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Purpose:TRC102, a small-molecule base-excision repair inhibitor, potentiates the cytotoxicity of pemetrexed and reverses resistance by binding to chemotherapy-induced abasic sites in DNA. We conducted a phase I clinical trial combining pemetrexed and TRC102 with cisplatin–radiation in stage III nonsquamous non–small cell lung cancer (NS-NSCLC).Patients and Methods:Fifteen patients were enrolled from 2015 to 2019. The primary objective was to determine the dose-limiting toxicity and maximum tolerated dose of TRC102 in combination with pemetrexed, cisplatin, and radiotherapy. Secondary objectives were to assess toxicity, tumor response, and progression-free survival at 6 months. Based on our preclinical experiments, pemetrexed–TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated in the second cycle. After completion, two additional cycles of pemetrexed–cisplatin were given. Toxicities were assessed using NCI CTACAE versions 4/5.Results:The median age was 69 years (45–79) with the median follow-up of 25.7 months (range, 7.9–47.4). No dose-limiting toxicities and no grade 5 toxicity were seen. Hematologic and gastrointestinal toxicities were the most common side effects. No clinical radiation pneumonitis was seen. Of 15 evaluable patients, three had complete response (20%), and 12 had partial response (80%). The 6-month progression-free survival was 80%, and the 2-year overall survival was 83%.Conclusions:Pemetrexed–TRC102 combined with cisplatin/radiotherapy in NS-NSCLC is safe and well tolerated. The recommended phase II dose is 200 mg TRC102 along with cisplatin–pemetrexed. No additional safety signal was seen beyond the expected CRT risks. A phase II trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen, is warranted.

Supplementary Data from Adding Base-Excision Repair Inhibitor TRC102 to Standard Pemetrexed–Platinum–Radiation in Patients with Advanced Nonsquamous Non–Small Cell Lung Cancer: Results of a Phase I Trial

Purpose: TRC102, a small-molecule base-excision repair inhibitor, potentiates the cytotoxicity of pemetrexed and reverses resistance by binding to chemotherapy-induced abasic sites in DNA. We conducted a phase I clinical trial combining pemetrexed and TRC102 with cisplatin–radiation in stage III nonsquamous non–small cell lung cancer (NS-NSCLC). Patients and Methods: Fifteen patients were enrolled from 2015 to 2019. The primary objective was to determine the dose-limiting toxicity and maximum tolerated dose of TRC102 in combination with pemetrexed, cisplatin, and radiotherapy. Secondary objectives were to assess toxicity, tumor response, and progression-free survival at 6 months. Based on our preclinical experiments, pemetrexed–TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated in the second cycle. After completion, two additional cycles of pemetrexed–cisplatin were given. Toxicities were assessed using NCI CTACAE versions 4/5. Results: The median age was 69 years (45–79) with the median follow-up of 25.7 months (range, 7.9–47.4). No dose-limiting toxicities and no grade 5 toxicity were seen. Hematologic and gastrointestinal toxicities were the most common side effects. No clinical radiation pneumonitis was seen. Of 15 evaluable patients, three had complete response (20%), and 12 had partial response (80%). The 6-month progression-free survival was 80%, and the 2-year overall survival was 83%. Conclusions: Pemetrexed–TRC102 combined with cisplatin/radiotherapy in NS-NSCLC is safe and well tolerated. The recommended phase II dose is 200 mg TRC102 along with cisplatin–pemetrexed. No additional safety signal was seen beyond the expected CRT risks. A phase II trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen, is warranted.

Purpose Patients enrolled in Phase 1 clinical trials have typically exhausted standard therapies and often are choosing between a clinical trial and hospice care. Significant symptom burden can result in early trial discontinuation and confound trial outcomes. This study aimed to examine differences in study duration, symptom burden, adverse events (AE), and quality of life (QOL) between those receiving structured palliative care versus usual supportive care. Patients and methods Sixty‐eight patients enrolled in phase 1 clinical trials and 39 of their CGs were randomly assigned to receive structured palliative care or usual supportive care. Patient QOL was measured monthly using the Functional Assessment of Cancer Therapy and Memorial Symptom Assessment Scale. The Quality of Life in Life‐Threatening Illness–Family Care Version and Caregiver Reaction Assessment were used for CGs. AEs and use of palliative care resources were compared between arms. Results Mean duration of the phase 1 study was 142 days in the palliative care arm versus 116 days in the usual care arm (p = 0.55). Although not statistically significant, patients in the palliative care arm experienced fewer AEs and better QOL, as did their CGs, compared to those receiving usual care. Conclusions Phase 1 patients and their CGs have physical and psychosocial needs warranting palliative care services. Results suggest that structured palliative care is associated with the increased duration of the study and improved patient and CG QOL., Phase 1 patients and their caregivers have physical and psychosocial needs warranting palliative care services. Providing structured palliative care servies to this population was associated with increased duration on phase 1 study and improved patient and caregiver QOL.

There is an increased risk of congestive heart failure (CHF) following anthracycline-based chemotherapy in patients with Diffuse Large B-cell lymphoma (DLBCL). Little is known about risk factors of CHF, other cardiovascular events (CVE), and CVE effect on outcomes. We conducted a retrospective review of 463 newly diagnosed DLBCL patients treated between 2002 and 2016 with anthracycline containing regimens. At a median follow up of 71.3 months, 10.4% patients developed new CHF, 4.97% had new atrial fibrillation and 3.2% had new coronary artery disease. Age over 65, advanced stage DLBCL and diabetes were associated with increased cumulative incidence of CVE. Patients with prior diabetes had decreased progression-free survival and overall survival in comparison to non-diabetics. Patients who had a CVE in the first year had significant worse OS then patients who did not have a CVE (Hazard Ratio 10.0, 95% CI, 7.24-13.88). A risk score incorporating age at DLBCL diagnosis, baseline lymphocyte count, disease stage and diabetes stratified into groups with low, intermediate and high risk for CVE, with 1-year cumulative incidence of CVE of 5.3%, 7.9% and 13.4%. Diffuse large B-cell lymphoma patients treated with anthracycline containing regimens have high incidence of CVE, which are not limited to CHF. Clinical variables at the time of diagnosis can identify the group of DLBCL patients at highest risk of CVE, for whom preventive interventions should be considered.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for malignant and non-malignant blood diseases. Drug use may be associated with adverse outcomes. We performed a retrospective analysis to assess non-relapse mortality (NRM) and overall survival (OS) in HCT patients with drug use. The medical charts of 232 patients were reviewed. Recipients of matched unrelated donor (MUD) or matched related donor (MRD) transplants were included. Drug use was defined by either metabolic evidence or provider documentation prior to transplant. Transplants were MUD (n = 148) or MRD (n = 84). Median follow-up duration was 15.5 months. There were 35 (15%) patients in the drug use group and 197 (85%) patients in the control group; 49% and 60.4% were in remission at the time of transplant, respectively. In univariate analysis, drug use was associated with a 3-year cumulative incidence of NRM of 43% vs 29% for the control group (p = 0.048), and an HR of 1.75, (95% CI: 1.02–2.99). After controlling for age, sex, disease status, and graft type, drug use was associated with a hazard ratio (HR) of 1.6 (95% CI: 0.95–2.92) for NRM, and an HR 1.2 (95% CI: 0.74–1.94) for OS. Larger cohorts may be needed to further evaluate this association.

Azacitidine (AZA) maintenance following allogeneic hematopoietic cell transplantation (HCT) for acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) may reduce relapse risk and improve survival. Given logistic and toxicity-related challenges, identifying subgroups appropriate for this approach is an unmet need. Using data from two centers, we retrospectively compared event-free survival (EFS) and overall survival (OS) of AML and MDS patients who received AZA maintenance (

Venous thromboembolic events (VTE) are a frequent complication of lymphoma. We conducted a retrospective analysis to compare VTE risk in diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Subjects were randomly assigned to training and validation sets to identify risk factors of VTE and evaluate risk model performance, including the Khorana score. A group of 790 patients were diagnosed from 2002 to 2014 (DLBCL = 542, FL = 248). Median follow- up was 49 months. We observed 106 VTE, with higher incidence in DLBCL (5-year cumulative incidence = 16.3% vs 3.8% in FL patients). Five-year OS for patients with VTE was 51.4% vs 73.1% in patients without VTE (P < .001). Baseline VTE risk factors identified in the training cohort included lymphoma subtype, previous VTE, ECOG performance status ≥2, decreased albumin, increased calcium, elevated WBC, absolute lymphocyte count or monocyte count, and presence of bulky disease. Addition of new variables to the Khorana score improved its performance measured by Akaike information criterion and Concordance index. A new risk model including lymphoma subtype, albumin, WBC count, and bulky disease was validated in time-based ROC analyses. These findings were confirmed in the validation cohort. Lymphoma subtypes have different VTE risk. The effect of lymphoma subtype was independent from disease burden and the use of systemic therapy. The Khorana risk-score was validated in time to event analyses, and a more robust lymphoma-specific VTE risk score is proposed. These findings suggest lymphoma patients with highest VTE risk can be identified with baseline parameters.

