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Blood-based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity remain a barrier to ctDNA replacing tissue-based testing. We hypothesized that testing immediately after starting treatment would yield an increased abundance of ctDNA in plasma because of tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing.Three prospective cohorts of patients with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained patients starting platinum doublet chemoradiation (n = 10) and cohort 2 (C2) initiating platinum doublet cytotoxic chemotherapy ± immunotherapy (n = 10). Cohort 3 (C3) contained patients receiving palliative radiation. Two baseline samples were collected. In C1 and C2, subsequent samples were collected 3, 6, 24 and 48 h post initiation of chemotherapy. Patients in C3 had samples collected immediately prior to the next three radiotherapy fractions. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst®-Lung assay.A total of 40 patients were enrolled. Detectable ctDNA was present at baseline in 32 patients (80%), 4 additional patients (50%) had detectable ctDNA in post-treatment samples. Seven patients with detectable ctDNA at baseline (23%) had new genetic alterations detected in post-treatment samples. Mutant molecule numbers increased with treatment in 24 of 31 (77%) pts with detectable ctDNA. ctDNA levels peaked a median of 7 h (IQR:2-26 h) after the initiation of chemotherapy and a median of 2 days (IQR:1-3 days) after radiation was commenced.ctDNA levels increase in the hours to days after starting treatment. ctDNA testing in the acute post-treatment phase can yield results that were not evident in pre-treatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and improve sensitivity for the detection of treatment-resistant clones.(NCT03986463).

Background Perinatal cannabis use is increasing, and clinician counselling is an important aspect of reducing the potential harm of cannabis use during pregnancy and lactation. To understand current counselling practices, we conducted a systematic review and integrative mixed-methods synthesis to determine “how do perinatal clinicians respond to pregnant and lactating patients who use cannabis?” Methods We searched 6 databases up until 2021-05-31. Eligible studies described the attitudes, perceptions, or beliefs of perinatal clinician about cannabis use during pregnancy or lactation. Eligible clinicians were those whose practice particularly focusses on pregnant and postpartum patients. The search was not limited by study design, geography, or year. We used a convergent integrative analysis method to extract relevant findings for inductive analysis. Results Thirteen studies were included; describing perspectives of 1,366 clinicians in 4 countries. We found no unified approach to screening and counselling. Clinicians often cited insufficient evidence around the effects of perinatal cannabis use and lacked confidence in counselling about use. At times, this meant clinicians did not address cannabis use with patients. Most counselled for cessation and there was little recognition of the varied reasons that patients might use cannabis, and an over-reliance on counselling focussed on the legal implications of use. Conclusion Current approaches to responding to cannabis use might result in inadequate counselling. Counselling may be improved through increased education and training, which would facilitate conversations to mitigate the potential harm of perinatal cannabis use while recognizing the benefits patients perceive.

Aim: Cisplatin causes acute kidney injury (AKI) in approximately one-third of patients. Serum creatinine and urinary output are poor markers of cisplatin-induced (AKI). Metabolomics was utilized to identify predictive or early diagnostic biomarkers of cisplatin-induced AKI. Methods: Thirty-one adult head and neck cancer patients receiving cisplatin (dose ≥ 70 mg m2 -1) were recruited for metabolomics analysis. Urine and serum samples were collected prior to cisplatin (pre), 24-48 hours after cisplatin (24-48h), and 5-14 days (post) after cisplatin. Based on serum creatinine concentrations measured at the post timepoint, 11/31 patients were classified with clinical AKI. Untargeted metabolomics was performed using liquid chromatography-mass spectrometry. Results: Metabolic discrimination was observed between “AKI” patients and “no AKI” patients at all timepoints. Urinary glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate were significantly different between AKI patients and no AKI patients prior to cisplatin infusion. Urinary glycine and hippuric acid sulfate were lower (-2.22-fold and -8.85-fold), whereas 3-hydroxydecanedioc acid and suberate were higher (3.62-fold and 1.91-fold) in AKI patients relative to no AKI patients. Several urine and serum metabolites were found to be altered 24-48 hours following cisplatin infusion, particularly metabolites involved with mitochondrial energetics. Conclusion: We propose glycine, hippuric acid sulfate, 3-hydroxydecanedioc acid, and suberate as predictive biomarkers of predisposition to cisplatin-induced AKI. Metabolites indicative of mitochondrial dysfunction may serve as early markers of subclinical AKI.

Perinatal cannabis use is increasing, and clinician counselling is an important aspect of reducing the potential harm of cannabis use during pregnancy and lactation. To understand current counselling practices, we conducted a systematic review and integrative mixed-methods synthesis to determine "how do perinatal clinicians respond to pregnant and lactating patients who use cannabis?"We searched 6 databases up until 2021-05-31. Eligible studies described the attitudes, perceptions, or beliefs of perinatal clinician about cannabis use during pregnancy or lactation. Eligible clinicians were those whose practice particularly focusses on pregnant and postpartum patients. The search was not limited by study design, geography, or year. We used a convergent integrative analysis method to extract relevant findings for inductive analysis.Thirteen studies were included; describing perspectives of 1,366 clinicians in 4 countries. We found no unified approach to screening and counselling. Clinicians often cited insufficient evidence around the effects of perinatal cannabis use and lacked confidence in counselling about use. At times, this meant clinicians did not address cannabis use with patients. Most counselled for cessation and there was little recognition of the varied reasons that patients might use cannabis, and an over-reliance on counselling focussed on the legal implications of use.Current approaches to responding to cannabis use might result in inadequate counselling. Counselling may be improved through increased education and training, which would facilitate conversations to mitigate the potential harm of perinatal cannabis use while recognizing the benefits patients perceive.Cannabis use during pregnancy and breastfeeding is common and understanding current physician counselling approaches is important to identify gaps and to make suggestions for practice. We conducted a systematic review of the literature to understand how physicians respond to pregnant or breastfeeding patients who use cannabis. We found 13 eligible articles in our review and our analysis showed that there was no common approach to screening and counselling patients. Physicians often described needing more training and education to support their confidence. Additionally, physicians often did not address the various medical reasons for which patients might use cannabis during pregnancy and breastfeeding. We suggest that counselling approaches may be improved through increased education and training. This could facilitate conversations to help mitigate the potential harm of cannabis use while recognizing the benefits patients perceive and thus establish strong patient–physician relationships.

