tbuckley/cabot-search huggingface dataset:
A novel CRISPR-directed gene editing method that catalyzes precise gene segment replacement <i>in vitro</i> enabling multiplex site-directed mutagenesis.
Authors: Gabi Tarcic, Brett M Sansbury, Amanda M Wagner, Shaul Barth, Ester Paniri, Eric B Kmiec
Journal: Journal of Clinical Oncology (2019)

e14688 Background: Functional analysis of the multitude of mutations found in tumors is a major goal to better understand their role and to optimize patient treatment. PCR-based site-directed mutagenesis (SDM) techniques are often used to engineer these variants. While these tools are efficient, they are not without significant limitations, most notably off-site mutagenesis, limited scalability and lack of multiplexing capabilities. To overcome many of these limitations, we describe a novel, fast and simple method for the introduction of both simple and complex gene mutations in plasmid DNA by using in vitro CRISPR based DNA editing. Methods: For each mutation, a specifically designed pair of CRISPR/Cas12a ribonucleoprotein complexes are used to execute site-specific double-strand breaks on plasmid DNA enabling the excision of a defined DNA fragment. This is followed by donor DNA replacement and bacterial colony expansion. We term this method, CRISPR-directed DNA Mutagenesis (CDM). Results: Using CDM we have been able to synthesize known oncogenic mutations as well as novel variants in 8 different cancer genes. These mutations have been synthesized with over 60% success rate, compared to about 40% success rate in SDM. More importantly, we show that in the CDM method there were no off-site mutations eliminating the need to sequence large portions of the gene. Conclusions: We have developed a novel multiplex site-directed mutagenesis method that can generate multiple unique mutations simultaneously within plasmids. CDM has proven capable of precise, rapid and robust mutation synthesis, including single base point mutations, site-specific deletions, insertions and duplications within targeted plasmids.
Completion of adjuvant chemotherapy with Cape/CAPOX in colon cancer: A retrospective database study.
Authors: Edward Chu, Xue Wang, Maxfield Frohlich, Melody Tran, Won Chan Lee
Journal: Journal of Clinical Oncology (2019)

e15116 Background: Fluorouracil-based adjuvant chemotherapy has been shown to improve survival of patients with early-stage colon cancer. Suboptimal adherence to oral chemotherapy, such as capecitabine, remains a serious issue and reduces treatment efficacy. Patient barriers to adherence include adverse effects and high medical costs. This study assesses the completion rates and associated factors in patients on capecitabine monotherapy (Cape) and capecitabine with oxaliplatin (CAPOX) for adjuvant treatment of early-stage colon cancer. Methods: Patients with a primary/secondary diagnosis of early-stage colon cancer between April 2013-March 2017, and 1+ claim of Cape or CAPOX within 60 days of colectomy were identified from the MarketScan Commercial/Medicare Database. Therapy completion rates (treatment ≥7 cycles) were calculated. Multivariate logistic regressions analyses were used to assess the factors (patients’ age, gender, payer type, geography, comorbidities, healthcare costs, etc.) associated with treatment completion. Results: A total of 679 patients met the eligibility criteria (mean age ± SD: 57.3 ± 11.5 years, 54% male), of which 382 (56%) were on Cape (mean age ± SD: 60.2±12.4) and 297 (44%) on CAPOX (mean age ± SD: 53.6±9.0). Completion rates were 43% in Cape and 42% in CAPOX. The baseline overall mean monthly healthcare cost was significantly higher in non-completers vs. completers (Cape: $9,870 vs $7,169, P=0.003; CAPOX: $10,009 vs $8,068, P=0.01). Multivariate logistic regression showed that patients &lt;65 years of age on CAPOX were more likely to complete treatment than patients ≥65 years on CAPOX (Odds Ratio=5.1, P=0.03). Conclusions: Cape and CAPOX completion rates are suboptimal in patients with early-stage colon cancer. Non-completion of therapy is associated with significantly higher baseline healthcare costs for both Cape and CAPOX, as is older age for CAPOX. The low completion rates highlight the unmet need for more effective strategies to optimize oral chemotherapy for the adjuvant treatment of early-stage colon cancer. [Table: see text]
Focal radiation for oligometastatic castration-resistant prostate cancer (FORCE): A phase II randomized trial.
Authors: Zachery Reichert, David C. Smith, Todd Matthew Morgan, Morand Piert, Scott A. Tomlins, Frank Cameron Cackowski, Megan Veresh Caram, Jason W.D. Hearn, Phillip Lee Palmbos, Caitlin Schonewolf, Sarah Elizabeth Yentz, Daniel Eidelberg Spratt
Journal: Journal of Clinical Oncology (2019)