Simple Summary A critical need for optimal management of human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) patients is the development of therapeutic strategies to exploit the inherent vulnerabilities of this unique disease. We identified fenofibrate, an FDA-approved drug, as a potent anti-cancer agent for HPV+ HNSCC. Fenofibrate induced the accumulation of the p53 tumor suppressor and re-programmed the tumor microenvironment to drive immune cell infiltration. We provide compelling evidence to reposition fenofibrate as a single agent or in combination with standard therapies for the HPV+ HNSCC setting. Abstract Human papillomavirus-associated head and neck squamous cell carcinoma (HPV+ HNSCC) is recognized as a distinct disease with unique etiology and clinical features. Current standard of care therapeutic modalities are identical for HPV+ and HPV− HNSCC and thus, there remains an opportunity to develop innovative pharmacologic approaches to exploit the inherent vulnerabilities of HPV+ HNSCC. In this study, using an inducible HPVE6E7 knockdown system, we found that HPV+ HNSCC cells are addicted to HPVE6E7, such that loss of these viral oncogenes impaired tumorigenicity in vitro and in vivo. A number of druggable pathways, including PPAR and Wnt, were modulated in response to HPVE6E7 loss. Fenofibrate showed significant anti-proliferative effects in a panel of HPV+ cancer cell lines. Additionally, fenofibrate impaired tumor growth as monotherapy and potentiated the activity of cisplatin in a pre-clinical HPV+ animal model. Systemic fenofibrate treatment induced p53 protein accumulation, and surprisingly, re-programmed the tumor-immune microenvironment to drive immune cell infiltration. Since fenofibrate is FDA-approved with a favorable long-term safety record, repositioning of this drug, as a single agent or in combination with cisplatin or checkpoint blockade, for the HPV+ HNSCC setting should be prioritized.

Simple Summary Bladder cancer is a heterogeneous disease with high recurrence rates. The current prognostication depends on tumor stage and grade and there is a need for predictive biomarkers that can distinguish between progressive versus non-progressive disease. We have identified a 3-gene signature panel having prognostic value in bladder cancer, which could aid in clinical decision making. Abstract Bladder cancer prognosis remains dismal due to lack of appropriate biomarkers that can predict its progression. The study aims to identify novel prognostic biomarkers associated with the progression of bladder cancer by utilizing three Gene Expression Omnibus (GEO) datasets to screen differentially expressed genes (DEGs). A total of 1516 DEGs were identified between non-muscle invasive and muscle invasive bladder cancer specimens. To identify genes of prognostic value, we performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. A total of seven genes, including CDKN2A, CDC20, CTSV, FOXM1, MAGEA6, KRT23, and S100A9 were confirmed with strong prognostic values in bladder cancer and validated by qRT-PCR conducted in various human bladder cancer cells representing stage-specific disease progression. ULCAN, human protein atlas and The Cancer Genome Atlas datasets were used to confirm the predictive value of these genes in bladder cancer progression. Moreover, Kaplan–Meier analysis and Cox hazard ratio analysis were performed to determine the prognostic role of these genes. Univariate analysis performed on a validation set identified a 3-panel gene set viz. CDKN2A, CTSV and FOXM1 with 95.5% sensitivity and 100% specificity in predicting bladder cancer progression. In summary, our study screened and confirmed a 3-panel biomarker that could accurately predict the progression and prognosis of bladder cancer.

Recognition of individual identity using the periocular region (i.e., periocular recognition) has emerged as a relatively new modality of biometrics and is a potential substitute for face recognition when facial occlusion happens, e.g., when wearing a mask. Moreover, many application scenarios occur at nighttime, such as nighttime surveillance in law reinforcement. We therefore study the topic of periocular recognition at nighttime using the infrared spectrum. However, the useful and effective area for periocular recognition is quite limited compared to that of face recognition since only the eyes are exposed. As a result, the performance of periocular recognition algorithms is relatively low. This issue of limited area poses a serious challenge even though many state-of-the-art face recognition algorithms yield high performance. This situation is even more deteriorated when periocular recognition is performed at nighttime. Thus, we in this paper propose an image super-resolution (SR) based technique for nighttime periocular recognition in which we enlarge the small-sized periocular image to have a larger effective area while retaining a high image quality. Super-resolution of the periocular images is achieved by a CNN model which first conducts interpolation of the periocular area to an expected size and then finds a nonlinear mapping between the input low quality periocular image and the output high quality periocular image. To validate our method, we compare our deep learning-based SR method with the original case of none SR involved at all, as well as the other two cases using traditional SR methods, namely bilinear interpolation and bicubic interpolation. In terms of quality metrics such as PSNR and SSIM as well as recognition metrics such as GAR and EER, our method significantly outperforms all the other three methods.

Face detection is one of the most important research topics in the field of computer vision, and it is also the premise and an essential part of face recognition. With the advent of deep learning-based techniques, the performance of face detection has been largely improved and more and more daily applications have been witnessed. However, face detection is greatly affected by environmental illumination. Most of existing face detection algorithms neglect harsh illumination conditions such as nighttime condition where lighting is insufficient or it is totally dark. These conditions are often encountered in real-world scenarios, e.g., nighttime surveillance in law enforcement or civil settings. How to overcome the problem of face detection in the darkness becomes a critical and urgent demand. We thus in this paper study face detection in the darkness using infrared (IR) imaging. We build an IR face detection dataset and design a deep learning-based model to study the face detection performance. Specifically, the deep learning model is a Single Stage Detector which has the advantage of fast speed and lower computation cost compared with other face detectors that consists of multiple stages. In the experiment, we also compare the performance of our deep learning model with that of a well-known traditional face detection algorithm, AdaBoost. In terms of True Positive Rate (TPR), our model significantly outperforms AdaBoost by 5% -- a dramatic boost from 87% to 92%, which suggests our deep learning-based method with IR imaging can indeed meet the requirement of real-world nighttime face detection applications.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant, clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein in serum, 50 years, respectively. Although renal failure is a defining feature of MM, frequently patients (pts) with a variety of renal pathologies have less than 10% plasma cell burden in the bone marrow, therefore they cannot be categorized as MM to be eligible for an anti-myeloma therapy. However, it is clear that there is a causative relationship between MGUS and the pathologic process in kidneys in at least a subset patient and starting anti-myeloma therapy potentially can reverse or slow down the renal insult caused by MGUS. This led to the creation of the new entity and term, "monoclonal gammopathy of renal significance" (MGRS), to properly convey the nature of these relationship. Therefore, MGRS depicts a subset of MGUS and ascertains that the significance of the monoclonal gammopathy is no longer undetermined. The epidemiology and health care burden of MGRS remains largely unknown. The incidence of MGRS, based on reports from single institutions, is estimated about 6%-10% of cases of MGUS (Nelson Leung et al. Blood. 2012), which suggests a total prevalence of 0.5-1% in the total United States population, accounting for a significant health care burden of 1.5-3 million cases with MGRS. Since pathologic characterization of MGRS is recent, a novel study to define the epidemiology of this subset of MGUS, its temporal course in relation to chronic kidney disease kidney (CKD), the risk factors for progression to end stage renal disease (ESRD) is urgently needed. Methods: All pts from the University Hospitals Cleveland Medical Center, Cleveland, OH, diagnosed with CKD from 2000 to 2019 were included. We identified all cases with diagnosis of MGUS by ICD code. Time to end stage renal disease (TTESRD) was measured from the date of diagnosis of CKD to the date of diagnosis of ESRD and was censored at the date of last follow-up for those without ESRD with death as competing risk. The overall survival (OS) was measured from the date of diagnosis of CKD to the date of death The Fine and Gray method was used for comparisons of cumulative incidence of ESRD between groups. The effect of important factors on TTESRD was further evaluated using multivariable Fine and Gray method. Survivor distribution was estimated using Kaplan-Meier methods and the difference of OS between/among groups was examined by log-rank test. Results: The final data for the statistical analysis reported here contains 626 pts with MGUS and CKD and 15337 pts with CKD alone. The median follow up was 19.7 (range: 0.03, 128) months. Patient's characteristics and distribution of diabetes (DM), hypertension (HTN) and CKD stage at both cohorts are shown in Table-1. Progression to ESRD: There was no difference between rate of progression to ESRD (as the binary outcome) in the cohort of pts with CKD and MGUS and the cohort of CKD without MGUS, 4.8% vs. 6%, respectively (p: 0.2). Univariate analysis of TTESRD showed lack of MGUS, Black race, DM, and CKD stage at baseline as statistically significant factors associated to progression to ESRD (Fig.1). Multivariable analysis on TTESRD including factors (MGUS status, age, gender, race, CKD stage, diabetes and hypertension) demonstrated higher CKD stage at baseline, younger age at time of CKD diagnosis, male gender and black race as the significant factors are associated with shorter TTESRD (Fig.3). Progression by CKD stage advancement: The CKD stage at baseline was compared to the CKD stage at year 1 and year 5 during follow-up. The progression by stage was 28.5% at year 1 for pts without MGUS vs. 29.3% for those with MGUS (p = 0.73). The progression by stage was 38.7% at year 5 for pts without MGUS vs. 39.4 % for those with MGUS (p = 0.89).There was no difference between median OS for pts with CKD with or without MGUS (Fig-2) Conclusion: Here we presented the data of around 16,000 CKD pts based on the MGUS diagnosis in 19 years time span and we could not detect any higher trend for CKD pts with MGUS to develop ESRD or move to higher CKD stage. These data can suggest MGRS forms a quite thin slice of the whole MGUS population. Assessing finding of this study in a larger national database is warranted. Disclosures Caimi: Amgen: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Verastem: Other: Advisory Board; Bayer: Other: Advisory Board. de Lima:Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding. Malek:Takeda: Other: Advisory board , Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding.

