Citations

Abstract Background: Bladder cancer is a leading cause of cancer death in the United States1. The histology in > 90% of cases is urothelial carcinoma (UC). Tumors may present either as non-muscle-invasive (NMIBC) or muscle-invasive disease (MIBC). Current standard of care for patients with high risk NMIBC includes transurethral resection of bladder tumor (TURBT) followed by intravesical immunotherapy with Bacillus Calmette-Guerin (BCG)2. Meanwhile, patients with BCG unresponsive NMIBC or MIBC are recommended to undergo radical cystectomy (RC), which adversely impacts quality of life and is associated with significant morbidity3. MV-NIS is an investigational oncolytic measles virus with an excellent clinical safety profile4. This ongoing phase I clinical study is designed to test the safety, efficacy and identify the recommended phase 2 dose (RP2D) of intravesical MV-NIS in patients with NMIBC or MIBC who are scheduled for RC and not eligible for neoadjuvant chemotherapy. Methods: Bladder UC patients were evaluated for eligibility and provided informed consent prior to enrolling. To date 8 patients have been enrolled: 4 to the single dose safety cohort, and 4 to the multi-dose expansion cohort. Patients were administered intravesical ~1x109 TCID50 MV-NIS once at least 1 week prior to RC (safety cohort), or twice at 4 and 2 weeks prior to RC (expansion cohort). Patients were closely monitored during the 2-hour instillation period. Tumor specimens from the pre-treatment TURBT and post-treatment RC were analyzed to determine pre- and post-treatment pathological stage and evaluate tumor killing and immune cell infiltrate. Results: Intravesical MV-NIS treatment was well tolerated in all patients. Only a single Adverse Event (AE) attributable to MV-NIS treatment (Grade 1 hematuria). AEs Grade>2 were related to post-surgical complications. Tumor downstaging was observed in 4 of 8 patients. Among 4 patients in the expansion cohort, 2 had no residual disease (pT0). Central assessment of RC tissues showed significant inflammatory infiltrate in all treated bladder specimens. Detailed analyses are ongoing to characterize MV infection and immune infiltrate in bladder tissue. Conclusions: The higher-than-expected rate of tumor downstaging and pT0 pathology, paired with the significant immune infiltrate observed in post-treatment bladder tissue, provide compelling evidence that intravesical MV-NIS has clinical activity against UC. These results support the use of two doses of ~1x109 TCID50 as the RP2D in future clinical studies for BCG unresponsive NMIBC or MIBC patients. MV-NIS induced inflammation may act synergistically with checkpoint blockade therapies. References 1. Siegel, R.L., Miller, K.D. & Jemal, A. CA Cancer J Clin 69, 7-34 (2019). 2. Knowles, M.A. & Hurst, C.D. Nature reviews. Cancer 15, 25-41 (2015). 3. Zakaria, A.S., et al. Can Urol Assoc J 8, 259-267 (2014). 4. Galanis, E., et al. Cancer research 75, 22-30 (2015). Citation Format: Tanner S. Miest, Bradley Leibovich, Stephen Bardot, Paul R. Young, Stephen A. Boorjian, Mark Gonzalgo, Loren Herrera-Hernandez, Matthew K. Tollefson, Jeffrey Karnes, Paige Nichols, Tessa Kroeninger, Rachel Graham, Carole Lahana, Monica Reckner, Alysha Newsom, Nandakumar Packiriswamy, Janice Anoka, Kah Whye Peng, Erol Wiegert, Alice Bexon, Shruthi Naik. Safety and efficacy of neoadjuvant intravesical oncolytic MV-NIS in patients with urothelial carcinoma [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P190.