Rates of perinatal cannabis use are rising, despite clinical evidence about the potential for harm. Accordingly, pregnant and lactating people who perceive a benefit from cannabis use may have a difficult time making informed decisions about cannabis use.We conducted a systematic review of mixed-methods research to synthesize existing knowledge on the perspectives of pregnant people and their partners about cannabis use in pregnancy. Six health and social science databases were searched up until May 30, 2021. There were no methodological, time, or geographic limits applied. We employed a convergent integrative approach to the inductive analysis of findings from all studies.We identified 26 studies describing views of 17,781 pregnant and postpartum people about cannabis use in pregnancy. No studies describing the views of partners were identified, and only one study specifically addressed the perspectives of lactating people. Comparative analysis revealed that whether cannabis was studied alone or grouped with other substances resulted in significant diversity in descriptions of participant decision-making priorities and perceptions of risks and benefits. Studies of cannabis alone demonstrated a complex decision-making process whereby perceived benefits are balanced against the available information about risk, which is often unclear and uncertain. Clear and helpful information was difficult to identify, and health care providers were not described as a helpful and trusted resource for decision-making.Decision-making about cannabis use is difficult for pregnant and lactating people who perceive a benefit from this use, although this decisional difficulty is seldom reflected in studies that examine cannabis as one of multiple substances that pregnant or lactating people may use. Our review suggests several approaches clinicians may take to encourage open and supportive conversations to facilitate informed decisions about cannabis use during the perinatal period.

Background: Lymphedema has been a prevalent and often severe side effect for patients receiving treatment for breast cancer typically resulting in physical and psychosocial distress as well as decreased quality of life. With no widely effective or safe drug treatment(s) for lymphedema, this study aimed to assess the efficacy of combined Lymphdiaral™ drops and ointment for treatment-related lymphedema. Methods: This open label, randomized, parallel-group trial ran over 12 weeks with a final follow-up visit at 24 weeks. One hundred and thirty-four (n = 134) patients were consented to the study. Of these, 119 patients were randomized to either standard care group (compression garment) or treatment group (compression garment plus Lymphdiaral™ drops and ointment) and follow-up data was obtained. The primary objective was the reduction in lymphedema as measured by change in arm volume. Results: The values for the arm volumes did not show a statistically significant decrease in both the standard care or treatment groups. Additionally, there was no statistical difference in arm volume reduction between the groups. Conclusions: This first randomized trial shows, that the homeopathic drug combination of Lymphdiaral™ drops and ointment does not improve lymphedema in breast cancer patients. Citation Format: Jawaid Younus, Morgan Black, Lyn Kligman, Brenda Leung. Efficacy of Lymphdiaral™ in breast cancer patients with lymphedema [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 P2-12-15.

Objective. Detection of circulating tumor DNA (ctDNA) in cancer patients can potentially serve as a noninvasive, sensitive test of disease status. The purpose of this study was to determine the ability to detect BRAF (V600E) mutations in the plasma of patients with thyroid nodules, with the goal of distinguishing between benign and malignant nodules. Methods. Consecutive patients with thyroid nodules who consented for surgery were recruited. Plasma samples were obtained preoperatively and one month postoperatively. Quantitative PCR was used to determine the levels of the BRAF (V600E) mutation preoperatively and postoperatively. Results. A total of 109 patients were recruited. On final pathology, 38 (32.8%) patients had benign thyroid nodules, 45 (38.8%) had classical papillary thyroid cancer (PTC), 23 (19.8%) had nonclassical PTC, and 3 (2.6%) had follicular thyroid cancer. 15/109 patients had detectable BRAF (V600E) ctDNA in their preoperative samples—all of them having classical PTC. Higher T-stage and extrathyroidal extension in PTC were associated with positive BRAF (V600E) ctDNA ( p < 0.05 ). Eighty-eight pairs of preoperative and postoperative plasma samples were collected and analyzed. Of these eighty-eight paired samples, a total of 13/88 (14.8%) patients had detectable BRAF (V600E) ctDNA in their preoperative samples—all of them having classical PTC. 12 of these 13 patients had no detectable BRAF (V600E) postoperatively, while one remaining patient had a significant decline in his levels ( p < 0.05 ). Conclusion. BRAF (V600E) circulating thyroid tumor DNA can be detected in plasma and is correlated with a final diagnosis of the classical variant of PTC. Given that a postoperative drop in BRAF (V600E) ctDNA levels was observed in all cases suggests its utility as a tumor marker.

TPS12144 Background: Patients with locally advanced squamous cell carcinoma of the head and neck (LASCCHN) receive curative chemoradiation (CRT) with Cisplatin, as a standard of care. A meta-analysis of 52 randomized trials comparing Low Dose (LD) and High Dose (HD) schedules demonstrated differing toxicity profiles but hearing effects were not rigorously studied. Hearing loss associated with HD Cisplatin can result in survivorship challenges. A local study suggested a protective effect for LD Cisplatin in relation to ototoxicity and pharmacogenomic markers, MATE1 and COMT, to be associated with risk for ototoxicity. We hypothesize that LD cisplatin is associated with reduced frequency of hearing loss when compared to the standard HD cisplatin in LASCCHN patients on CRT and that differences in MATE1/COMT can predict for cisplatin-related ototoxicity and be identified prior to treatment. Our goal is to develop an innovative personalized treatment pathway incorporating predictive pharmacogenomics markers to improve the tolerability and survivorship outcomes of curative CRT for LASCCHN. Methods: This is a prospective, open-label, randomized clinical trial. Following informed consent, eligible LASCCHN patients planned for primary CRT will be stratified by tumor p16 status and then randomized in 1:1 fashion to either concurrent LD Cisplatin (40mg/m2 every week) or HD cisplatin (100mg/m2 every 3 weeks). The primary outcome is to measure the change in incidence of CTCAE grade ≥2 hearing loss and hearing-related quality of life (QOL) at 1 year. As part of secondary and exploratory outcomes, differences in survival, loco-regional control, global QOL and other toxicities (e.g. nephrotoxicity, neurotoxicity) will be assessed. The relationship between MATE1 and COMT, as predictors for cisplatin-related ototoxicity will be evaluated. Cost-effectiveness analyses comparing the two regimens will be assessed. Statistical plan: Based on rates of CTCAE grade ≥2 hearing loss in an earlier study (Winquist et al., 2016), assuming a conservative rate of hearing loss, amongst treated patients, of 60% with HD cisplatin and 30% with LD cisplatin, a total sample size of 92 patients would achieve > 80% statistical power, (two-sided, alpha = 0.05 test of two proportions) to detect these differences. 100 patients would be targeted to accrual for an assumed 5% noncompliance rate. For hearing related QOL, a two-sided, alpha = 0.05, two-sample t-test with 50 patients per group would achieve > 80% statistical power to detect an effect size of 0.60 and > 95% power to detect an effect size of 0.75. All analyses will be based primarily on the intent-to-treat population. An arms-length data and safety monitoring committee (DSMC) will review safety data bi-annually. Trial accrual status: 60 participants have been accrued. Clinical trial information: NCT03649048.