Dynamic compression tests were conducted using a split Hopkinson pressure bar along the transverse direction at strain rates (SRs) of 3200 and 6000 s−1. The initial microstructure significantly affected the flow stress behavior and microstructural evolution of the two studied AM80 magnesium alloys. Under the same SR loading, the as-extruded alloy exhibited an apparently higher flow stress. At a SR of 6000 s−1, the flow stress of the as-extruded alloy exhibited a visible decrease (~ 34 MPa) as the strain increased to ~ 0.2, whereas a constant flow stress was exhibited by the solution-treated alloy. High-density dislocations and mechanical twins were detected in the two alloys at a SR of 3200 s−1. Interestingly, dynamic recrystallization (DRX) with an average grain size of ~ 2 µm was only identified in the as-extruded alloy as the applied SR increased to 6000 s−1. The increased localized deformation in the as-extruded alloy due to the retained strain energy and high critical twinning stress improved the DRX driving force, thereby resulting in visibly different micrographs of the two alloys when impacted at the SR of 6000 s−1.

Four different welding sequences of double-pulse MIG welding were conducted for 6061-T6 aluminum alloy automobile bumpers by using nonlinear elastoplasticity finite element method based on ABAQUS software. The post-welding residual stress and deformation were definitely different among the four welding sequences. The results showed that the highest temperature in Solution A was approximately 200 °C higher than the melting point of base metal. High residual stress was resulted from this large temperature gradient and mainly concentrated on the welding vicinity between beam and crash box. The welding deformation primarily occurred in both of the contraction of two-ends of the beam and the self-contraction of crash box. Compared with other welding sequences, the residual stress in Solution A was the smallest, whereas the welding deformation was the largest. However, the optimal sequence was Solution B because of the effective reduction of residual stress and good assembly requirements.

The majority of bladder cancers present with non-muscle invasive disease (NIMBC) confined to the superficial layers of the bladder wall, however, 50-70% of patients will subsequently progress to muscle-invasive bladder cancer (MIBC) that will require more aggressive treatment. For patient stratification, the current prognostication relies on tumor stage and grade, which remains challenging due to the lack of appropriate biomarker(s) to monitor disease progress. Therefore, there is an urgent need for predictive biomarkers that can distinguish between progressive versus non-progressive disease for the identification of patients to better stratify their risk of progression. Here we aim to identify novel prognostic biomarker(s) associated with disease progression by exploring bladder cancer patient gene expression database. We explored and analyzed the transcriptomic gene expression of bladder cancer patient datasets consisting of NIMBC and MIBC subtype from the NCBI GEO (GSE154261, GSE57813, and GSE37317) database. These datasets were analyzed using GEO2R (an R-based web application) and Limma R packages. Pathway enrichment analysis of differentially expressed genes (DEGs) between the NMIBC and MIBC group was analyzed using the ingenuity pathway analysis (IPA), metascape web-based portal, and Cytoscape. The above finding was functionally validated in human bladder cancer cell lines; RT4 (transitional cell papilloma), J82 (transitional cell carcinoma), HT1197 (bladder carcinoma), and 253JB-V (metastatic phenotype) and compared with the relative expression ofUROtsa (benign) urothelial cell line. A total of 1516 DEGs were identified between non-muscle-invasive and muscle-invasive bladder cancer specimens. To identify genes of prognostic value, we performed Gene Ontology (GO) and Kyoto Gene and Genomic encyclopedia (KEGG)analysis. A total of seven genes including CDKN2A, CDC20, CTSV, FOXM1, MAGEA6, KRT23, and S100A9 were confirmed with strong prognostic values in bladder cancer and validated by qRT-PCR conducted in various human bladder cancer cells representing stage-specific disease progression. ULCAN, human protein atlas, and The Cancer Genome Atlas datasets were used to confirm the predictive value of these genes in bladder cancer progression. Moreover, Kaplan-Meier analysis and Cox-hazard ratio analysis were performed to determine the prognostic role of these genes. Univariate analysis performed on a validation set identified a 3-panel gene set viz. CDKN2A, CTSV and FOXM1 with 95.5% sensitivity and 100% specificity in predicting bladder cancer progression. Our study screened and confirmed a panel of a 3-genes biomarkers that could precisely predict the progression and prognosis of bladder cancer. Citation Format: Shiv Shankar Verma, Eswar Shankar, Spencer Lin, Vaibhav Singh, E. Ricky Chan, Shufen Cao, Gregory T MacLennan, Lee E. Ponsky, Sanjay Gupta. Assessment and prognostic implication of 3-gene signature identified as potential biomarker in bladder cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5168.

e17001 Background: Prostate cancer is thought of as an immunologically cold tumor, however a small proportion of patients treated with immunotherapy have impressive responses. Studies into the effect of autoimmune disease on risk of prostate cancer have yielded contradictory results and little is known about the survival of patients with concurrent autoimmune disease and prostate cancer. This study compared outcomes in patients with prostate cancer with and without autoimmune disease. Methods: This study was a retrospective analysis of patients from the SEER-Medicare databases from 2007-2014 with prostate cancer. Patients with a history of autoimmune disease were identified using ICD-9 codes. The effects of autoimmune disease on overall survival (OS) and cancer-specific survival (CSS) were estimated using multivariable Cox regression and Gray’s method respectively controlling the effects of age, race and chronic kidney disease (CKD). The cumulative CSS was estimated taking death as a competing risk. Results: The overall prevalence of investigated autoimmune diseases among the 172,061 patients with prostate cancer was 23.74%. The most common autoimmune diseases identified were rheumatoid arthritis (RA) (20.93%), psoriasis (2.43%) and ulcerative colitis (UC) (0.91%). In stage IV prostate cancer, OS (p = 0.018) and CSS (p < 0.001) were significantly higher in patients with autoimmune disease, with a median OS of 55 months compared to 48 months in patients without autoimmune disease. After adjusting for the effects of age, race, and CKD, autoimmune disease was still predictive of higher OS (HR: 1.41, 95% CI: 1.33 – 1.5, p < 0.0001) and CSS (HR: 1.30, 95% CI: 1.21 – 1.39, p < 0.0001). Patients with autoimmune disease and stage II and III prostate cancer had lower OS (p values < 0.0001) compared to patients without autoimmune disease. Conclusions: The study showed higher prevalence of RA, Crohn disease, UC, and systemic lupus erythematosus in patients with prostate cancer compared to cohorts of similar age ranges in the general population. History of autoimmune disease predicted significantly higher OS and CSS in patients with stage IV prostate cancer even when age, race and CKD were controlled for. It is possible that an improvement in OS with a history of autoimmune disease was evident in stage IV but not in stages II and III because anti-tumor autoimmune activity plays a larger role when prostate cancer effects regional lymph nodes or has distant metastases.