Abstract Background The National Institutes of Health define African Americans or Blacks, American Indians, Alaska Natives, Hispanics or Latinos, Native Hawaiians, and other Pacific Islanders as being underrepresented in medicine. A number of studies have demonstrated that improving diversity of such underrepresented demographics within the medical profession improves patient outcomes, medical education and reduces health disparities in patients from vulnerable racial or socioeconomic groups. Despite this recognition, significant underrepresentation of various racial, ethnic, and sexual identities still exists within nearly all medical specialties. Aims The purpose of this study was to a gain a greater understanding of the current state of diversity, equity, and inclusion (DEI) efforts among U.S. hematology and medical oncology fellowship training programs. We explored the perspectives of adult and pediatric fellowship program directors regarding current recruitment strategies and suggestions for improvement to help mitigate the effects of implicit and explicit bias. Here, we present an interim analysis of the data using descriptive statistics. Methods: We convened a multi-institutional collaboration of fellowship program directors, teaching faculty, and staff members of the American Society of Hematology to develop a survey examining perceptions of DEI efforts among hematology and medical oncology fellowship program directors. The survey was pilot tested in a small group of program directors representing 6 different academic programs (5 adult, 1 pediatric). The final online survey was distributed via email to 224 fellowship program directors at U.S. adult and pediatric hematology and medical oncology fellowship programs. The survey included 29 questions regarding perspectives on bias within the fellowship selection process, current DEI initiatives, and current faculty and fellow demographics. Survey respondents were asked to rate the importance of numerous factors in determining which applicants to invite utilizing a scale of 0-10, with 0 and 10 representing lowest and highest importance, respectively. To measure program director perceptions of certain applicant groups, survey respondents were asked to rate applicant demographics as being advantaged/disadvantaged based on survey options ranging from 0-5, with 0 and 5 representing very disadvantaged and very advantaged, respectively. Results: At interim analysis, 41 of 224 program directors completed the survey for an interim response rate of 21%, including 25 adult program directors and 16 pediatric program directors, with representation from university and community programs. Of the program directors surveyed, 28 (68%) reported having access to a dedicated diversity committee or DEI policies in place to improve recruitment of underrepresented applicants. In determining which applicants to invite, respondents placed highest value on the applicant's program director letter (mean score ± standard deviation: 7.44±1.93), caliber of the applicant's residency program (7.28±2.06) and letters of recommendations (7.15±2.23). Survey respondents viewed white and male applicants as representing the most advantaged demographic group, while LGBTQI, age>40, and U.S. citizen and non-citizen international medical graduates were the most disadvantaged (Table 1). Suggestions regarding improving DEI in the fellowship selection process included implementing bias training, identifying potentially disadvantaged applicants in ERAS, increasing faculty diversity, and pairing underrepresented applicants with interviewers based on applicant preference. Conclusion: While the majority of hematology and medical oncology fellowship program directors report having DEI programs or policies to improve recruitment of underrepresented applicants, perceptions of advantaged/disadvantaged groups may extend beyond demographics traditionally viewed as being underrepresented in medicine. As our survey is ongoing, we plan to reanalyze our data when the survey has been finalized with a higher response rate utilizing multivariable regression to identify themes that may further improve DEI efforts within the fellowship selection process. Figure 1 Figure 1. Disclosures LaCasce: Bristol-Myers Squibb Company.: Other: Data Safetly and Monitoring. Murphy: North American Thrombosis Foundation: Honoraria. Naik: Rigel: Research Funding. Podoltsev: Pfizer: Honoraria; Blueprint Medicines: Honoraria; Incyte: Honoraria; Novartis: Honoraria; Celgene: Honoraria; PharmaEssentia: Honoraria; Bristol-Myers Squib: Honoraria; CTI BioPharma: Honoraria.

AbstractThe study aimed at widening the clinical and genetic spectrum of ASXL3‐related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3‐related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3‐related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro‐behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low‐hanging columella. The presented data will inform clinical management of individuals with ASXL3‐related syndrome and improve interpretation of new ASXL3 sequence variants.