We describe three portable volumetric audio/video arrays capable of identifying species-specific fish sounds in the wild. Each array can record fish sounds, acoustically localize the fish in three-dimensions (using linearized or fully non-linear inversion), and record video to identify the species and observe their behavior. The design of each array accommodates specific logistical and financial constraints, covering a range of nearshore habitats and applications. The first platform is composed of six hydrophones, an acoustic recorder, and two video cameras secured to a 2 × 2 × 3 m PVC frame. Hydrophone placement is defined using simulated annealing to maximize localization accuracy. The second platform uses a single video camera, four hydrophones, and an acoustic recorder on a one cubic meter PVC frame. It can be deployed on heterogeneous substrates but has lower localization capabilities. The third platform consists of four hydrophones connected to an acoustic recorder mounted on a tethered underwater drone with built-in video. It allows remote control and real-time positioning in response to observed fish presence but with reduced localization capabilities. The three platforms were deployed off British Columbia, Canada, and used to identify and characterize new sounds from quillback rockfish, copper rockfish, and lingcod.

To examine the utility of a patient-level information video as part of the contraception consultation visit. Specifically, to assess the impact of the video on women's contraception choice, and, further, to assess patient and provider acceptability of incorporating the video into the patient visit.A pre-post study design was used to assess the impact on patients' contraceptive choices and knowledge. Participants (n = 49) answered questions regarding contraceptive preferences and knowledge of long-acting reversible contraception (LARC), then watched a 12-minute patient-level counselling video that presented evidence-based information about contraception in descending order of effectiveness. Clinicians (n = 39) also viewed the video and completed a survey. A retrospective chart review of 100 contraception visits was completed.Patient preference for IUDs increased significantly, whereas condoms decreased pre-to-post video (hormonal: 8.2% to 20.4%; copper: 0% to 16%; condoms: 32.7% to 18%, P 0.05). Although 74.4% of clinicians believed that the hormonal IUD was the "ideal" form of contraception when no contraindications were present, 95% stated that the oral contraceptive pill was most often prescribed, and a chart review revealed that the oral contraceptive pill was discussed at 88% of contraceptive counselling visits. Both patients and clinicians found the video useful and acceptable.A patient-level contraceptive information video improved interest in LARC. Both patients and clinicians viewed the video as an acceptable addition to the contraceptive counselling visit.

Spleen tyrosine kinase (SYK) is a promoter of cell survival in a variety of cell types, including normal and cancerous epithelial cells. We hypothesized that SYK would an important therapeutic target to inhibit for the treatment of HNSCC.SYK protein abundance in patient tumours was evaluated. SYK protein and mRNA abundance was used to examine patient survival and human papillomavirus (HPV) status. Small-interfering RNAs and gene editing with CRISPR/Cas9 were used to evaluate SYK expression on proliferation in HNSCC cell lines. The potency of SYK inhibitor ER27319 maleate on cellular proliferation was tested using a panel of 28 HNSCC cell lines and in vivo in HNSCC patient-derived xenograft (PDX) models.Moderate to high protein expression of SYK was observed in 24% of patient tumors and high SYK expression was exclusively observed in HPV-positive samples (p 0.001). SYK inhibition with RNA interference, gene editing or a SYK inhibitor (ER27319) decreased cell proliferation and migration. Treatment of PDXs with ER27319 maleate was observed to reduce tumour burden in vivo in two of three models.HPV-positive HNSCC harbours high SYK protein levels. We demonstrate that proliferation, migration and overall burden of these tumours can be reduced by genetic or pharmacologic inhibition of SYK. Taken together, these data establish SYK as a therapeutic target for HNSCC.

One barrier to the use of intrauterine devices (IUDs) as a contraceptive method is the experience of anxiety and pain during the insertion procedure. Previous reviews have focused on pharmacological methods used to relieve pain during IUD insertion; however, few similar reviews have examined non-pharmacological methods to relieve pain or strategies to reduce anxiety. The objectives of this study were to identify and categorize strategies for reducing anxiety and pain with respect to IUD insertion and the ways in which anxiety and pain were assessed. In particular, the study aimed to identify non-pharmacological interventions and studies that included anxiety as a research outcome. A literature search was conducted of all English-language studies between inception and the week of July 29, 2018 from the following online databases: Medline, Embase, Cochrane Library, and PubMed. The search revealed 426 studies after removal of duplicates, 35 of which fulfilled the inclusion criteria. A total of 29 studies were identified as assessing pharmacological interventions for the management of pain, and six studies assessed non-pharmacological interventions. Only one study included a measurement of patient anxiety during the procedure as an outcome measure. Research on non-pharmacological interventions for the management of anxiety and pain during IUD insertion is lacking. This review found that evidence for the studied pharmacological interventions is conflicting, and there is very little evidence on understanding the effectiveness of strategies to manage anxiety during the IUD insertion procedure. Further high-quality research on non-pharmacological pain and anxiety management strategies is warranted.