TPS5096 Background: Metastasis Directed Therapy (MDT) is the focus of recently completed and ongoing clinical trials. For biochemically recurrent prostate cancer, MDT delays the initiation of androgen deprivation, but is noncurative as &gt; 75% of patient’s progress within 3 years. In metastatic castration-resistant prostate cancer (mCRPC), focal therapies are common for palliation of pain, but not routinely recommended for controlling systemic disease. Whole genome sequencing has demonstrated that mCRPC metastases seed new metastases and patients with a greater burden disease develop more rapid resistance to next-generation hormone therapies. Therefore, MDT to all visible disease may be beneficial in oligometastatic CRPC. Methods: This is a prospective, randomized phase 2 clinical trial with a primary endpoint of progression-free (radiographic + clinical) survival at 18 months. Secondary endpoints include objective disease PFS, PSA PFS, PSA response rate, non-irradiated distant MFS and PROs. The utility of 68 Ga-PSMA PET/CT will be explored and sequential analysis of circulating tumor DNA/circulating tumor cells will be done. Sites of disease are defined by all available imaging (minimum of CT or MRI, NM bone scan, but potentially molecular imaging). Oligometastatic CRPC is defined as between 1 and ≤5 treatment sites. Eligible patients with progressive oligometastatic CRPC may have prior sipuleucel-T but no therapy for mCRPC. Docetaxel or abiraterone within the hormone sensitive phase is allowed. Patients will be randomized 1:1 (stratified by 1-2 vs 3-5 oligometastases and whether molecular imaging in mCRPC is available) to physician’s choice vs. physician’s choice + MDT. MDT may be delivered via multiple radiation oncology techniques to cytotoxic doses. If the prostate itself has not been treated (on MDT arm), it will be treated and count as 1 site. Statistical analysis will provide objective PFS by arm with associated 90% confidence intervals. The study is recruiting 72 randomized patients at the University of Michigan Rogel Cancer Center and soon the Ann Arbor Veteran’s Administration Hospital. The trial is funded by the Prostate Cancer Foundation and a University of Michigan Cancer Center Trial Support Award. Clinical trial information: NCT03556904.
Cardiovascular complications of immune checkpoint inhibitor therapy.
Authors: Samip R. Master, Arelis Robinson, Glenn Morris Mills, Richard P Mansour
Journal: Journal of Clinical Oncology (2019)

2568 Background: Cardiac toxicity has largely been underestimated toxicity of checkpoint inhibitors. There have been several cases of myocarditis and fatal heart failure reported in patients treated with checkpoint inhibitors. We did a retrospective analysis of data of adverse effects of drugs that has been made available to public by the FDA. Methods: The FDA has made the data on adverse effects of various treatments available to general public through the FDA Adverse Events Reports System (FAERS) public dashboard. We investigated the cardiac toxicities of various immune check point inhibitor therapies available at FDERS for the years 2017-2018. Results: The reviewed the reported side effects of pembrolizumab, nivolumab, atezolizumab, avelumab, durvalumab and ipilimumab from FDA data. A total of 36,848 toxicities from immunotherapies were reported. Out of that, 2316(6.2 %) were cardio toxicities and 816 were fatal. The most common cardiac complications were as follows: myocarditis (15%), atrial fibrillation (13%), pericardial disease including pericardial effusion (13%), cardiac failure (17%) and coronary artery disease (19%). Approximately 50%, 43%, 40% 22% and 15 % of cases with myocarditis, ischemic heart disease, cardiac failure, atrial fibrillation and pericardia disease were fatal. Conclusions: Out of the reported cases of adverse reaction to check point inhibitor, 6.2% were cardio toxicities. 35% of cardio toxicities were fatal. Half of the cases who developed myocarditis died. There was no statistical difference in rate of cardiotoxicities caused by PD1, PDL1 or CTLA 4 inhibitors.
Human prostate cancer immune phenotypes after androgen deprivation therapy.
Authors: Matthew Dallos, Aleksandar Obradovic, Nivi Chowdhury, Zoila Lopez Bujanda, David Henry Aggen, Jessica Hawley, Dana E. Rathkopf, Charles G. Drake
Journal: Journal of Clinical Oncology (2019)

