Citations

INTRODUCTION: Significant variability between colonoscopy operators contributes to postcolonoscopy colorectal cancers (CRCs). We aimed to estimate postcolonoscopy colorectal neoplasia (CRN) detection by multi-target stool DNA (mt-sDNA), which has not previously been studied for this purpose. METHODS: In a retrospective cohort of patients with +mt-sDNA and completed follow-up colonoscopy, positive predictive value (PPV) for endpoints of any CRN, advanced adenoma, right-sided neoplasia, sessile serrated polyps (SSP), and CRC were stratified by the time since previous colonoscopy (0–9, 10, and ≥11 years). mt-sDNA PPV at ≤9 years from previous average-risk screening colonoscopy was used to estimate CRN missed at previous screening colonoscopy. RESULTS: Among the 850 studied patients with +mt-sDNA after a previous negative screening colonoscopy, any CRN was found in 535 (PPV 63%). Among 107 average-risk patients having +mt-sDNA ≤9 years after last negative colonoscopy, any CRN was found in 67 (PPV 63%), advanced neoplasia in 16 (PPV 15%), right-sided CRN in 48 (PPV 46%), and SSP in 20 (PPV 19%). These rates were similar to those in 47 additional average risk persons with previous incomplete colonoscopy and in an additional 68 persons at increased CRC risk. One CRC (stage I) was found in an average risk patient who was mt-sDNA positive 6 years after negative screening colonoscopy. DISCUSSION: The high PPV of mt-sDNA 0–9 years after a negative screening colonoscopy suggests that lesions were likely missed on previous examination or may have arisen de novo . mt-sDNA as an interval test after negative screening colonoscopy warrants further study.

INTRODUCTION: Gastroenterologists at all levels of practice benefit from formal mentoring. Much of the current literature on mentoring in gastroenterology is based on expert opinion rather than data. In this study, we aimed to identify gender-related barriers to successful mentoring relationships from the mentor and mentee perspectives. METHODS: A voluntary, web-based survey was distributed to physicians at 20 academic institutions across the United States. Overall, 796 gastroenterology fellows and faculty received the survey link, with 334 physicians responding to the survey (42% response rate), of whom 299 (90%; 129 women and 170 men) completed mentorship questions and were included in analysis. RESULTS: Responses of women and men were compared. Compared with men, more women preferred a mentor of the same gender (38.6% women vs 4.2% men, P < 0.0001) but less often had one (45.5% vs 70.2%, P < 0.0001). Women also reported having more difficulty finding a mentor (44.4% vs 16.0%, P < 0.0001) and more often cited inability to identify a mentor of the same gender as a contributing factor (12.8% vs 0.9%, P = 0.0004). More women mentors felt comfortable advising women mentees about work-life balance (88.3% vs 63.8%, P = 0.0005). Nonetheless, fewer women considered themselves effective mentors (33.3% vs 52.6%, P = 0.03). More women reported feeling pressured to mentor because of their gender (39.5% vs 0.9% of men, P < 0.0001). Despite no gender differences, one-third of respondents reported negative impact of the COVID-19 pandemic on their ability to mentor and be mentored. DISCUSSION: Inequities exist in the experiences of women mentees and mentors in gastroenterology, which may affect career advancement and job satisfaction.