When discussing universal health insurance coverage in the United States, policymakers often draw a contrast between the U.S. and high-income nations that have achieved universal coverage. Some will refer to these countries having "single payer" systems, often implying they are all alike. Yet such a label can be misleading, as considerable differences exist among universal health care systems.To compare universal coverage systems across three areas: distribution of responsibilities and resources between levels of government; breadth of benefits covered and extent of cost-sharing in public insurance; and role of private insurance.Data from the Organisation for Economic Co-operation and Development, the Commonwealth Fund, and other sources are used to compare 12 high-income countries.Countries differ in the extent to which financial and regulatory control over the system rests with the national government or is devolved to regional or local government. They also differ in scope of benefits and degree of cost-sharing required at the point of service. Finally, while virtually all systems incorporate private insurance, its importance varies considerably from country to country. A more nuanced understanding of the variations in other countries' systems could provide U.S. policymakers with more options for moving forward.

Background: Blood based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity, especially in patients with limited disease burden, remains a barrier to ctDNA replacing tissue-based testing. There is a paucity of data regarding the optimal time to measure ctDNA, specifically the dynamics of ctDNA levels in the hours to days following a new and effective treatment. We hypothesize that chemotherapy or radiation will yield an increased abundance of ctDNA in plasma by inducing tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing. Methods: Two prospective cohorts of twenty patients (pts) with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained patients starting the first cycle of platinum doublet chemoradiation (C1a, n=10) or the first cycle of platinum doublet cytotoxic chemotherapy ± immunotherapy without concurrent radiation (C1b, n=10). Cohort 2 (C2) contained patients receiving palliative radiation. Consenting patients provided baseline samples, the first ≤ 14 days prior to starting treatment and one immediately prior to treatment. In C1, subsequent samples were collected (A) 2-3, (B) 4-6, (C) 18-72 and (D) 42-96 hours post initiation of chemotherapy. Pts in C2 had samples collected immediately prior to radiotherapy fractions 2, 3, and 4. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst®-Lung assay. Results: Complete results were available for the first 28 of 40 enrolled pts, C1a - 8 pts, C1b - 8 pts, C2 - 12 pts. Detectable ctDNA was present at baseline in 21 pts (75%), 4 additional pts (14.3%) had detectable ctDNA in post treatment samples (C1a - 2pts, C1b - 1pt, C2 - 1pt). Three of the patients with detectable ctDNA at baseline (10.7%) had new genetic alterations detected in post treatment samples. A total of 7/28 pts (25%) had new genetic alterations detected in the post treatment samples. Mutant molecule numbers increased with treatment in 19 of 25 (76%) pts with detectable ctDNA, C1 - 11 of 15 pts (73.3%) and C2 - 8 of 10 pts (80%). ctDNA levels peaked a median of 2.2 hours (interquartile range (IQR): 1.5 - 2.9 hours) after the initiation of chemotherapy and a median of 1 day (IQR: 1-2 days) after radiation was commenced. The percentage increase in ctDNA levels was a median of 39.3% (IQR: -20.5 to +112.8%) in C1, with median increases of 22.0% and 39.3% in C1a and C1b, respectively. C2 had a median increase of 81.9% (IQR: 0 to +161.5%). Conclusion: ctDNA levels increase in the hours to days after starting a new treatment. ctDNA testing in the acute post treatment phase can yield results that were not evident in pretreatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and/or improve sensitivity for the detection of treatment-resistant clones. Citation Format: Daniel Breadner, Mark David Vincent, Rohann Correa, Morgan Black, Andrew Warner, Melody Qu, Diane Logan, Michael Sanatani, Jawaid Younus, Brian Yaremko, George Rodrigues, Phillip Blanchette, Joanna Laba, Edward Yu, David Goodale, Lori Lowes, Vasudeva Bhat, Albert Gratton, James Sinfield, Susan Archer, Clive Morris, Emma Green, Greg Jones, Alison Allan, David Palma, Jacques Raphael. Exploitation of treatment induced tumor lysis to enhance sensitivity of ctDNA analysis: a first-in-human pilot study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 770.

3530 Background: Blood based liquid biopsies examining circulating tumour DNA (ctDNA) have increasing applications in non-small cell lung cancer (NSCLC). Limitations in sensitivity remains a barrier to ctDNA replacing tissue-based testing. There is a paucity of data regarding the dynamics of ctDNA levels in the hours to days following a new treatment. We hypothesize that chemotherapy or radiation will yield an increased abundance of ctDNA in plasma by inducing tumor lysis, allowing for the detection of genetic alterations that were occult in baseline testing. Methods: Two prospective cohorts of 20 patients (pts) with stage III/IV NSCLC were enrolled. Cohort 1 (C1) contained pts starting the first cycle of platinum doublet chemoradiation (C1a, n=10) or the first cycle of platinum doublet cytotoxic chemotherapy ± immunotherapy without radiation (RT) (C1b, n=10). Cohort 2 (C2) contained pts receiving palliative RT alone. Two baseline samples were collected, the first ≤ 14 days prior to starting treatment and one immediately prior to treatment. In C1, subsequent samples were collected 3, 6, 24 and 48 hours post initiation of chemotherapy. Pts in C2 had samples collected immediately prior to RT fractions 2, 3, and 4. Samples were analyzed for ctDNA using the 36-gene amplicon-based NGS Inivata InVisionFirst-Lung assay. Results: Complete results were available for the first 35 of 40 enrolled pts, C1a – 10 pts, C1b – 9 pts, C2 – 16 pts. Detectable ctDNA was present at baseline in 27 pts (77%), 4 additional pts (11%) had detectable ctDNA in post treatment samples. Four of the patients with detectable ctDNA at baseline (15%) had new genetic alterations detected in post treatment samples. A total of 8/35 pts (23%) had new genetic alterations detected in the post treatment samples. Mutant molecule numbers increased with treatment in 23 of 31 (74%) pts with detectable ctDNA, C1 - 13 of 19 pts (68%) and C2 - 10 of 16 pts (63%). ctDNA levels peaked a median of 2.2 hours (IQR: 1.5 – 2.9 hours) after the initiation of chemotherapy and a median of 1 day (IQR: 1-2 days) after radiation was commenced. The percentage increase in ctDNA levels was a median of 29% (IQR: -18 to +112%) in C1. C2 had a median increase of 16% (IQR: 0 to +131%). Conclusions: ctDNA levels increase in the hours to days after starting treatment. ctDNA testing in the acute post treatment phase can yield results that were not evident in pretreatment testing. Application of this principle could improve ctDNA utility as an alternate to tissue-based testing and improve sensitivity for the detection of treatment-resistant clones.