Background: Bronchopulmonary dysplasia (BPD) is a chronic lung disease and major pulmonary complication after premature birth. We have previously shown that increased intermittent hypoxemia (IH) events have been correlated to adverse outcomes and mortality in extremely premature infants. We hypothesize that early IH patterns are associated with the development of BPD. Methods: IH frequency, duration, and nadirs were assessed using oxygen saturation (SpO2) waveforms in a retrospective cohort of 137 extremely premature newborns (

Secreted apolipoprotein L1 (APOL1) is well known as an innate immune factor, protecting against African trypanosomiasis. The intracellular form has multiple functions, including regulating autophagy, intracellular vesicle trafficking, and ion channel activity. The APOL1 protein (G0) has two common variants (denoted G1 and G2) in the C-terminal region and are associated with a high risk of chronic kidney disease (CKD) and progression to end-stage kidney disease. Our previous studies using molecular modeling suggested that APOL1 G1 and G2 stabilize an autoinhibited state of the C-terminus, leading to impaired intracellular interactions with SNARE proteins. To characterize the structural consequence of kidney disease-associated APOL1 variants further, we assigned the C-terminal region proteins using 1H, 13C, 15N multidimensional nuclear magnetic resonance (NMR) spectra in solution in the presence of membrane mimetic dodecylphosphocholine micelles. We then derived models for the three-dimensional structure of APOL1-G0, and -G1 and -G2 variant C-terminal regions using the chemical shifts of the main chain nuclei followed by NMR relaxation measurements. The data suggest that changes in the three-dimensional structure of APOL1 C-terminal region induced by kidney disease-associated variants, not least the alteration of key sidechains and their interactions, could disrupt membrane association and the yet to be characterized protein-protein interactions including its binding partners, such as SNARE proteins. Such interactions could underlie the intracellular mechanisms that mediate the pathogenesis of CKD. In the future, one may try to reverse such structural and dynamics changes in the protein by designing agents that may bind and then mitigate APOL1 variant-associated CKD.

Background Few small sample size studies have reported lymphocyte count was prognostic for survival in small-cell lung cancer (SCLC). This study aimed to validate this finding, to build prediction model for overall survival (OS) and to study whether novel models that combine lymphocyte-related variables can predict OS more accurately than a conventional model using clinical factors alone in a large cohort of limited-stage SCLC patients. Methods This study enrolled 544 limited-stage SCLC patients receiving definitive chemo-radiation with pre-radiotherapy lymphocyte-related variables including absolute lymphocyte count (ALC), platelet-to-lymphocyte ratio (P/L ratio), neutrophil-to-lymphocyte ratio (N/L ratio), and lymphocyte-to-monocyte ratio (L/M ratio). The primary endpoint was OS. These patients were randomly divided into a training dataset (n=274) and a validation dataset (n=270). Multivariate survival models were built in the training dataset, and the performance of these models were further tested in the validation dataset using the concordance index (C-index). Results The median follow-up time was 36 months for all patients. In the training dataset, univariate analysis showed that ALC (P=0.020) and P/L ratio (P=0.023) were significantly correlated with OS, while L/M ratio (P=0.091) and N/L ratio (P=0.436) were not. Multivariate modeling demonstrated the significance of ALC (P=0.063) and P/L ratio (P=0.003), and the improvement for OS prediction in combined models with the addition of ALC (C-index =0.693) or P/L ratio (C-index =0.688) over the conventional model (C-index =0.679). The validation dataset analysis confirmed a modest improvement of C-index with the addition of ALC or P/L ratio. All these models showed reasonable discriminations and calibrations. Conclusions This study validated the significant value of pre-radiotherapy ALC and P/L ratio on OS in limited-stage SCLC. The combined model with ALC or P/L ratio showed additional OS prediction values than the conventional model with clinical factors alone.

The role of filgrastim during acute myeloid leukemia (AML) induction therapy remains controversial. At our institution, newly diagnosed AML patients from 2003 through 2019 were retrospectively evaluated. Patients were stratified on whether they received filgrastim within 5 days after early assessment bone marrow (BMBx) and divided into early GCSF group (eGCSF) and no-eGCSF group. A total of 121 patients were included. We found significantly shorter hospital stay (median 24 vs 26 days

Background: Fecal immunochemical testing (FIT) and multi-target stool DNA testing (mt-sDNA) are recommended colorectal cancer screening options but require follow-up with colonoscopy to determine the source of a positive result. We performed a retrospective analysis in an academic health system to determine adherence to colonoscopy in these patients. Methods: We identified all patients aged 40 years and older with at least 1 primary care visit who had a positive FIT or mt-sDNA between January 2016 and June 2018. We identified receipt of colonoscopy within 6 months of the positive test and reviewed medical records to determine reasons for lack of colonoscopy. Results: We identified 308 eligible patients with positive FIT and 323 with positive mt-sDNA. Some patients with positive FIT (46.7%) and patients with positive mt-sDNA (71.5%) underwent colonoscopy within 6 months, and time to colonoscopy was also shorter with mt-sDNA (hazard ratio, 1.83; 95% CI, 1.48-2.25). These differences remained in a multivariable model adjusting for patient characteristics. Among patients without colonoscopy after positive FIT, 1 or more system, provider, and patient-related barriers were identified in 32.1%, 57.6%, and 36.3%, respectively. Among patients without colonoscopy after positive mt-sDNA, corresponding frequencies were 30.4%, 43.5%, and 57.6%, respectively. Conclusions: Follow-up colonoscopy was higher for mt-sDNA than FIT, which could be due in part to preselection by clinicians and/or patients. Among patients who did not follow-up, provider and system factors were as frequently encountered as patient factors. These findings reinforce the need for multi-level interventions to improve follow-up.

Allogeneic hematopoietic cell transplant (HCT) is a curative therapy for malignant and non-malignant blood diseases. Drug use may be associated with adverse outcomes. We performed a retrospective analysis to assess non-relapse mortality (NRM) and overall survival (OS) in HCT patients with drug use. The medical charts of 232 patients were reviewed. Recipients of matched unrelated donor (MUD) or matched related donor (MRD) transplants were included. Drug use was defined by either metabolic evidence or provider documentation prior to transplant. Transplants were MUD (n = 148) or MRD (n = 84). Median follow-up duration was 15.5 months. There were 35 (15%) patients in the drug use group and 197 (85%) patients in the control group; 49% and 60.4% were in remission at the time of transplant, respectively. In univariate analysis, drug use was associated with a 3-year cumulative incidence of NRM of 43% vs 29% for the control group (p = 0.048), and an HR of 1.75, (95% CI: 1.02-2.99). After controlling for age, sex, disease status, and graft type, drug use was associated with a hazard ratio (HR) of 1.6 (95% CI: 0.95-2.92) for NRM, and an HR 1.2 (95% CI: 0.74-1.94) for OS. Larger cohorts may be needed to further evaluate this association.

Background Next generation sequencing (NGS) of tumor of patients with advanced non–small cell lung cancer (NSCLC) is now a standard of care that informs the clinician on the best therapeutic approach for their patients. The purpose of our study was to investigate the overall impact of NGS testing on survival as well as potential racial differences in utilization, therapeutic decision, and genomic alterations. Method Using a large institutional database, 928 patients with stage IV NSCLC were identified. NGS testing using Foundation One platform was used. Clinical and genomic characteristics were compared by race. We used a propensity-modeling technique to compare groups that were sequenced or not in terms of overall survival. Time to event data was analyzed using Kaplan-Meier method and Cox model. Results A total of 295 patients underwent NGS. Patients undergoing NGS testing had significantly longer survival of 25.3 months versus those who did not undergo sequencing with a median survival of 14.6 months (P = .002) irrespective if they received targeted therapy or not. There was no difference in terms of NGS utilization based on race (P = .32). African American individuals had significantly higher rates of ALK rearrangements and mutations in PBRM1, SETD2, TSC2, and FBXW7. Conclusion Our study demonstrates that within a large single institution there is no racial difference in NGS utilization and that NGS testing directly impacts survival. We identify a number of differences in genomic findings between African American and white individuals.