Abstract Despite recent landmark advances in T-cell immunotherapy for the treatment of human cancer, metastatic solid tumors remain an intractable challenge. Macrophages are often the most abundant immune cell in the tumor microenvironment (TME), where they may convert into immunosuppressive (M2) tumor-associated macrophages (TAMs) and participate in disease progression. Currently, macrophage-orientated immunotherapeutic approaches under clinical development in oncology seek to reduce TAM infiltration (CSF-1 antagonists) or enhance TAM phagocytosis (CD47 antagonists). Transfer of autologous, activated, but nontargeted macrophages failed to demonstrate antitumor efficacy in past clinical trials. We hypothesized that genetically engineering human macrophages with CARs against tumor-associated antigens could redirect their phagocytic activity and lead to therapeutic efficacy with the potential for the induction of an antitumor T-cell response. We first demonstrate that CD3-zeta-based CARs are capable of inducing phagocytosis in human THP-1 macrophages, while truncated intracellular-domain deficient CARs were not. Targeted phagocytosis and clearance of CD19+, mesothelin +, and HER2+ cells by CARs targeted against each respective antigen was significantly superior to that by control untransduced (UTD) macrophages. We demonstrate that primary human macrophages, which are resistant to most viral vectors, are efficiently transduced by the chimeric fiber adenoviral vector Ad5f35 (~70% in 10 normal donors). Using Ad5f35, we engineered primary human macrophages with a CD3-zeta-based CAR against HER2. Anti-HER2 primary human CAR macrophages demonstrated targeted phagocytosis against HER2+ but not HER2- cell lines, with phagocytic activity dependent on both the CAR and antigen densities. Furthermore, CAR, but not UTD, macrophages led to potent dose-dependent killing of three distinct HER2-high cell lines in vitro. We sought to test the efficacy of anti-HER2 primary human macrophages in xenograft models of human HER2+ ovarian cancer. A single dose of CAR, but not UTD macrophages, led to tumor regression and improved overall survival in both intraperitoneal and disseminated models of disease. We show that macrophage transduction with Ad5f35, a double-stranded DNA virus, leads to a broad gene expression change, an interferon signaling signature, and phenotypic clustering toward classically activated M1 macrophages. CAR macrophages upregulated co-stimulatory ligand and antigen processing/presentation genes and led to enhanced T-cell stimulation in vitro and in vivo. Lastly, CAR, but not UTD, macrophages showed a broad resistance for M2 conversion in response to immunosuppressive cytokines. In conclusion, we show that primary human CAR macrophages are capable of targeted tumor phagocytosis, lead to improved overall survival in xenograft models, and demonstrate enhanced T-cell stimulation. CAR macrophages are a novel cell therapy platform for the treatment of human cancer. This abstract is also being presented as Poster B29. Citation Format: Michael Klichinsky, Marco Ruella, Olga Shestova, Andrew Best, Kristin Blouch, Xueqing M. Lu, Saad S. Kenderian, Miriam Y. Kim, Roddy O'Connor, Stephen Wallace, Miroslaw Kozlowski, Dylan M. Marchione, Maksim Shestov, Benjamin A. Garcia, Carl June, Saar Gill. Human chimeric antigen receptor (CAR) macrophages for cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr PR07.

AbstractBackgroundThe novel Coronavirus (SARS‐CoV‐2) has caused almost 2 million deaths worldwide. Both Food and Drug Administration and European Medicines Agency have recently approved the first COVID‐19 vaccines, and a few more are going to be approved soon.MethodsSeveral different approaches have been used to stimulate the immune system in mounting a humoral response. As more traditional approaches are under investigation (inactivated virus vaccines, protein subunit vaccines, recombinant virus vaccines), more recent and innovative strategies have been tried (non‐replicating viral vector vaccines, RNA based vaccines, DNA based vaccines).ResultsSince vaccinations campaigns started in December 2020 in both the US and Europe, gastroenterologists will be one of the main sources of information regarding SARS‐CoV 2 vaccination for patients in their practice, including vulnerable patients such as those with Inflammatory Bowel Disease (IBD), patients with chronic liver disease, and GI cancer patients.ConclusionsThus, we must ourselves be well educated and updated in order to provide unambiguous counseling to these categories of vulnerable patients. In this commentary, we aim to provide a comprehensive review of both approved COVID‐19 vaccines and the ones still under development, and explore potential risks, benefits and prioritization of vaccination.

Background: Quality of life (QOL) and psychological health has been reported to be decreased among women with gynecological conditions such as uterine fibroids (UFs). Materials and Methods: Women enrolled in the Comparing Options for Management: PAtient-centered REsults for Uterine Fibroids (COMPARE-UF) registry, receiving procedural therapy for symptomatic UFs, were eligible for this analysis if they completed a series of health-related QOL surveys administered at three time points (baseline, 6–12 weeks postprocedure, and 1 year postprocedure; n = 1486). Ethical approval for this study was obtained at each recruiting site and the coordinating center (NCT02260752, clinicaltrials.gov ). Results: More than 26% ( n = 393) of women reported moderate anxiety/depression on the baseline anxiety/depression domain of the Euro-QOL 5-dimension instrument. At both the 6–12 weeks and 1-year postprocedural follow-up, there was significant improvement in the UF QOL symptom severity score ( p < 0.001, p < 0.001), the total UF symptom QOL score ( p < 0.001, p < 0.001), and the Euro-QOL 5-dimension visual analog scale ( p < 0.001, p = 0.004) compared with the preprocedural baseline scores. The reporting of anxiety/depression decreased by 66.4% among women who were at baseline, whereas 5.6% of women previously reporting no anxiety/depression reported anxiety/depression at the 1-year follow-up. Conclusion: UF symptoms were more severe among women reporting anxiety/depression at baseline. At the 1-year follow-up, health-related QOL scores improved among all women and the prevalence of anxiety/depression decreased in most, but not all women, whereas severity of anxiety/depression worsened in a small percentage of women (5.6%). Overall, these results suggest that UF treatment improves symptoms of anxiety/depression associated with symptomatic UFs.