e12532 Background: Early Breast Cancer Trialist Collaborative Group meta-analysis suggested significant reduction in bone metastasis and breast cancer mortality among post-menopausal women diagnosed with early breast cancer when treated with an adjuvant bisphosphonate. Cancer Care Ontario and American Society of Clinical Oncology clinical practice guideline published in 2017, recommends the use of an adjuvant bisphosphonate in postmenopausal women who are candidates for adjuvant systemic therapy. Our goal was to evaluate trends and factors associated with adjuvant bisphosphonate usage since the guideline’s publication. Methods: This study is a retrospective review of postmenopausal women treated for early breast at the London Regional Cancer Program from 2017-2018. Univariate and a multivariable logistic regression models were used to investigate factors potentially associated with adjuvant bisphosphonate use including age, stage, grade, estrogen receptor, progesterone receptor, HER2 receptor status and previous use of adjuvant chemotherapy. The percentage of patients offered, receiving and declining therapy was also recorded and the time interval from surgery to start of bisphosphonate therapy (< 6 months, 6-12 months or >12 months). Results: We identified 286 postmenopausal breast cancer patients, of whom 75 (28%) received adjuvant bisphosphonate therapy. In our multivariable model, cancer stage [odds ratio (OR) stage II vs. I=2.26, 95% confidence interval (CI) 1.08-4.74) and OR Stage III vs. I=4.94, 95% CI 1.84-13.17] and previous use of adjuvant chemotherapy (OR=2.76, 95%CI 1.37-5.55) were significantly associated with adjuvant bisphosphonate use. Among 133 patients who received adjuvant systemic chemotherapy, 51% were offered adjuvant bisphosphonate and of these 81% patients accepted therapy. Among a total of 75 patients receiving adjuvant bisphosphonate therapy 19% initiated therapy within 6 months of surgery, 48% within 6-12 months of surgery, and 33% after 12 months following surgery. Conclusions: Stage and previous use of chemotherapy were significantly associated with adjuvant bisphosphonate therapy. Our study observes the potential underutilization of adjuvant bisphosphonate therapy and possible need to start treatment earlier in some patients. Further education and awareness of the clinical practice guidelines regarding adjuvant bisphosphonate therapy may be warranted and additional population-based study investigating treatment patterns and real-world effectiveness.

The detection of somatic single nucleotide variants (SNVs) is critical in both research and clinical applications. Studies of human cancer typically use matched normal (reference) samples from a distant tissue to increase SNV prediction accuracy. This process both doubles sequencing costs and poses challenges when reference samples are not readily available, such as for many cell-lines. To address these challenges, we created S22S: an approach for the prediction of somatic mutations without need for matched reference tissue. S22S takes underlying sequence data, augments them with genomic background context and population frequency information, and classifies SNVs as somatic or non-somatic. We validated S22S using primary tumor/normal pairs from four tumor types, spanning two different sequencing technologies. S22S robustly identifies somatic SNVs, with the area under the precision recall curve reaching 0.97 in kidney clear cell carcinoma, comparable to the best tumor/normal analysis pipelines. S22S is freely available at http://labs.oicr.on.ca/Boutros-lab/software/s22s.

Head and neck squamous cell carcinoma (HNSCC) is a common cancer diagnosis worldwide. Despite advances in treatment, HNSCC has very poor survival outcomes, emphasizing an ongoing need for development of improved therapeutic options. The distinct tumor characteristics of human papillomavirus (HPV)-positive vs. HPV-negative disease necessitate development of treatment strategies tailored to tumor HPV-status. High-throughput robotic screening of 1,433 biologically and pharmacologically relevant compounds at a single dose (4 μM) was carried out against 6 HPV-positive and 20 HPV-negative HNSCC cell lines for preliminary identification of therapeutically relevant compounds. Statistical analysis was further carried out to differentiate compounds with preferential activity against cell lines stratified by the HPV-status. These analyses yielded 57 compounds with higher activity in HPV-negative cell lines, and 34 with higher-activity in HPV-positive ones. Multi-point dose-response curves were generated for six of these compounds (Ryuvidine, MK-1775, SNS-032, Flavopiridol, AZD-7762 and ARP-101), confirming Ryuvidine to have preferential potency against HPV-negative cell lines, and MK-1775 to have preferential potency against HPV-positive cell lines. These data comprise a valuable resource for further investigation of compounds with therapeutic potential in the HNSCC.

PIK3CA is the only frequently-mutated, directly druggable oncogene in head and neck squamous cell carcinoma (HNSCC). However, it is unclear if a molecularly-driven intervention trial can be launched successfully, particularly within a single-institution setting secondary to the infrastructure necessary for mutation detection, mutation prevalence, and patient willingness to participate. This study aimed to evaluate 1) local frequency of PIK3CA activating mutations in HNSCC, 2) timeliness of our mutation-profiling clinical pathway, and 3) patients' willingness to enroll in a novel neoadjuvant drug trial. Tissue biopsies of 25 consecutive cases of HNSCC were tested for activating PIK3CA mutations at three mutational hotspots by real-time polymerase chain reaction. Mutations prevalence and number of working days accrued in determining PIK3CA mutational status were calculated. In addition, 30 HNSCC patients were surveyed prospectively regarding their willingness to participate in a hypothetical drug trial. Survey data were summarized descriptively. 4 of 25 (16 %) tumors harbored a PIK3CA activating mutation, including one at codon E542K, two at codon E545K/D, and one at codon H1047R. On average, this result was obtained in approximately 15 working days (range, 9-24 working days). The majority of patients surveyed (70 %) indicated their willingness to participate in a targeted PIK3CA trial. This study provides evidence that within a single institution, PIK3CA activating mutations can be detected with expected frequency, with sufficient timeliness and sufficient patient interest to mount a targeted intervention trial that may lead to improved tumor response in selected HNSCC patients.