Background Myelodysplastic syndrome (MDS) represents a heterogenous spectrum of pre-leukemic conditions with a wide range of outcomes. Higher risk MDS as classified by the revised international prognostic scoring system (IPSS-R) score is associated with poor overall survival and up to 30% of patients progressing to acute myeloid leukemia. Hypomethylating agents (HMA) such as azacitadine can improve cytopenias and delay progression to leukemia in about 30% of patients, but these agents may take months to promote response and initially exacerbate cytopenias. Thus treatment related biomarkers that help predict eventual hematologic response are of interest. CD177 is expressed in neutrophils and plays a role in cellular adhesion. In healthy cells, it exhibits bimodal expression by flow cytometry that is stable over time within an individual. The percentage of CD177 positive neutrophils is often decreased in hematopoietic malignancies and myelodysplastic syndromes. Our group has demonstrated that CD177 has diagnostic utility in the identification of myelodysplastic syndromes. As transcription of CD177 is regulated by CpG methylation of its promotor, we hypothesized that treatment with HMAs may improve CD177 expression in clinical responders and potentially guide continuation of HMA therapy. Methods To interrogate the above, we performed a retrospective review of patients with a diagnosed with MDS or MDS/MPN overlap syndromes who received disease modifying therapy with HMA at our institution from 2015 to 2018. Inclusion criteria required documentation of serial bone marrow biopsies with aspirate flow cytometry analysis. CD177 positivity was determined by increase in mean florescence intensity compared to isotype controls. Data was analyzed with using cox multivariate and univariate analysis correlating to treatment response. Results Of the 237 patients, 27 patients met the above criteria. Their average age was 62 (21 to 77) at time of diagnosis with 20 men and 7 women. They exhibited a range of R-IPSS risk stratification with four very high risk, eight high risk, six intermediate risk, and four low risk. Five cases were MDS/MPN overlap. Patients received on average 10 months of HMA treatment with a wide range from 1 month to 42 months of treatment. Median baseline CD177 positivity was 16, 31, 28.5, and 72 percent respectively amongst R-IPSS groups. Of the 27 patients analyzed with repeat bone marrow biopsies, eight patients exhibited 20% or greater increase in CD177(+) neutrophils, ten exhibited a decrease in CD177(+) neutrophils of 20% or greater, and nine exhibited less than a 20% change in CD177(+) neutrophils. with similar distribution of R-IPSS risk stratification amongst groups. (CD177-decreased: 1 very high, 3 high, 1 intermediate, 2 low risk, CD177-stable 1 very high, 2 high, 2 intermediate, and 1 low, Improved-CD177 1 very high, 4 high, 2 intermediate and 1 low). Cox proportional hazard analysis suggests that patients exhibiting a decrease or stable CD177 were less likely to exhibit a treatment response with results trending to significance (OR= 0.13 p=0.099). Conclusion Our initial data suggests that change in CD177 may help predict HMA treatment response. More uniform prospective analysis is indicated to compared CD177 changes over initial treatment. Furthermore, CD177 in peripheral blood and bone marrow samples correlate excellently (R 2=0.95). Prospective studies are underway to correlate CD177 change and initial treatment response utilizing flow analysis of pre-treatment CBCs. Disclosures No relevant conflicts of interest to declare.

Introduction Clonal cytopenia of undetermined significance (CCUS) represents a clonal group of cells with the presence of a hematologic malignancy-associated somatic mutation without meeting the morphologic criteria for MDS. CCUS patients have a variable risk of progression to MDS. The WHO requires at least 10% of a cell lineage have dysplastic morphology for the diagnosis of MDS, but CCUS patients have been described with no evidence of dysplasia (CCUS-ND) or with low level dysplasia (CCUS-D). We previously identified CCUS-D as biologically distinct with higher risk MDS mutations. We hypothesized that CCUS-D would be independently associated with the risk of progressive cytopenia over time and thus may have clinical relevance in the setting of CCUS. Methods Cases of CCUS were identified on review of bone marrow biopsies completed for the diagnosis of cytopenia from 8/2016 to 9/2018 with results of a custom 31-gene NGS hotspot panel to detect mutations in the following genes: ASXL1, BRAF, CALR, CBL, CSF3R, DNMT3A, ETV6, EZH2, FLT3, GATA2, IDH1, IDH2, JAK2, JAK3, KIT, KRAS, MPL, MYD88, NPM1, NRAS, PHF6, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, TET2, TP53, U2AF1, WT1, and ZRSR2. The classification of CCUS-D or CCUS-ND required two or more board-certified hematopathologists to score the degree of morphologic dysplasia on bone marrow aspirates with at least one of the following morphologic criteria: >2%-50% erythroid cells with megaloblastoid changes and/or basophilic stippling, >5%- Statistical differences of baseline characteristics were evaluated by T-test for continuous variables, and Chi-square / Fisher's exact test were used for association between categorical variables. The repeated measures over time for various outcomes (WBC, ANC, hemoglobin, platelet) were visualized using scatter plot supervised with lowess smoother. The effects of dysplasia on various longitudinal outcomes were estimated using linear mixed-effect models. Results We identified 54 CCUS patients on review of 200 marrows completed for undiagnosed cytopenia. Twenty-six patients were identified with CCUS-D, and 28 patients with CCUS-ND. Baseline clinical characteristics including age, gender, race, smoking status, or presence of infection at time of initial diagnosis were similar. Hematology laboratory parameters including White Blood Cell Count (WBC), Absolute Neutrophil Count (ANC), Hemoglobin (Hgb), and Platelet Count (Plts) did not differ. (Table 1). Patients with CCUS-D had an average of 1.62 mutated genes detected per patient with the most common being TET2 (26.19%), SRSF2 (14.29%), and DNMT3A (14.29%). Patients with CCUS-ND had an average of 1.41 mutations per patient with the most common being TET2 (31.57%) and DNMT3A (31.57%). Patients were followed for a median of 32.2 months and a range from 1.0 to 48.8 months. On long term follow up, WBC, ANC, Hgb and plts trended lower in patients with CCUS-D compared to CCUS-ND, but the difference was marginally statistically significant (p = 0.09, 0.16, 0.13, 0.64 respectively). We also evaluated the rate of change in hematology parameters and found no significant difference in change rate of WBC, ANC, and hgb (p = 0.25, 0.13, and 0.28, respectively). There was a significant difference in the change rate of platelet counts between the two groups (p = 0.026). In particular, patients with CCUS-D had decreasing platelet counts at a rate of -0.04119 10E9/L/day and patients with CCUS-ND had increasing platelet counts at a rate of 0.01075 10E9/L/day. Two patients in the CCUS-D cohort progressed to MDS at an average of 938.5 days. One patient with CCUS-ND progressed to Large Granular Lymphocytic Leukemia at 805 days. Conclusions Low level (< 10%) dysplasia in cell lineages in CCUS is associated with a higher rate of decline in platelet counts but was not independently associated with increased risk of progressive neutropenia, leukopenia, or anemia. Longer follow up may be required to further understand the clinical significance of low level dysplasia in CCUS. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Multiple Myeloma (MM) is a cancer of terminally differentiated plasma cell resides in bone marrow, which is always preceded by clinically asymptomatic precursor states. The process of malignant transformation however is not fully understood. Analyses of cells from precursor state have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes found in MM cells. Furthermore, mice xenografts from patient (pt) with precursor disease showed progressive growth on its own suggesting progression potential is counteracted by active extrinsic restraints that prevent its progression to MM (Das R et al. Nature Medicine, 2016). Hence, precursor progression to MM can be viewed as a dynamic process in which the clonal mass is the net result of pro-growth, pro-survival replicative capacity of the myeloma clones vs. anti-tumor immunity. The change in the net clonal mass sometimes is large enough to be detected by measurable fluctuations in serum monoclonal protein spike (M-spike) levels and reflects a highly dynamic battle between plasma cell clone and cell-mediated anti-myeloma immunity among those pts. The prognostic value of this highly dynamic state on risk of progression to MM is largely unknown. In this study we sought to assess the association between the dynamic M-spike pattern and the risk of progression from a precursor clone to MM. Methods: All pts with positive serum electrophoresis (SPEP) values measured from January 2011 to January 2021 for our institution were included for this study. All pts that had 3g/l or had clear evidence of progression by serial increasing M-spike values were excluded.. We assigned the pattern of M-spike values over time into two groups according to stability. To eliminate the test-to-test variability, we defined stable disease as lack of more than 20% difference from lowest M-spike, and fluctuating disease if the difference exceeds 20%. The time-to-treatment (TTT) was then measured from the first positive SPEP to the time of treatment and was censored at the date of last follow-up for pts who did not have anti-myeloma treatment with death as competing risk. The effect of M-spike pattern on TTT, treating as binary outcome, was also evaluated using logistic regression analysis. Univariate analysis of TTT was performed using Gray's method. All tests were two-sided and p-value ≤ 0.05 were considered statistically significant. Results: A total of 565 pts were studied, 193 with a fluctuating pattern and 372 with a stable pattern. Median age at first positive SPEP was 76 years old (range: 38-101), 271 (48%) of them were male; 427 (75%) were Caucasian and 123 (22%) African American. Baseline creatinine was 1.17 mg/dl (range 0.5-11.2 SD 0.94). Baseline albumin was 3.97 g/dl (range 1.6-5.2 SD 0.47), 336 pts (59%) were IgG, 75 (13%) IgA, and 142 (25%) had IgM M-spike; 326 (58%) pts had Kappa light chain and 239 (42%) had Lambda. Autoimmune diseases were more common in the stable disease pattern (17% vs. 10% p=0.028), the most frequent one was Rheumatoid arthritis in 33 pts (6%). Furthermore, baseline albumin was statistically higher in pts in the stable cohort (4.04 vs. 3.85g/dl, p= Conclusion: The dynamic pattern of M-spike seen here with fluctuating values over time (over time is two words) was significantly predictive of progression to MM in pts with a precursor disease state. These findings may reflect a different nature of tumor vs. immune system balance and possible impaired immunity in these pts which may have implications for future clinical trials that evaluate the efficacy of anti-myeloma immunotherapeutics. Furthermore, our finding suggest that fluctuations in M-spike levels may be factored into risk models that predict the progression to MM among pts with precursor clones. Larger studies are warranted to further study this concept. Figure 1 Figure 1. Disclosures Malek: Medpacto Inc.: Research Funding; Janssen: Other: Advisory board ; Takeda: Honoraria; Cumberland Inc.: Research Funding; Amgen: Honoraria; BMS: Honoraria, Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board.