Abstract The goal of this study was to evaluate safety, efficacy, and immunological activity of Vesicular Stomatitis Virus (VSV) expressing a species relevant (canine) interferon-beta (IFN-β) and the sodium iodide symporter (NIS), henceforth called VSV, in companion dogs with naturally occurring appendicular osteosarcoma. The hypothesis was that VSV would track to the tumor, induce oncolysis, and lead to enhanced infiltration of immune cells, expansion of virus- and tumor specific T-cell clones, and improved survival outcomes.The first 15 dogs enrolled in the VSV Immunotherapy and Genomics of Osteosarcoma Research (VIGOR) study received a single iv dose of VSV (1x109 TCID50/kg) 10 days before amputation and adjuvant carboplatin chemotherapy. The final 13 dogs were randomized in a double-blinded fashion to receive either a single dose of VSV or placebo. Outcome data were compared to those from an historical control group of 57 dogs with appendicular osteosarcoma treated between 2006 and 2018 using the standard of care of alone. VSV treatment was associated with mild systemic effects (fever and inflammation), which were self-limiting and caused no symptomatology. Alterations in the tumor microenvironment (micronecrosis, increased fibrosis, and increased inflammation) were more common and more pronounced in VSV treated dogs than in placebo-treated dogs.Reduction in the expression of co-regulated cell cycle gene clusters in tumors after VSV-treatment was observed in dogs with longer survival. Conversely, increased expression of co-regulated immune/inflammatory gene clusters was observed in both VSV-treated dogs and in placebo-treated dogs, suggesting this might be, at least partly, due to the biopsy procedures. Assessment of changes in the clonal composition of T cells within the tumors, draining lymph nodes, and systemic circulation is in progress. No differences were evident in median event-free or overall survival times among the different groups, although aspects of the study design and sample size could obscure differences. Intriguingly, a “tail” of nine dogs (41%) that were long-term survivors (>450 days) was apparent in the VSV-treated group. All but one of these long-term survivors had evidence of inflammation in the pre-treatment tumor samples or showed increased inflammation in the post-treatment samples. We conclude that neoadjuvant VSV has an excellent safety profile and provides a survival benefit for a subset of dogs with spontaneous bone cancer. Ongoing work seeks to establish distinguishing characteristics that identify those individuals most likely to benefit from this therapy, as well as to evaluate the potential to enhance this benefit through the addition of novel immunomodulatory agents as part of our efforts to translate this approach to human cancer patients. Citation Format: Kelly M. Makielski, Aaron L. Sarver, Aishwarya Sathyanarayan, Michael S. Henson, Kathleen M. Stuebner, Alexandru-Flaviu Tabaran, Ingrid Cornax, Gerard O'Sullivan, Andrea Chehadeh, Donna Groschen, Kelly Bergsrud, Lauren J. Mills, Amber L. Winter, Sara Pracht, Milcah C. Scott, Michael A. Farrar, Gary R. Cutter, Joseph S. Koopmeiners, Stephen J. Russell, Shruthi Naik, Jaime F. Modiano. Oncolytic Vesicular Stomatitis Virus expressing a species relevant interferon-beta is safe and provides a survival benefit when added as neoadjuvant to the standard of care for dogs with naturally occurring bone cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1747.

Since its emergence at the end of 2019, SARS-CoV-2, the causative agent of COVID-19, has caused over 100 million infections and 2.4 million deaths worldwide. Recently, countries have begun administering approved COVID-19 vaccines, which elicit strong immune responses and prevent disease in most vaccinated individuals.

10024 Background: Inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm of intermediate malignancy, predominantly seen in children and young adults. Given its rarity, data are limited. We describe the largest cohort of patients with IMT to date, with an aim to further characterize this poorly understood tumor. Methods: A multi-institutional review was performed at 18 North American hospitals participating in the Pediatric Surgical Oncology Research Collaborative to identify IMT patients ≤39 years, diagnosed from 2000-2018. Descriptive statistics are described as median and interquartile range. Multivariable analysis was used to identify predictors of event free survival (EFS). Results: 182 patients were identified with a median age of 11 years (5-17); 52% were female. 33% of tumors were thoracic, 26% abdominal/pelvic, 20% head/neck, and 14% genitourinary. Common presenting symptoms included pain (29%), respiratory symptoms (24%), weight loss (12%), and a palpable mass (10%). Median tumor size was 3.9 cm (1.9-6.5). Anaplastic lymphoma kinase (ALK) overexpression was identified via immunohistochemistry in 53% of patients tested. One third of patients had abnormal cytogenetics, with 12% of the entire cohort having an ALK mutation. 7% of patients had distant disease at diagnosis. 13% of patients received neoadjuvant therapy including chemotherapy (3%), ALK inhibitor (4%), radiation (0.5%), non-steroidal anti-inflammatories (NSAIDs) (7%), or steroids (2%). Of those who underwent resection with known margin status (n = 158), 66% had complete resection, 20% had microscopic positive margins, and 14% had gross residual disease. Just over 40% of patients had an en bloc resection of involved organs, most commonly lung (26%). 21% of patients received adjuvant therapy, including chemotherapy (3%), ALK inhibitor (9%), radiation (0.5%), NSAIDs (8%), or steroids (5%). 12% of all patients received an ALK inhibitor: 24% neoadjuvant, 62% adjuvant, and 14% without surgery. Median follow-up time was 36 months (14-69). Overall 5-year survival (OS) was 95% and 5-year EFS was 80%. Predictors of recurrence included respiratory symptoms, larger tumor size, or distant disease at diagnosis. Gender, race, age and primary site were not predictive of EFS. Likewise, there was no association of ALK overexpression or ALK mutation with EFS. The presence of gross or microscopic margins following resection was not associated with recurrence. Conclusions: IMT is a rare tumor with favorable OS. Five year recurrence rate was 20%. Presenting with respiratory symptoms, larger tumor size, or metastatic disease was associated with recurrence, while ALK positivity was not. Notably, a positive margin after resection was not associated with increased recurrence, indicating that aggressive attempts at surgical resection that would compromise form or function may not be warranted.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.