Background Evidence-based patient education and consistent, timely communication is key to ensuring good outcomes among joint replacement patients. Mount Sinai Hospital (MSH) participates in the mandatory CMS bundle for comprehensive joint replacement (CJR). MSH’s bundled payment strategy focuses on the development of a standardized model of care, built around evidence-based best practices to achieve the triple aims of strengthening population health while controlling cost and improving the quality of care. MSH launched a comprehensive digital navigation program (DNP) to guide joint replacement patients and their caregivers through pre-surgical preparation and recovery. Objective The objective was to improve the quality of care for joint replacement patients through creation of a digital navigation program specifically tailored to Medicare patients (age 65+) across the continuum of care. Methods Mount Sinai App Lab, in collaboration with the Department of Orthopedics, developed three digital therapeutic modules that were delivered through the RxUniverse Digital Medicine platform (Rx.Health, NY). These automated messages, programmed to send at specific times, included exercise instructions, medication reminders, and suggestions for how to prepare the home for optimal recovery. Messages specifically targeted key patient outcomes: length of stay, readmissions, ambulation on postoperative day 0, and discharge disposition. Staff “prescribed” each module to patients to ensure that engagement aligned with their process of care. Results Clinicians, patients, and their caregivers were receptive to the DNP. Patients showed a high rate of engagement, clicking links to educational content 873 times, and patients called their case manager or surgeon’s office to clarify their next steps when prompted. After 9 months, clinical outcomes for the digital navigation program were compared to other Medicare patients who had not received it. DNP patients had significantly shorter length of stay than their peers (2.81 vs 4.31 days). They also had a lower readmission rate (1.9% vs 2.9%) as well as a higher rate of discharge to home (87.8% vs 64.3%) and were more likely to ambulate on the day of surgery (47.9% vs 33.3%). Twenty patients responded to an end-of-program survey about their experience; 18 patients (90%) agreed that the program was helpful with the process of their total joint replacement surgery, 2 patients neither agreed nor disagreed (10%), and 0 patients disagreed. When asked about their satisfaction with the message volume, 19 patients answered “yes, this was the perfect number,” (95%) and 1 patient answered “no, I want fewer messages” (5%). Patient qualitative feedback was very positive. Patients reported, “Texts reassured me and helped me along with my progress and recovery,” and “Good support. Thank you.” A third said, “The texting program serves as a great reminder as what to do and when.” Conclusions The CJR DNP provided a direct, automated channel to educate and support patients at each stage of care. It demonstrated that digital navigation technology can be used even among non-digital native populations. It resulted in a significantly reduced length of stay and hospital readmissions among participating patients. Next steps include scaling the program across the health system and adding Spanish-language support. Similar programs are now being implemented for other surgical and disease use cases.

The inherent genetic instability of cancer cells and the dependence of many tumor types on oncogenic drivers contribute selectivity of anticancer agents against tumor cells. However, that selectivity is limited, and toxicity to normal cells remains a major limitation to the success of chemotherapy. Aiming to increase selectivity by exploiting cancer cell genetic instability, we demonstrated that the small molecule IBR2 (an inhibitor of the DNA repair protein RAD51) enhanced cytotoxicity of numerous anticancer drugs, including agents that do not directly target DNA (J Pharmacol Expt Ther, 364: 46-54, 2018). Given the potential importance of combining IBR2 with anticancer treatment to increase therapeutic index, IBR2 was tested in combination with other untested agents against a panel of tumor cell lines. In addition, studies were expanded to include IBR120 [(R)-3-(2-(benzylsulfonyl)isoindolin-1-yl)-1h-indole], a new small molecule RAD51 inhibitor that is reportedly more selective against cancer cell lines (Euro J Med Chem 96: 196-208, 2015). Four-day drug exposures were conducted in 96-well plates. Relative cell density, determined using vital stains (alamarBlue©, neutral red), was reported as a percent of the fluorescence/absorbance of control cultures. Cell lines were representative of tumors from breast (MCF-7, SK-BR-3), prostate (LNCaP, DU145), colon (HT-29), stomach (N87), skin (SK-MEL-5), and lung (A549b, H1650, H1975), including osimertinib-resistant derivatives of the non-small-cell lung cancer (NSCLC) cell lines. The chemotherapy agents included inhibitors of epidermal growth factor receptor (EGFR) family (osimertinib, afatinib, lapatinib), Bcr-Abl (imatinib), B-raf (vemurafenib), multiple tyrosine kinases (regorafenib), sex steroid receptors (4-OH-tamoxifen, enzalutamide), and microtubules (vincristine). Both IBR2 and IBR120 decreased the concentration of drugs that inhibited proliferation by 50% (IC50) by up to 90%, indicating synergy between the agents. However, there were a small number of combinations in which no synergy was observed, indicating selectivity for this interaction. In the NSCLC cell lines, IBR2, IBR120, osimertinib, gefitinib, and afatinib decreased the cellular content of RAD51 by over 80% within 24 h (western blot with antibody 3C10), at concentrations at or lower than their IC50 value. The contribution of this decrease in RAD51 to synergy is being investigated. Studies are ongoing to determine the effect of IBR120 on growth of explants of the NSCLC cell line H1650 in mice, after which the combination of IBR120 and osimertinib will be tested in vivo. The ability of IBR2 and IBR120 to enhance antiproliferative activity of a wide variety of anticancer agents and their potential selectivity for cancer cells make possible their future use as systemic therapy potentiators to improve clinical outcomes. Citation Format: Peter J. Ferguson, Morgan Black, Rene Figueredo, Mark D. Vincent, James Koropatnick. Synergistic antiproliferative activity between anticancer drugs and RAD51 inhibitors IBR2 and IBR120 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3057.