5083 Background: The prostate tumor microenvironment (TME) is generally non-inflamed. However, we previously showed in pre-clinical models that androgen deprivation therapy (ADT) induces a complex immune cell infiltrate. Whether ADT similarly promotes inflammation in patients remains unclear. Therefore, we collected specimens from patients with localized prostate cancer treated with neoadjuvant degarelix and hypothesized that we could decipher key changes in the immune TME after ADT utilizing a novel cancer systems biology approach. Methods: We identified a cohort of patients treated with neoadjuvant degarelix (240mg SQ) as part of two clinical trials (NCT01696877, NCT01542021). Patients were treated with degarelix either 4 days (N = 13), 7 days (N = 17) or 14 days (N = 8) prior to radical prostatectomy. RNA was extracted from FFPE tissue and analyzed by RNAseq. To deconvolute fractional contributions of different immune cell subsets we performed CIBERSORT and Uniform Manifold Approximation and Projection (UMAP) analysis. Treatment groups were compared to a cohort of untreated matched controls (N = 37). Results: Degarelix induced a complex immune cell infiltrate in human primary prostate tumors with an increase in both pro- and anti-inflammatory cells subsets and changes in expression of immune checkpoints compared to untreated matched controls. Degarelix therapy also significant changed associated gene signatures within the lymphoid and myeloid compartments over time. Conclusions: ADT leads to profound immune remodeling within the prostate TME. Our analysis of human primary prostate tumors supports the hypothesis that the optimal time for immunologic intervention is the peri-castration period. These data also suggest that combinatorial immunotherapy strategies that target particular immune cell subsets will likely be required to successfully promote robust anti-tumor immune responses in prostate cancer.
SAT0014 DECREASED CIRCULATING CD19+CD24HICD38HIREGULATORY B CELLS IN ACPA POSITIVE RHEUMATOID ARTHRITIS: EFFECT OF IL-6 RECEPTOR BLOCKADE
Authors: Paula Fortea-Gordo, Alejandro Villalva, Laura Nuño, Maria-Jose Santos-Bornez, Irene Monjo, Diana Peiteado, Amaya Puig-Kröger, Paloma Sanchez-Mateos, Alejandro Balsa, Maria-Eugenia Miranda-Carus
Journal: Annals of the Rheumatic Diseases (2019)

<h3>Background</h3> CD19+CD24<sup>hi</sup>CD38<sup>hi</sup> B cells have a regulatory capacity and their frequency is altered in the peripheral blood of patients with various autoimmune conditions, including RA. <h3>Objectives</h3> To determine the frequency of circulating CD19+CD24<sup>hi</sup>CD38<sup>hi</sup> regulatory B cells (cBreg) in ACPA+ vs ACPA- patients with RA, and its possible modification by IL-6R blockade. <h3>Methods</h3> Peripheral blood was drawn from ACPA+ (n= 37) or ACPA- (n=19) RA patients treated with conventional synthetic DMARDs (csDMARDs), and from ACPA+ (n=31) or ACPA- (n=12) RA patients treated with tocilizumab; in additon one age and gender-matched healthy control was studied alongside with each patient (n= 99). After isolation by Ficoll-Hypaque gradient, PBMCs were stained with antibodies to CD3, CD4, CD19, CD24, and CD38, and examined by flow cytometry. <h3>Results</h3> A decreased frequency of cBreg cells was observed in ACPA+ but not ACPA- RA patients treated with csDMARDs. Interestingly, the frequency of cBreg cells showed a significant negative correlation with ACPA titers (r = -0.44, p = 0.021). In contrast, no correlation was found between the frequency of cBreg cells and either RF titres or disease activity as determined by the DAS28 score. However, not only in ACPA- but also in ACPA+ patients receiving tocilizumab, the percentage of cBreg cells was not different from that observed in HC. Four ACPA+ patients treated with csDMARDs who initiated tocilizumab, demonstrated a significant elevation of their cBreg frequency at 12 months. <h3>Conclusion</h3> A decreased frequency of cBreg cells is apparent in ACPA+ but not ACPA- RA patients receiving csDMARDs, that is related with ACPA titres but not with RF titres or disease activity. In contrast, in ACPA+ patients treated with tocilizumab, the frequency of CD19+CD24<sup>hi</sup>CD38<sup>hi</sup> B cells is comparable to that observed in HC, suggesting that IL-6R blockade is able to modify the altered Breg cell balance. <h3>Reference</h3> [1] Flores-Borja F, et al. Sci Transl Med. 2013;5:173ra23. <h3>Disclosure of Interests</h3> Paula Fortea-Gordo: None declared, Alejandro Villalva: None declared, Laura Nuño: None declared, Maria-Jose Santos-Bornez: None declared, Irene Monjo: None declared, Diana Peiteado: None declared, Amaya Puig-Kröger: None declared, Paloma Sanchez-Mateos: None declared, Alejandro Balsa Grant/research support from: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Consultant for: Abbvie, Pfizer, Novartis, BMS, Nordic, Sanofi, Sandoz, Lilly, Paid instructor for: Pfizer, Speakers bureau: Pfizer, Novartis, UCB, Nordic, Sanofi, Sandoz, Lilly, Maria-Eugenia Miranda-Carus Grant/research support from: Roche Pharma, BMS
Neoadjuvant chemo-immunotherapy for the treatment of stage IIIA resectable non-small-cell lung cancer (NSCLC): A phase II multicenter exploratory study—Final data of patients who underwent surgical assessment.
Authors: Mariano Provencio, Ernest Nadal, Amelia Insa, Rosario Garcia-Campelo, Joaquín Casal Rubio, Manuel Domine, Margarita Majem, Delvys Rodriguez-Abreu, Alex Martinez Marti, Manuel Cobo, Guillermo Lopez-Vivanco, Elvira del Barco, Reyes Bernabé, Nuria Vinolas, Isidoro Barneto, Santiago Viteri, Paloma Martín-Martorell, Maria Jove, Fabio Franco, Bartomeu Massuti
Journal: Journal of Clinical Oncology (2019)

