tbuckley/cabot-search huggingface dataset:
Predictors of early hospice or death in patients with inoperable lung cancer treated with curative intent.
Authors: Anna Mary Brown Laucis, Kimberly A. Hochstedler, Thomas Pence Boike, Benjamin Movsas, Craig William Stevens, Larry Llyn Kestin, Michael M. Dominello, Joel Wilkie, Inga S. Grills, Martha Matuszak, James Hayman, Peter Alexander Paximadis, Matthew J. Schipper, Shruti Jolly
Journal: Journal of Clinical Oncology (2021)

e20525 Background: Treatment for inoperable stage II-III non-small cell lung cancer (NSCLC) involves aggressive chemo-radiotherapy (CRT). While outcomes have improved with immunotherapy, some patients transition to hospice or die early in their treatment course. To help identify these patients, we developed a predictive model for early poor outcomes in NSCLC patients treated with curative intent. Methods: In a statewide consortium involving 27 sites, information was collected prospectively on stage II-III NSCLC patients who received curative CRT from April 2012 to November 2019. We defined an early poor outcome as termination of treatment due to hospice enrollment or death within 5 months of initiating radiation therapy. Potential predictors included clinical characteristics and patient reported outcomes (PROs) from validated questionnaires. Logistic regression models were used to assess potential predictors and build predictive models. Multiple imputation was used to handle missing data. We used Lasso regularized logistic regression to build a predictive model with multiple predictor variables. Results: Of the total of 2267 included patients, 128 patients discontinued treatment early due to hospice enrollment or death. The mean age of the 128 patients was 71 years old (range 48-91) and 59% received concurrent chemotherapy. Significant uni-variable predictors of early hospice or death were advanced age, worse ECOG performance status, high PTV volume, short distance to normal tissue critical structures, high mean heart dose, uninsured status, lower scores on the Functional and Physical Well-Being scale and the Lung Cancer Symptoms sub-scale of the FACT-L quality of life instrument, as well as higher levels of patient-reported lack of energy, cough, and shortness of breath. The best predictive model included age, ECOG performance status, PTV volume, mean heart dose, patient insurance status, and patient-reported lack of energy and cough. The pooled estimate of area under the curve (AUC) for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. Conclusions: Our models identified a combination of clinical variables and PROs that may help identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at a high risk of early hospice enrollment or death. These preliminary results are encouraging and warrant further evaluation in a larger cohort of patients.
Accurate early-stage colorectal cancer detection through analysis of cell-free circulating tumor DNA (ctDNA) methylation patterns.
Authors: James M. Kinross, Pol Canal-Noguer, Marko Chersicola, Primož Knap, Marko Bitenc, Alexandre Perera-Lluna, Michael H. A. Roehrl, Kristi Kruusmaa
Journal: Journal of Clinical Oncology (2021)

3606 Background: Colorectal cancer (CRC) screening programs suffer from poor uptake and biomarkers have limited diagnostic accuracy. The measurement of the methylation status of tumor-derived cell-free DNA in plasma may address these challenges. We used a targeted methylation panel, tumor-derived signal deduction and machine learning algorithm to refine a blood test for the detection of early-stage CRC. Methods: This was a prospective, international multicenter observational cohort study. Plasma samples were collected either prior to a scheduled colonoscopy as part of standard colorectal cancer screening or prior to colonic surgery for primary CRC. Differentially methylated regions (DMRs) were initially selected by analyzing CRC and control tissue samples with whole genome bisulfite sequencing. A targeted sequencing assay was designed to capture these DMRs in plasma ctDNA. Individual sequencing reads were evaluated for cancer-specific methylation signal and scores calculated for each DMR in a sample. A panel of methylation scores originating from 203 DMRs was used in a prediction model building and validated in a test cohort of patients. Results: Calculated scores were used to train a machine learning model on 68 ctDNA samples from 18 early stage (I-II) and 16 late-stage (III-IV) CRC patients and 34 age, BMI, gender and country of origin matched neoplasia-free controls (median age 63 [50-74], mean BMI 27 [19.5-37], female 50%, Spanish and Ukrainian population, distal cancers 50%). This model was then applied to an independent set of subjects from Spanish, Ukraine and Germany, including 36 stage I-IV cancer patients (median age 61.5 [55-82], BMI 28 [16-39], female 47%, 42% of the tumors were distal) and 159 age and sex matched controls. 87 of the control patients had a negative colonoscopy finding (cNEG), 19 had hyperplastic polyps (HP), 37 had small non-advanced adenomas (NAA) and 16 were diagnosed with other benign gastrointestinal diseases (GID). The model correctly classified 92% (33/36) of CRC patients. Sensitivity per cancer stage ranged from 83% (5/6) for stage I, 92% (11/12) for stage II, 92% (12/13) for stage III to 100% (5/5) for stage IV. Specificity of the model was 97% (154/159), with 100% (37/37) NAA, 94% (15/16) GID, 95% (18/19) HP and 97% cNEG patients correctly identified. Lesion location, gender, BMI, age and country of origin were not significantly correlated to prediction outcome. Conclusions: Methylation sequencing data analyzed using read-wise scoring approach combined with a machine-learning algorithm is highly diagnostic for early-stage (I-II) CRCs (89% sensitivity at 97% specificity). This method could serve as the basis for a highly accurate and minimally invasive blood-based CRC screening test with significant implications for the clinical utility of ctDNA in early-stage cancer detection.
Expanding Discovery in Cardiovascular Genome-Wide Association Studies
Authors: Pradeep Natarajan, Elizabeth M. McNally
Journal: JAMA Cardiology (2021)