Background: Recently reported randomized clinical trials (RCTs) have confirmed the importance of concurrent cisplatin in the curative treatment of HPV-related oropharynx cancer treated with definitive radiotherapy (RT) (Mehanna ESMO 2018, Trotti ASTRO 2018). However, the optimal cisplatin dose and schedule in this setting remain unclear. Concurrent high-dose cisplatin (HDC) given every 3 weeks is considered standard but associated with increased risks of infection, vomiting and nephrotoxicity (Szturz 2018). Cisplatin-associated hearing loss (CAHL) has been less well studied. Noronha et al (2018) reported less permanent deafness but inferior cancer outcomes with weekly cisplatin at a dose of 30 mg/m2 compared to HDC. However, meta-analysis of RCTs shows no difference in mortality with weekly compared to HDC (Szturz 2018). RCT results to date suggest a minimum total dose of 200 mg/m2 cisplatin be delivered at a minimum dose of 40 mg/m2 per week for optimal anticancer effect. Weekly cisplatin schedule, MATE1 polymorphisms (SNPs), absence of COMT SNPs and lower cochlear RT dose independently predict lower CAHL risk (Teft 2019). We hypothesize that if there is a small incremental antitumor benefit of HDC in oropharyngeal cancer patients who are expected to be cured, it is offset by the negative quality of life (QoL) impact of permanent hearing loss. This RCT was designed to confirm reduced ototoxicity with weekly compared to q3weekly cisplatin when combined with RT, quantitate effects on hearing-related QoL, and validate pharmacogenomic risk factors. Methods: This randomized clinical trial will be conducted at two comprehensive cancer centres in Ontario, Canada and is open to enrollment. 100 patients will be stratified by tumor HPV status and randomized (1:1) to receive cisplatin either 100 mg/m2 IV q21days for 3 doses (control arm) or 40 mg/m2 IV weekly (experimental arm) during RT. Eligible patients will have squamous cell carcinoma of the oral cavity, oropharynx, larynx, nasal cavity, hypopharynx or unknown primary site planned for IMRT + cisplatin with curative intent after assessment by a multidisciplinary team, and must be deemed suitable for HDC by the treating medical oncologist. Patients with prior head or neck RT, baseline hearing impairment or known/suspected nasopharyngeal cancer are ineligible. RT will be once daily IMRT 5 days weekly to total dose of 70 Gy/35F (64 Gy/30F if postoperative). The trial is powered to evaluate co-primary endpoints of hearing-related QoL (by HHIA & HHIE) and CAHL grade 2 or greater (CTCAE 4.03) at 1 year. Secondary endpoints include: need for amplification, tinnitus, health-related QoL, and grade 3 or worse neuropathy and neuropathy all at 1 year. Overall and progression-free survival, locoregional control, and cost-effectiveness will also be assessed. Citation Format: Eric Winquist, Brandon Meyers, Greg Pond, Sebastien Hotte, Morgan Black, Christina Parker, Anthony Nichols, David Palma, Richard Kim, Sara Kuruvilla. Randomized assessment of cisplatin dose interval for ototoxicity in the treatment of locally advanced squamous cell carcinoma of the head and neck undergoing curative concurrent chemoradiotherapy (RADIO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT122.

Albendazole is an anti-helminthic drug that has been shown to exhibit anti-cancer properties, however its activity in head and neck squamous cell cancer (HNSCC) was unknown. Using a series of in vitro assays, we assessed the ability of albendazole to inhibit proliferation in 20 HNSCC cell lines across a range of albendazole doses (1 nM-10 μM). Cell lines that responded to treatment were further examined for cell death, inhibition of migration and cell cycle arrest. Thirteen of fourteen human papillomavirus-negative HNSCC cell lines responded to albendazole, with an average IC50 of 152 nM. In contrast, only 3 of 6 human papillomavirus-positive HNSCC cell lines responded. Albendazole treatment resulted in apoptosis, inhibition of cell migration, cell cycle arrest in the G2/M phase and altered tubulin distribution. Normal control cells were not measurably affected by any dose tested. This study indicates that albendazole acts to inhibit the proliferation of human papillomavirus-negative HNSCC cell lines and thus warrants further study as a potential chemotherapeutic agent for patients suffering from head and neck cancer.

Urinary tract infections (UTIs) are common in young children and are seen in emergency departments (EDs) frequently. Left untreated, UTIs can lead to more severe conditions. Our goal was to undertake a quality improvement (QI) initiative to help minimize the number of children with missed UTIs in a newly established tertiary care pediatric emergency department (PED). A retrospective chart review was undertaken to identify missed UTIs in children < 3 years old who presented to a children’s hospital’s ED with positive urine cultures. It was found that there was no treatment or follow-up in 12% of positive urine cultures, indicating a missed or possible missed UTI in a significant number of children. Key stakeholders were then gathered and process mapping (PM) was completed, where gaps and barriers were identified and interventions were subsequently implemented. A follow-up chart review was completed to assess the impact of PM in reducing the number of missed UTIs. Following PM and its implementation within the ED, there was no treatment or follow-up in only 1% of cases. Based on our results, the number of potentially missed UTIs in the ED decreased dramatically, indicating that PM can be a successful QI tool in an acute care pediatric setting.

Halfway through a dev bootcamp? Straight out of college with a CS degree? Hacking away at Hartl after your day job? Now what? With articles about how employable you are and how much money you can make printed daily, it can be hard to stay focused on the most important tangibles – the job search, interview readiness, and your early career goals. In this talk, we’ll cover how to prepare yourself and your projects for the interview process, and how to adequately vet the companies interested in you, allowing you to not only secure a rails job, but one that you love.

