven sites received whole blood and six sites received PBMC samples from single donors over a 2‐week interval. Each site labeled replicate samples and acquired data on Helios™ instruments using an assay‐specific acquisition template. All acquired sample files were then automatically analyzed by Maxpar Pathsetter™ software. A cleanup step eliminated debris, dead cells, aggregates, and normalization beads. The second step automatically enumerated 37 immune cell populations and performed label intensity assessments on all 30 markers. The inter‐site reproducibility of the 37 quantified cell populations had consistent population frequencies, with an average %CV of 14.4% for whole blood and 17.7% for PBMC. The dry reagent coupled with automated data analysis is not only convenient but also provides a high degree of reproducibility within and among multiple test sites resulting in a comprehensive yet practical solution for deep immune phenotyping.

Background: Laparoendoscopic single site surgery (LESS) is feasible for more complex procedure types, but the technical challenges and learning curve posed by LESS makes traditional multi-incision laparoscopy still the preferred technique. The aims of this study were to understand the restricted mobility and positional requirements of these more complex procedures and to generate innovative instrument designs to overcome these restrictions. Methods: A two-phase study was conducted where three lightly-embalmed (fresh tissue) cadavers were utilized to estimate in vivo mobility restriction and positional requirements. These data were combined to quantifying instrument force and positional requirements to develop a novel design for a LESS-specific grasper. Results: The LESS-specific has an ergonomic curved axial handle and locking mechanism that enables surgeons to relax their grip without the grasper releasing. Conclusion: Further design adaptations are needed to optimize the size, angles, and curvature of the tool, as well as to add two points of articulation for rapid intracorporeal adjustment.