Introduction: There is increased risk of congestive heart failure (CHF) following anthracycline-based chemotherapy in patients with Diffuse Large B-cell lymphoma (DLBCL). Other than increased cumulative anthracycline dose, little is known about risk factors for developing CHF and other cardiovascular events (CVE). Methods: We conducted a retrospective analysis of 539 DLBCL patients diagnosed at University Hospitals Seidman Cancer Center between 2002 - 2016. Baseline patient and disease characteristics, patterns of treatment and outcomes after therapy, including response, survival, relapse, CVE, and causes of death were collected. Time-to-CVE was measured from the date of DLBCL diagnosis to the date of CVE diagnosis and censored at the date of last follow-up for those without CVE, considering death as competing risk. The cumulative incidence of CVE was estimated taking death as competing risk into account. Univariate and multivariable analysis on time-to-CVE was done using Gray's method. Multicollinearity was tested and some of the highly correlated covariables were excluded in the final analysis. CVE risk scores were computed for each patient as a linear combination of the factors included in the multivariable model and their respective coefficients. The optimal cutoff point was identified by searching the spectrum of the risk scores to have the best discrimination of time-to-CVE among patients at low/high risks. All tests were two-sided and p-value ≤ 0.05 were considered statistically significant. Results: We identified 463 patients who received anthracycline to be included in the statistical analysis. Baseline clinical and disease characteristics including comorbidities, clinical risk factors are outlined in Table 1. After a median follow up of 71.1 (range: 0.3 - 216.1) months, 5-year PFS was 59% with median PFS of 82.7 (95% Cl: 71.1 - 115.7) months and 5-year OS was 71% with median OS of 152.6 (95% CI: 127.5 - 162) months. CVE were identified in 92 patients (19.9%), with 128 events identified. The most common CVE was new onset of CHF in 10.4% of patients, followed by atrial fibrillation (4.9%) and asymptomatic heart failure ( 3%) (Table 2). The 3, 6 and 9-year cumulative incidence of CVE for early stage was 13.1%, 15.2% and 18.5%, respectively and 22.2%, 31.4% and 36.5% for advanced stage, respectively (p-value = 0.026). Similarly, the cumulative incidence of CVE was increased in patients with diabetes, with a 3-year cumulative incidence of CVE of 9.4% vs. 17.5% in patients with and without diabetes, respectively. Proportional hazards regression for time-to-CVE identified age >65 years, CD10 expression by IHC, diabetes, and hypertension as significant predictors of time-to-CVE on univariate analysis. On multivariable regression analysis with advanced age at diagnosis, stage, baseline lymphocyte count, and diabetes; stage was still significant in predicting time-to- CVE controlling the effects of advanced age and diabetes, which were also marginally significant. A predictive formula was created to help identify patients at highest risk for cumulative incidence of CVE. Using advanced age (over 65 years of age), baseline lymphocyte count above 800/µL, advanced stage at diagnosis and history of diabetes patients could be stratified into groups with low, intermediate and high risk for CVE (Table 4 and Figure 1). Risk score = Age >65 (3 points) + Lymphocyte count > 800/µL (-1 point) + Stage III/IV(8 points) + Diabetes (3 points) (Table 3) One-year cumulative incidence of CVE was 5.3% for low-risk patients, 7.9% for intermediate risk patients and 13.4% for high risk patients (Figure 1). Conclusions: Our analysis indicates a high risk of CVE in anthracycline treated DLBCL patients, with 19.9% of patients having a CVE in our cohort. The proposed CVE predictive score uses clinical and laboratory parameters routinely collected on all new DLBCL patients and can be easily assessed in the clinical setting. Patients in the high-risk group have a cumulative incidence of CVE of 13.4% at 1 year and would likely benefit from surveillance and interventions. Use of a clinical risk score can aid in the identification of patients at highest CVE risk to conduct studies of surveillance and prevention of this common complication. Figure 1 Figure 1. Disclosures Boughan: Beigene: Speakers Bureau. Caimi: Seattle Genetics: Consultancy; Verastem: Consultancy; Amgen Therapeutics.: Consultancy; Kite Pharmaceuticals: Consultancy; TG Therapeutics: Honoraria; ADC Theraputics: Consultancy, Research Funding; Genentech: Research Funding; XaTek: Patents & Royalties: Royalties from patents (wife).

Patients undergoing hematopoietic cell transplantation (HCT) experience decline in their physical activity during their transplant admission. There is limited experience with prospective monitoring of transplant recipients. We therefore measured physical activity and sleep patterns of subjects undergoing autologous and allogeneic HCT. Eighty-three patients were consented for this study. Sixty-three patients competed the study and had their physical activity prospectively assessed using the fitness-tracking device Fitbit HR. Outcomes included adherence, physical activity, readmission, hematopoietic engraftment, and 100-day survival. Sixty percent of patients (n = 37) underwent autologous HCT, and 40% (n = 26) underwent allogenic HCT. Both groups had a comparable number of steps at admission to the hospital. The number of daily steps during the study period was lower in the allogeneic group (2159 versus 3008, P = .07), as was the minimum number of steps recorded over the transplant admission (allogeneic HCT = 395 versus autologous HCT = 848, P = .01). Patients undergoing allogeneic HCT were less active on the day before discharge (1956 steps versus 3183 steps, P = .08). In multivariate analysis, physical activity was not associated with HCT-related outcomes. Patients undergoing HCT experience significant decline in their physical activity during their transplant admission that does not recover by the time of discharge. This effect can be objectively measured using fitness tracking devices.

To investigate the stress response and the corresponding microstructure evolution of AM80 magnesium alloy under quasi-static and dynamic loading, as-cast AM80 alloy was compressed over a wide range of strain rate at room temperature. The experimental results show that the flow stress responses exhibit a negative strain rate sensitivity (SRS) under quasi-static loading while a positive SRS under dynamic loading. Furthermore, deformation bands generated under dynamic loading are relatively homogeneous with a visibly higher density compared with those generated under quasi-static loading. The activation of extension twinning is significantly enhanced under dynamic loading. The dislocation density and extension twins apparently decrease as the applied strain rate increases from 1400 to 2300 s−1 due to the adiabatic temperature rise, which results in the limited increase in flow stress.