Introduction: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common cancer worldwide, with an incidence of ~600 000 new cases per year and a 50% mortality rate for advanced disease. The mutational landscape of HNSCC has been recently elucidated, introducing the possibility for targeted therapeutic approaches. PIK3CA—which encodes the α-catalytic subunit of PI3K (PI3Kα)—is the most frequently altered actionable target in HNSCC, however it is not presently clear which patients benefit most from PI3Kα-inhibition. BYL719 is a leading PI3Kα inhibitor in clinical development for HNSCC. We previously examined the responses of a large panel of genetically-characterized HNSCC cell lines to BYL719 and identified activating HRAS G12V mutations as strong predictors for BYL719 resistance. Here we examine if this mutation is able to individually modulate BYL719 response through overexpression and knockdown studies. Methods: To determine if HRAS G12V was able to modulate BYL719 sensitivity, we knocked down HRAS in HRAS G12V and HRAS wild-type (WT) cell lines using RNA interference, and then treated cells over 10-point dose ranges with BYL719. Sensitivity was determined by calculating IC50 (half-maximal inhibitory concentration) values at 72 hours using PrestoBlue®. Constructs expressing wildtype (WT) HRAS or HRAS G12V were transfected into BYL719-sensitive cells for overexpression studies and cells were selected using G418 Sulfate for 1 month. Proliferation and BYL719 sensitivity (IC50 values) were measured as described. Immunoblotting was used to examine activity of the PI3K-AKT axis with and without BYL719 (1μM) for 24 hours. Results & Conclusions: HRAS knockdown sensitized HRAS G12V lines to BYL719 (lower IC50), but did not affect the response of WT HRAS cells. WT HRAS and HRAS G12V overexpression significantly increased cellular proliferation and promoted BYL719 resistance. In HRAS G12V cell lines, we observed high levels of active phosphorylated AKT (S473/T308), even in the presence of BYL719. Collectively these findings highlight the predictive role of HRAS G12V for innate BYL719 resistance and contribute to our understanding of which patients may respond best on BYL719 therapy. Citation Format: Kara M. Ruicci, Ren Sun, Morgan Black, Nicole Pinto, John Yoo, Kevin Fung, Danielle Macneil, Lauire Aillies, Joseph S. Mymryk, Paul C. Boutros, John W. Barrett, Anthony C. Nichols. HRAS G12V predicts for innate resistance to PI3Kα inhibition in head and neck squamous cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3162. doi:10.1158/1538-7445.AM2017-3162

Background There is an urgent need for better therapeutics in head and neck squamous cell cancer (HNSCC) to improve survival and decrease treatment morbidity. Recent advances in high-throughput drug screening techniques and next-generation sequencing have identified new therapeutic targets in other cancer types, but an HNSCC-specific study has not yet been carried out. We have exploited data from two large-scale cell line projects to clearly describe the mutational and copy number status of HNSCC cell lines and identify candidate drugs with elevated efficacy in HNSCC. Methods The genetic landscape of 42 HNSCC cell lines including mutational and copy number data from studies by Garnett et al., and Barretina et al., were analyzed. Data from Garnett et al. was interrogated for relationships between HNSCC cells versus the entire cell line pool using one- and two-way analyses of variance (ANOVAs). As only seven HNSCC cell lines were tested with drugs by Barretina et al., a similar analysis was not carried out. Results Recurrent mutations in human papillomavirus (HPV)-negative patient tumors were confirmed in HNSCC cell lines, however additional, recurrent, cell line-specific mutations were identified. Four drugs, Bosutinib, Docetaxel, BIBW2992, and Gefitinib, were found via multiple-test corrected ANOVA to have lower IC50 values, suggesting higher drug sensitivity, in HNSCC lines versus non-HNSCC lines. Furthermore, the PI3K inhibitor AZD6482 demonstrated significantly higher activity (as measured by the IC50) in HNSCC cell lines harbouring PIK3CA mutations versus those that did not. Conclusion HNSCC-specific reanalysis of large-scale drug screening studies has identified candidate drugs that may be of therapeutic benefit and provided insights into strategies to target PIK3CA mutant tumors. PIK3CA mutations may represent a predictive biomarker for response to PI3K inhibitors. A large-scale study focused on HNSCC cell lines and including HPV-positive lines is necessary and has the potential to accelerate the development of improved therapeutics for patients suffering with head and neck cancer. This strategy can potentially be used as a template for drug discovery in any cancer type. Electronic supplementary material The online version of this article (doi:10.1186/2050-6511-15-66) contains supplementary material, which is available to authorized users.

Next-generation sequencing (NGS) has revolutionized the field of genomics and improved our understanding of cancer biology. Advances have been achieved by sequencing tumor DNA and using matched normal DNA to filter out germ line variants to identify cancer-specific changes. The identification of high incidences of activating mutations in head and neck squamous cell carcinoma (HNSCC) amenable to drug targeting has been made, with clear distinctions between the mutational profile of HPV-positive and HPV-negative tumors. This wealth of new understanding undoubtedly ameliorates our understanding of HNSCC cancer biology and elucidates clear targets for drug targeting which will guide future personalized medicine.

Background and significance Anaplastic thyroid cancer (ATC) is rare, but its clinical presentation is often dramatic and aggressive and is nearly uniformly fatal. Oncolytic viral therapy is a potential strategy to improve outcomes for patients suffering with this disease. Methods Seven established ATC cell lines were infected with a panel of poxviruses to identify which virus had the most potential as an oncolytic agent. These included myxoma, vaccinia, and tanapox viruses, all modified to express green fluorescence protein (GFP). Viral proliferation was assessed by fluorescence and viral amplification. The effect on cell line growth was assessed by the Presto Blue metabolic assay and a live-dead assay. A replication assay was performed to assess the production of infectious progeny. An additional five ATC cell lines were tested using the assays described above for susceptibility to vaccinia virus. Results ATC cell lines were differentially susceptible to each virus. Vaccinia virus was superior to myxoma and tanapox viruses for the control of anaplastic thyroid cancer in vitro. Although subsequent investigation using an expanded panel of cell lines revealed differential susceptibility to vaccinia virus, effective control of cell proliferation was still achieved using higher titers. Conclusions Vaccinia virus was the most potent of the tested poxviruses and was highly effective in controlling proliferation and inducing cell death in ATC cell lines. The efficacy of these viruses offers hope for improving outcomes for patients suffering with ATC.