8509 Background: Patients with stage IIIA (N2 or T4N0) are potentially curable but median overall survival is only around 15 months and complete pathologic response with conventional chemotherapy (CT) is no more than 9%. Methods: A Phase II, single-arm, open-label multicenter study of resectable stage IIIA N2-NSCLC adult patients with CT plus IO as a neoadjuvant treatment: three cycles of Nivolumab (NV) 360mg IV Q3W + paclitaxel 200mg/m2 + carboplatin AUC 6 IV Q3W followed by adjuvant NV treatment for 1 year. After complete neoadjuvant therapy, tumor assessment is performed prior to surgery. Surgery is performed in the 3rd or 4th week after day 21 of the third cycle of neoadjuvant treatment. The study aims to recruit 46 pts. The primary endpoint is Progression-Free Survival (PFS) at 24 months. Efficacy is explored using objective pathologic response criteria. We present final data on all patients included in this study that underwent surgical assessment. Results: At the time of submission, 46 pts had been included and 41 had undergone surgery. CT-IO was well-tolerated and surgery was not delayed in any patient. None of the pts withdrew from the study preoperatively due to progression or toxicity. 41 surgeries had been performed and all tumors were deemed resectable, with R0 resection in all cases. 34 pts (83%) achieved major pathologic response (MPR) (CI 95% 71-95%), and 24 (71%) of them had a complete pathologic response (CPR) (CI 95% 54-87%). Downstaging was seen in 90% (CI 95% 81-100%) of cases. By RECIST, 29 pts (71%) (CI 95% 56-85%) had partial response and 3 (7%) (CI 95% 0-16%) complete response. Conclusions: This is the first multicentric study to CT-IO in the neoadjuvant setting in stage IIIA. Neoadjuvant CT-IO with nivolumab in resectable IIIA NSCLC yields a high complete pathologic response rate that has never been seen previously and unsuspected by RECIST criteria. Preliminary correlative analyses in blood samples are included in a separate abstract. EudraCT Number: 2016-003732-20. Clinical trial information: NCT 03081689.
Impact of sarcopenia for patients with localized muscle invasive bladder cancer treated by neoadjuvant cisplatin based chemotherapy and radical cystectomy.
Authors: Emilien Billon, Pierre Regnier, Valeria De Luca, Serge Brunelle, Jochen Walz, Slimane Dermeche, Mathilde Guerin, Cecile Vicier, Thomas Maubon, Stanislas Rybikowski, Nicolas Branger, Sami Fakhfakh, Geraldine Pignot, Gwenaelle Gravis
Journal: Journal of Clinical Oncology (2019)