Background: The introduction of novel targeted agents that inhibit specific cellular pathways has improved the prognosis of chronic lymphocytic leukemia (CLL) patients. CLL patients have a higher risk of secondary malignancies, but this risk has not yet been defined for patients treated with targeted agents, including inhibitors of BTK, PI3K or BCL2. Methods: We conducted a retrospective cohort study of CLL patients managed at a large tertiary care center between 1994 and 2018. Patients were classified according to whether they were treated with cytotoxic chemotherapy alone, chemoimmunotherapy or if they received a targeted agent (BTK inhibitor, PI3K inhibitor, BCL2 inhibitor) during the course of their disease. Time to first secondary malignancy corresponds to time elapsed between CLL diagnosis and the earliest secondary malignancy. Cumulative incidence of secondary malignancy was estimated considering competing risk of death. Multivariable analysis of cumulative risk of secondary malignancies was performed using Gray's method. Survival analysis was done with the Kaplan Meier method, comparisons were done using log - rank. Results: 265 CLL patients received care at our institution, median age (range) at diagnosis was 62 years (28-94), 168 (63.4%) were male, 199 (82.9%) were white, and 107 (41.5%) had Rai stage 3 or 4 at diagnosis. Median follow up was 10.5 years. Treatment was prescribed for 185 (70.1%) patients, 33 (17.7%) patients received only chemotherapy, 110 (59.1%) received chemoimmunotherapy, and 43 (23.1%) received targeted agents in the course of their disease. Median time to treatment was 11 months (IQR 1 - 177). Patients who did not receive therapy had a shorter median follow up (8.5 years) compared with treated patients (11.8 years) (p = Eighty patients developed a secondary malignancy (30.9%). The secondary malignancy of earliest onset was cutaneous malignancy in 40 patients (50.0%), solid tumor in 31 patients (38.8%), and hematologic malignancy in 9 patients (11.3%). Median time from diagnosis of CLL to secondary malignancy was 48 months (IQR 22 - 107), with 5- and 10-year cumulative incidence of secondary malignancy of 19.8% and 29.8%, respectively. Among solid tumors, cancers of the lung (8), colon (5), and prostate (4) were most common. Median time from diagnosis of CLL to solid tumor or hematologic malignancies was 48 months (IQR 24 - 91), with 5- and 10-year cumulative incidence of 10.7% and 18.4%, respectively. A total of 45 patients developed skin cancer following CLL diagnosis (20%); 17 of these patients were diagnosed with multiple cutaneous malignancies. Thirty-two patients were diagnosed with basal cell carcinoma, 27 with squamous cell carcinoma, and 5 with melanoma. Median time from diagnosis of CLL to cutaneous malignancy was 48 months (IQR 21 - 121), with 5- and 10-year cumulative incidence of 10.5% and 13.8%, respectively. Pairwise comparisons did not demonstrate statistically significant differences in median follow up of patients without secondary malignancy (9.6 years, 95% CI = 8.8-11.6), non-cutaneous secondary malignancies (10.8 years, 95% CI 9.5 -18.5), or cutaneous malignancies (11.8 years, 95% CI 10.6 -16.3). The cumulative incidence of secondary malignancies was not different among treatment groups (p = 0.9), but the cumulative incidence of cutaneous malignancies was higher among patients treated with targeted agents (p = 0.046) (figure 2). On multivariate analysis, age was the single risk factor associated with secondary malignancies (Figure 3), whereas the risk of cutaneous malignancies was also affected by treatment with targeted agents (hazard ratio = 3.1, 95% CI = 1.37-7.07) (figure 4). Conclusions: Secondary malignancies continue to be an important complication of CLL in the era of targeted therapies. We observed a higher cumulative incidence of cutaneous malignancies in patients treated with targeted drugs. As CLL patients treated with targeted agents experience improved survival, surveillance for secondary malignancies, in particular cutaneous cancers, remains an important health maintenance intervention. Disclosures Malek: Clegene: Other: Advisory board , Speakers Bureau; Takeda: Other: Advisory board , Speakers Bureau; Sanofi: Other: Advisory board; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Amgen: Honoraria; Janssen: Other: Advisory board, Speakers Bureau. de Lima:Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. Caimi:Celgene: Speakers Bureau; Bayer: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Verastem: Other: Advisory Board; Amgen: Other: Advisory Board.

Ras genes potently drive human cancers, with mutated proto-oncogene GTPase KRAS4B (K-Ras4B) being the most abundant isoform. Targeted inhibition of oncogenic gene products is considered the "holy grail" of present-day cancer therapy, and recent discoveries of small-molecule KRas4B inhibitors were made thanks to a deeper understanding of the structure and dynamics of this GTPase. Because interactions with biological membranes are key for Ras function, Ras-lipid interactions have become a major focus, especially because such interactions evidently involve both the Ras C terminus for lipid anchoring and its G-protein domain. Here, using NMR spectroscopy and molecular dynamics simulations complemented by biophysical- and cell-biology assays, we investigated the interaction between K-Ras4B with the signaling lipid phosphatidylinositol (4,5)-phosphate (PIP2). We discovered that the β2 and β3 strands as well as helices 4 and 5 of the GTPase G-domain bind to PIP2 and identified the specific residues in these structural elements employed in these interactions, likely occurring in two K-Ras4B orientation states relative to the membrane. Importantly, we found that some of these residues known to be oncogenic when mutated (D47K, D92N, K104M, and D126N) are critical for K-Ras-mediated transformation of fibroblast cells, but do not substantially affect basal and assisted nucleotide hydrolysis and exchange. Moreover, the K104M substitution abolished localization of K-Ras to the plasma membrane. The findings suggest that specific G-domain residues can critically regulate Ras function by mediating interactions with membrane-associated PIP2 lipids; these insights that may inform the future design of therapeutic reagents targeting Ras activity.

8514 Background: While the incidence of small cell lung cancer (SCLC) has been decreasing in recent years, an increasing proportion of our patients are younger African American (AA) women. There have been no studies describing these changes as well its impact on outcome and potential genomic differences amongst white and AA populations. Methods: We maintain a clinical/genomic/pathological database of all patients with SCLC treated at our comprehensive cancer center starting from 1998. We compared the baseline characteristics and outcomes (Overall survival [OS] and progression-free survival [PFS]) between AA and white patients, and between females and males. In addition, we looked at genomic alterations in >350 cancer-related genes and compared the frequency and types of mutations in our study population. Results: A total of 917 patients with SCLC were included (median age 66 years, 486 female, 179 African American). Amongst the African American patients, 67.6% were female, a striking difference compared to the white population, where only 49.1% were women (P 0.05). There was an increase in mutational frequency in AA women compared to both AA men and white patients. PIK3CA and KIT mutations were more frequent in females while APC mutations were more frequent in males (P=0.041 for all comparisons). There was a trend toward increased mutational frequencies in TP53, PTEN, and NOTCH1 in AA patients. The relative frequency of gene alterations is shown in the table. In univariable analysis, NOTCH1 mutation was associated with improved OS (HR 0.24 [0.06-0.96], P=0.04). Conclusions: In this large cohort of patients with SCLC followed over 2 decades, there was a striking 2-fold higher incidence of SCLC in AA females than in AA males, although there were no differences in OS or PFS by sex or race. Several genomic alterations occur in higher frequencies in AA patients and AA women, in particular, have higher mutational frequencies.[Table: see text]

Background: Outcome of Multiple Myeloma (MM) patients has improved as the result of the introduction of novel medications and use of autologous hematopoietic cell transplantation. However, this improvement comes at the expense of increased financial burden. It is largely unknown if socioeconomic factors influence MM survival. Methods: We used the National Cancer Database, a database that houses data on 70% of cancer patients in the US, to evaluate the effect of socioeconomic factors on the survival of 117,926 MM patients diagnosed between 2005 and 2014. Results: Patients aged ≥65 years who were privately insured lived longer than patients with Medicare (42 months vs. 31 months, respectively, p &lt, 0.0001). Treatment in academic institutions led to better survival (HR: 1.49, 95% CI: 1.39, 1.59). Younger age, fewer comorbidities, treatment in academic centers, and living in a higher median income area were significantly associated with improved survival. After adjusting for confounders, survival of Medicare patients was similar to those with private insurance. However, the hazard of death remained higher for patients with Medicaid (HR: 1.59, 95% CI: 1.36, 1.87) or without insurance (HR: 1.62, 95% CI: 1.32, 1.99), compared to privately insured patients. Conclusion: Economic factors and treatment facility type play an important role in the survival of MM patients.