The aim of this study is to evaluate whether NIS radiomics can distinguish lung adenocarcinomas from granulomas on non-contrast CT scans, and also to improve the performance of Lung-RADS by reclassifying benign nodules that were initially assessed as suspicious. The screening or standard diagnostic non-contrast CT scans of 362 patients was divided into training (St, N = 145), validation (Sv, N = 145), and independent validation (Siv, N = 62) sets from different institutions. Nodules were identified and manually segmented on CT images by a radiologist. A series of 264 features relating to the edge sharpness transition from the inside to the outside of the nodule were extracted. The top 10 features were used to train a linear discriminant analysis (LDA) machine learning classifier on St. In conjunction with the LDA classifier, NIS radiomics classified nodules with an AUC of 0.82 ± 0.04, 0.77, and 0.71 respectively on St, Sv, and Siv. We evaluated the ability of the NIS classifier to determine the proportion of the patients in Sv that were identified initially as suspicious by Lung-RADS but were reclassified as benign by applying the NIS scores. The NIS classifier was able to correctly reclassify 46% of those lesions that were actually benign but deemed suspicious by Lung-RADS alone on Sv.

8009 Background: Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses have been associated with better progression free survival (PFS) and overall survival (OS). Serum (SIFE) and urine immunofixation are the currently used markers for biochemical documentation of CR after which marrow is tested for plasma cell clearance. Next generation flow cytometry and sequencing are used to document the presence of minimal residual disease (MRD). Mass spectrometry of blood by MALDI (Mass-Fix) is a new simple, inexpensive, sensitive, and specific means of detecting monoclonal immunoglobulins. To better test the hypothesis that Mass-Fix is superior to existing methodologies to predict for survival outcomes—especially SIFE-- samples from the STAMINA trial (NCT01109004), a trial comparing 3 transplant approaches among patients who have already received induction, were employed. Methods: Five-hundred and seventy-five patients were included. Samples from enrollment post-induction (post-I) and 1-year post enrollment (1YR) were tested when available. Four response parameters were assessed univariately: Mass-Fix, SIFE, complete response, and MRD by next generation flow cytometry. Mass spectrometry spectra were evaluated in a blinded fashion. Complete response was according to the 2006 International Myeloma Working Group criteria. Multivariate Cox proportional hazard models using stepwise regression were developed to explore the independent effect of the different response parameters on PFS and OS and interactions with other risk factors. Results: Of the 4 response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses (Table). Of the 4 post-I measurements, only MRD predicted for PFS; however, Mass-Fix was the only post-I measurement to predict for OS. Of all the 1-year measures, both 1YR Mass-Fix and 1YR MRD positivity predicted for inferior PFS and OS. In models including MRD and Mass-Fix, SIFE and CR were not prognostic for PFS or OS. Conclusions: Mass-Fix is a powerful means to track monoclonal proteins. The full utility of Mass-Fix was not exploited given the absence of a diagnostic sample and the fact that only serum (and not urine) was tested. Despite these limitations, it performed well at pre-induction and at 1 year. Mass-Fix provides a convenient and non-invasive means of predicting for myeloma outcomes. Clinical trial information: NCT01109004. [Table: see text]

Abstract Recent advances in treatment have transformed the management of cancer. Despite these advances, cardiovascular disease remains a leading cause of death in cancer survivors. Cardio-oncology has recently evolved as a subspecialty to prevent, diagnose, and manage cardiovascular side effects of antineoplastic therapy. An emphasis on optimal management of comorbidities and close attention to drug interactions are important in cardio-oncologic care. With interdisciplinary collaboration among oncologists, cardiologists, and pharmacists, there is potential to prevent and reduce drug-related toxicities of treatments. The cytochrome P450 (CYP450) family of enzymes and the P-glycoprotein (P-g) transporter play a crucial role in drug metabolism and drug resistance. Here we discuss the role of CYP450 and P-g in drug interactions in the field of cardio-oncology, provide an overview of the cardiotoxicity of a spectrum of cancer agents, highlight the role of precision medicine, and encourage a multidisciplinary treatment approach for patients with cancer.