e18286 Background: Several studies suggested the prognostic importance of sarcopenia in survival or treatment complications in cancer. The concept of cancer prehabilitation before surgery is gaining wide recognition. The aim of our study was to assess the impact of sarcopenia on chemotherapy toxicities and survival in patients with localized muscle invasive bladder cancer (MIBC). Methods: Between January 2012 and December 2017, patients who underwent neoadjuvant platinum-based chemotherapy (NAC) followed by radical cystectomy (RC) for cT2-T4 N0 M0 MIBC were retrospectively selected, from a single institution cohort. Using CT scan: before NAC, after NAC and after cystectomy, sarcopenia was defined according to the Lumbar Skeletal Muscle Index (SMI) in L3 assessed by two observers blinded to patients’ status. Results: 82 patients were selected, 62 men (75.6%) and 20 women (24.4%), with a median age of 64.5 years (31 to 80). 35 were considered severe sarcopenic (SMI &lt; 35cm 2 /m 2 for women and SMI &lt; 50 cm 2 /m 2 for men) before NAC. The characteristics between severe and non-severe sarcopenic patients were not significantly different except for weight (71.7 vs 81.1kg, p = 0.006) and BMI (24.0 vs 28.4kg/m 2 , p = 8.0x10 -6 ). Sarcopenia pre-chemotherapy was significantly associated with nausea (p = 0.003), hypokalemia (p = 0.023) and with platinum dose-intensity during NAC (p = 0.007) but was not significantly associated with overall survival (OS) or disease-free survival (DFS). Sarcopenia post-cystectomy was correlated with the OS (HR = 0.94, CI95% [0.89-0.99], p = 0.01), but not DFS. In multivariate analysis, factors associated with OS were post cystectomy sarcopenia (p = 0.038), pN status (p = 0.001) and glomerular filtration rate (p = 0.045). Conclusions: For localized MIBC, sarcopenic status before platinum based NAC could predict some chemotherapy toxicities. After radical cystectomy, sarcopenia is an independent prognostic factor for OS. Improve patients care by prehabilitation during NAC and before surgery, using physical, nutritional and psycho-social supports, could decrease chemotherapy toxicities and improve survival particularly for sarcopenic patients.
Does the innovative 4R Care Delivery Model improve timing and sequencing of guideline recommended breast cancer care in safety net and non-safety net centers?
Authors: Christine B. Weldon, Julia Rachel Trosman, Della F. Makower, Bruce D. Rapkin, Moreen Bozier, Eileen Knightly, Cathleen M. Schaeffer, Kent Hoskins, Christopher Gallagher, Shelly S. Lo, Cathy Grace-Louthen, Alyssa Throckmorton, Lindi Vanderwalde, Editha A. Krueger, Jennifer Van Horn, Lidia Schapira, Cesar Augusto Santa-Maria, Arliene Ravelo, Al Bowen Benson, William John Gradishar
Journal: Journal of Clinical Oncology (2019)

562 Background: Under the NCI ASCO Teams Project, we proposed a 4R Model which enables patient (pt) and care team to manage timing and sequencing of interdependent care with a novel multimodality 4R Care Project Plan (Trosman JOP ’16). 4R (Right Info/Care/Patient/Time) was previously piloted at 3 Chicago centers (Weldon ASCO ‘18). Methods: A new study tested impact of 4R on timing and sequencing of guideline recommended care at 4 safety net and 3 non safety net US centers. 4R Plans were provided to stage 0-III breast cancer pts Jan-Nov’18, 4R cohort. Clinical and pt reported data analyses compared 4R cohort (N=105) to a historical control cohort of pts who received care pre-4R, Jan - Dec ’17 (N=190). Results: We significantly improved 3 referral metrics and 4 referral completion metrics - receipt of care by pts who were referred (Table). After referrals, safety net pts had a significant increase in 4R vs control cohort in receiving genetic consult (72%, 21/29 vs. 42%, 18/43, p=.02) and dental visit (100%, 6/6 vs. 20%, 1/5, p=.02). They had lower increases in flu shot referrals (41%, 24/58, vs 36%, 37/104, NS) and dental referrals (10%, 6/58, vs 5%, 5/104, NS) than non safety net pts who had significant increases. Other metrics improved at a similar rate for safety net and non safety net pts. Conclusions: 4R markedly improved referral and receipt of interdependent guideline recommended breast cancer care. For most metrics safety net pts benefited from 4R at a similar or higher rate than non safety net pts, indicating that 4R may reduce care disparities. Low increases in referrals for safety net pts and in trial referral/enrollment for all pts must be addressed. An expansion of 4R across the US continues this work. [Table: see text]
Abstract 15428: A Five Pound Weight Gain is Associated With ED and Office Visits in Patients With Heart Failure
Authors: Jill Howie-Esquivel, Kathleen Dracup, Charles McCulloch, Linda G Park
Journal: Circulation (2017)

Introduction: Heart failure (HF) patients are regularly counseled to identify a 5-pound weight gain in 7 days for early detection of an acute exacerbation of HF. However, little data support the no...
TAVR vs Surgery in Low-Risk Patients
Authors: Anita Slomski
Journal: JAMA (2019)

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