3634 Background: Phase 1 clinical trials are the first step in developing new cancer therapeutics. Patients enrolled in these studies have typically exhausted standard therapies and are at a point in their disease trajectory where they often are choosing between a phase 1 clinical trial and hospice care. These patients may have significant symptom burden, which can result in early trial discontinuation and confound phase 1 trial outcomes, including toxicity profiles, which may influence further drug development. This study aimed to determine the palliative care needs of patients enrolled on phase 1 clinical trials and their caregivers (CGs), along with differences in study duration, adverse event (AE) and symptom profiles, and quality of life (QOL) between those receiving structured palliative care vs usual supportive care. Methods: 68 patients enrolled on phase 1 clinical trials were randomly assigned to receive structured palliative care or usual supportive care. 39 of their CGs were enrolled and assigned to the same arm as the patient. Quality of life metrics were obtained monthly: the Functional Assessment of Cancer Therapy-General and Memorial Symptom Assessment Scale -Short Form for patients, and The Quality of Life in Life Threatening Illness - Family Carer Version and Caregiver Reaction Assessment for CGs. Palliative care resources utilized were assessed for those in the palliative care arm, and referrals to supportive care services assessed in those in the usual care arm. AEs recorded on the Phase 1 trials were evaluated & compared between arms. Results: Mean duration on phase 1 study was 132 days in the palliative care arm vs 114 days in the usual care arm (p = 0.55). Total weighted AE rate (# of AE [x] AE grade per month) was 26.9 in the palliative care arm vs 34.0 in the usual care arm (p = 0.53). Patients in the palliative care arm experienced better QOL and lower symptom burden, as did their CGs, compared to those in the usual care arm. While the differences in outcomes were not statistically significant, all results favored structured palliative care. Conclusions: Phase 1 patients and their CGs have physical and psychosocial needs which warrant palliative care services. Preliminary results suggest structured palliative care is associated with increased duration on study (by nearly 3 weeks), improved patient and CG QOL, and reduced patient symptom and CG burden. A larger study is warranted to confirm these results and further develop the ideal palliative care intervention in these populations. Clinical trial information: NCT02543541 .

12104 Background: Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy for patients with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% in some reports impeding maximal benefit of this agent. The optimal management of IMiDs-associated skin is unclear. The concurrent weekly Dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD. Furthermore, we assessed the impact of this desensitization regimen on clinical outcome. Methods: A total of 160 patients were evaluated. The incidence of rash was found to be 13% (n = 21). A cohort of age- and gender-matched without rash (n = 39) was randomly selected. The effects of rash on overall and progression free survival (OS and PFS) were further estimated using Cox regression controlling the effects of age and gender. Results: Median time to development of rash after IMiD initiation was 28 days (range, 2-232). Rashes were graded as low (I-II) in 89% (n = 17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all patients were able to restart the same IMiD with none re-experiencing any dermatologic adverse effect afterward. Comparing to no-rash controls, there was no significant difference in PFS (0.13) or OS (p = 0.12) in multivariate regression model. Conclusions: Proposed 3-week corticosteroid regimen showed 100% success rate in reinstituting IMiDs in our cohort. It may provide a highly effective and practical short term immunosuppression required to enable patients to restart IMiDs and enjoy comparable outcome to pts without skin rash.

4623 Background: The role of neoadjuvant chemotherapy (NAC) for resectable pancreatic cancer (RPC) remains controversial. We sought to compare the outcomes of NAC with upfront surgery (UFS). Methods: The study retrospectively enrolled patients with RPC who had UFS or received neoadjuvant FOLFIRINOX (FFX) or gemcitabine plus albumin-bound paclitaxel (GA). Between-group differences were assessed with T-test for continuous variables, and Chi-square / Fisher’s exact test for categorical variables. The overall survival (OS) and recurrence-free survival (RFS) were determined by the Kaplan-Meier method with Wilcoxon test for the difference between groups. The effects of NAC vs. UFS on OS and RFS were further estimated using Cox regression controlling the effects of age and CA 19-9. Results: Between 2011 and 2019, 131 patients with RPC underwent UFS followed by adjuvant chemotherapy (gemcitabine, n = 65; gemcitabine/capecitabine, n = 18; FFX, n = 9). Up to 32 patients (24.4%) could not receive adjuvant chemotherapy due to surgical complications or poor recovery. Total 50 patients with RPC received NAC (FFX, n = 32; GA, n = 18). Median of 5.5 cycles of FFX or 3 cycles of GA were given prior to surgery. Resection rate was 72% (FFX 62.5%; GA 88.9%). The rest (28%) were no longer surgical candidates due to disease progression rather than toxicities from NAC. On surgical pathological review, complete resection (R0) was achieved in 83.3% of resected cases after NAC (FFX 90%; GA 75%) and 79.4% with UFS. The tumor size distribution was: pT1 11.1%, pT2 41.7%, pT3 44.4% with NAC; pT1 5.4%, pT2 18.3%, pT3 76.3% with UFS. The nodal status distribution was: pN0 27.8%, pN1 55.5%, pN2 16.7% with NAC; pN0 23.7%, pN1 71.0%, pN2 5.3% with UFS. Median pre-treatment CA 19-9 was 321.95 unit/mL in the NAC group and 79.99 unit/mL in the UFS group (p = 0.009). Median age was 70.5 in the NAC group and 72 in the UFS group (p = 0.374). There was no significant difference in the performance status between the two groups. In Kaplan-Meier analysis, there was a significant difference of OS between UFS and NAC with median OS of 648 days under UFS versus 884 days under NAC (p = 0.029); the median of RFS was 390 days under UFS versus 392 days under NAC (p = 0.953). The hazard ratio (NAC vs UFS) adjusted for CA19-9 and age was 0.7 (p = 0.176) for OS and 0.98 (p = 0.918) for RFS. Conclusions: We observed a signal of tumor downstaging, higher R0 rate, and improved OS with NAC compared with UFS. Further prospective trials are needed to validate these results.

The N-terminal transactivation domain (NTD) of estrogen receptor alpha, a well-known member of the family of intrinsically disordered proteins (IDPs), mediates the receptor’s transactivation function to regulate gene expression. However, an accurate molecular dissection of NTD’s structure-function relationships remains elusive. Here, using small-angle X-ray scattering (SAXS), nuclear magnetic resonance (NMR), circular dichroism, and hydrogen exchange mass spectrometry, we show that NTD adopts a mostly disordered, unexpectedly compact conformation that undergoes structural expansion upon chemical denaturation. By combining SAXS, hydroxyl radical protein footprinting and computational modeling, we derive the ensemble-structures of the NTD and determine its ensemble-contact map that reveals metastable regional and long-range contacts, including interactions between residues I33 and S118. We show that mutation at S118, a known phosphorylation site, promotes conformational changes and increases coactivator binding. We further demonstrate via fluorine-19 (19F) NMR that mutations near residue I33 alter 19F chemical shifts at residue S118, confirming the proposed I33-S118 contact in the ensemble of structural disorder. These findings extend our understanding of IDPs’ structure-function relationship, and how specific metastable contacts mediate critical functions of disordered proteins. Highlights A compact disorder is observed for the N-terminal domain (NTD) of estrogen receptor Multi-technique modeling elucidates the NTD ensemble structures Ensemble-based contact map reveals metastable contacts between I33 and S118 19F-NMR data validate the proposed I33-S118 contact in the IDP

Ras genes are potent drivers of human cancers, with mutated K-Ras4B being the most abundant isoform. Targeted inhibition of oncogenic gene products is considered the holy grail of present-day cancer therapy, and recent discoveries of small molecule inhibitors for K-Ras4B greatly benefited from a deeper understanding of the protein structure and dynamics of the GTPase. Since interactions with biological membranes are key for Ras function, the details of Ras - lipid interactions have become a major focus of study, especially since it is becoming clear that such interactions not only involve the Ras C-terminus for lipid anchoring, but also the G-protein domain. Here we investigated the interaction between K-Ras4B with the signaling lipid phosphatidyl inositol (4,5) phosphate (PIP2) using NMR spectroscopy and molecular dynamics simulations, complemented by biophysical and cell biology assays. We discovered that the β2 and β3 strands as well as helices 4 and 5 of the GTPase G-domain bind to PIP2, and that these secondary structural elements employ specific residues for these interactions. These likely occur in two orientation states of the protein relative to the membrane. Importantly, we found that some of these residues, which are known to be oncogenic when mutated (D47K, D92N, K104M and D126N), are critical for K-Ras-mediated transformation of fibroblast cells, while not substantially affecting basal and assisted nucleotide hydrolysis and exchange. We further showed that mutation K104M can indeed abolish localization of mutant K-Ras to the plasma membrane. These findings suggest that specific G-domain residues play an important, previously-unknown role in regulating Ras function by mediating interactions with membrane PIP2 lipids. Thus, a detailed description of the novel K-Ras-PIP2 binding surfaces is likely to inform the future design of therapeutic reagents.