508 Background: I-SPY 2 is a multicenter, phase 2 trial using response-adaptive randomization within molecular subtypes defined by receptor status and MammaPrint (MP) risk to evaluate novel agents as neoadjuvant therapy for women with high-risk breast cancer. SD-101 is an investigational Toll-like receptor 9 (TLR9) agonist CpG-C class oligodeoxynucleotide that stimulates the production of IFN-α and interleukin (IL)-12, functional maturation of plasmacytoid dendritic cells, and production of cytotoxic antibodies. IT SD-101 was combined with systemic anti-PD-1 antibody Pb to investigate the antitumor and immunologic activity of this novel immunotherapeutic strategy. Methods: Women with tumors ≥ 2.5cm were eligible for screening. Only pts (pts) with HER2- disease were eligible for this treatment. Treatment included weekly P x 12 in combination with IT SD-101 2 mg/ml (1 ml for T2 tumors, 2 ml for >T3 tumors) weekly x 4, then q3 weeks x 2, and IV Pb q3 weeks x 4, followed by doxorubicin/cyclophosphamide (AC) q2-3 weeks x 4 (SD-101+Pembro 4). Pts in the control arm received weekly P x 12 followed by AC q2-3 weeks x 4. The I-SPY 2 methods have been previously published. This investigational arm was eligible for graduation (>85% chance of success in a 300-person phase 3 neoadjuvant trial) in 3 of 10 pre-defined signatures: HER2-, hormone receptor (HR)+/HER2- and HR-/HER2-. Results: 75 pts were randomized and evaluable in SD-101+Pembro 4 treatment arm. The control arm included 329 historical controls enrolled since April 2010. The study arm was stopped due to maximal patient accrual. Pt characteristics were balanced; 56% HR+, 44% HR-. The probability that SD-101+Pembro4 was superior to control exceeded 97% for all eligible tumor signatures, but did not reach the threshold for graduation in any of the signatures. However, it is notable that the rate of pCR/Residual Cancer Burden 1 (RCB1) in the HR+/HER2- signature was 51%. Preliminary safety events for SD-101+Pembro 4 include increased rates of fever, neutropenia, febrile neutropenia, transaminitis, and immune-related events, including adrenal insufficiency. Conclusions: The SD-101+Pembro 4 regimen was active but did not meet the pre-specified threshold for graduation in I-SPY 2. pCR/RCB 1 analysis suggests improved response in the HR+/HER-negative signature compared to control. The clinical significance of these findings needs to be weighed against the potential risk of immune-related toxicities. Clinical trial information: NCT01042379. [Table: see text]

Abstract Background Risankizumab (RZB), an IL-23 inhibitor, is being investigated for Crohn’s disease (CD). MOTIVATE (NCT03105128) and ADVANCE (NCT03104413) were two double-blind, randomised, placebo (PBO)-controlled phase 3 trials evaluating the efficacy and safety of RZB as induction therapy for CD after inadequate response or intolerance to biologic treatment, or conventional or biologic treatment. We investigated the effect of RZB on patient-reported outcomes (PROs) in these two trials. Methods Patients with moderately to severely active CD (CD activity index of 220–450, Simple Endoscopic Score for CD excluding the narrowing component ≥ 6 or ≥ 4 for isolated ileal disease, and average daily stool frequency ≥ 4 and/or average daily abdominal pain score ≥ 2) were randomised 1:1:1 (MOTIVATE; N=569) or 2:2:1 (ADVANCE; N=850) to intravenous RZB 600 mg, RZB 1200 mg or PBO at Weeks 0, 4 and 8. PROs assessed were Inflammatory Bowel Disease Questionnaire (IBDQ), Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), and 36-Item Short Form Health Survey (SF 36). Least-squares mean change from baseline to Week 4 and 12 were assessed for each PRO. Additionally, the proportion of patients achieving IBDQ remission (IBDQ total score ≥ 170 points) was evaluated. Comparisons between RZB dosage groups and PBO were based on Cochran-Mantel-Haenszel or chi-square/Fisher’s exact tests; missing data were reported using non-responder imputation. Results In the MOTIVATE (100% biologic inadequate responder [bio-IR]) and ADVANCE (57% bio-IR) trials, significant (P&lt;0.05) improvements in nearly all PROs evaluated were seen as early as Week 4 (Figures 1–4). At Week 12, significant improvements in all PROs were reported for both doses of RZB compared with PBO in both trials, except for the SF-36 Mental Component Summary score (RZB 1200 mg in MOTIVATE), which improved, but not significantly. In MOTIVATE, at Week 4 and 12, IBDQ remission was achieved by significantly (P&lt;0.05) more patients taking RZB (600 mg, 25.1%/38.3%; RZB 1200 mg, 31.9%/44.6%) than PBO (15.5%/26.8%). Results were similar in ADVANCE: RZB 600 mg 30.9%/44.5%, RZB 1200 mg 33.7%/51.5%, and PBO 18.4%/29.8% at weeks 4 and 12, respectively (P&lt;0.001 for both RZB groups compared to PBO). Conclusion Patients with active CD and an inadequate response to conventional or biologic treatment who received RZB (600 mg or 1200 mg) induction therapy reported significant improvements in disease-specific (IBDQ) and general health-related PROs (FACIT and SF-36) compared with PBO, with improvements seen as early as Week 4. Funding statement: Study was funded by AbbVie. Acknowledgement: Medical writing support was provided by Joann Hettasch of Fishawack Facilitate Ltd, and was funded by AbbVie.