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Genetic spectrum and clinical features in a cohort of Chinese patients with autosomal recessive cerebellar ataxias
Authors: Hao-Ling Cheng, Ya-Ru Shao, Yi Dong, Hai-Lin Dong, Lu Yang, Yin Ma, Ying Shen, Zhi-Ying Wu
Journal: Translational Neurodegeneration (2021)

Although many causative genes have been uncovered in recent years, genetic diagnosis is still missing for approximately 50% of autosomal recessive cerebellar ataxia (ARCA) patients. Few studies have been performed to determine the genetic spectrum and clinical profile of ARCA patients in the Chinese population.Fifty-four Chinese index patients with unexplained autosomal recessive or sporadic ataxia were investigated by whole-exome sequencing (WES) and copy number variation (CNV) calling with ExomeDepth. Likely causal CNV predictions were validated by CNVseq.Thirty-eight mutations including 29 novel ones were identified in 25 out of the 54 patients, providing a 46.3% positive molecular diagnostic rate. Ten different genes were involved, of which four most common genes were SACS, SYNE1, ADCK3 and SETX, which accounted for 76.0% (19/25) of the positive cases. The de novo microdeletion in SACS was reported for the first time in China and the uniparental disomy of ADCK3 was reported for the first time worldwide. Clinical features of the patients carrying SACS, SYNE1 and ADCK3 mutations were summarized.Our results expand the genetic spectrum and clinical profiles of ARCA patients, demonstrate the high efficiency and reliability of WES combined with CNV analysis in the diagnosis of suspected ARCA, and emphasize the importance of complete bioinformatics analysis of WES data for accurate diagnosis.
The evaluation of a digital solution to improve the implementation of NCCN guidelines.
Authors: Matthew Stewart Prime, Chaohui Guo, Francoise Blanchard
Journal: Journal of Clinical Oncology (2021)

e13542 Background: NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) are the most commonly used guidelines in the US and globally, and aim to improve and facilitate quality, effective, efficient and accessible cancer care. The guidelines are constantly updated, as such, the number, scope, length and detail have continuously increased, which has placed challenges for clinicians to remain up to date. Solutions are highly needed to improve the usability and implementation of the NCCN Guidelines. The NAVIFY Guidelines application was developed to provide digitised NCCN Guidelines, to facilitate navigation, and to enable the real-time capture of clinical decisions, including reasons for deviation from guidelines. We assessed the usability and performance of the NAVIFY Guidelines application. Methods: A 60-minute remote, semi-structured interview and task-based user test was undertaken with 10 medical oncologists from diverse geographies (6 US, 2 UK, 2 Germany). No participants had prior experience with the digital solution. Participants tested the experience of using the NAVIFY Guidelines application on their computer by completing tasks for one of 3 tumor types (breast, lung or AML). Screen and audio activities were recorded via Zoom. At the end of the test, participants were asked to rate the performance of NAVIFY Guidelines and complete statements on a System Usability Scale (SUS) questionnaire. Results: NAVIFY Guidelines SUS score was on average 82.3 (80.8 – 84.0), classified as A score (i.e., excellent; NPS [net promoter score]: promoter level). Success ratings across all 6 tasks was 86%, as shown in Table1. The overall impression from participants was largely positive. "Ease of use" was the most salient theme followed by “logical structure” and the “value of being integrated with patient data”. Participants identified that the key value of NAVIFY Guidelines was improving communication between the care team and improving the documentation of guideline adherence. 3 participants saw the potential in teaching settings. Conclusions: NAVIFY Guidelines has been developed to support clinicians to apply the latest clinical recommendations, improve the documentation of decisions and to facilitate better communication between specialists, and with patients. Preliminary research has shown that NAVIFY Guidelines has excellent usability (score A) &amp; high NPS. Overall NAVIFY Guidelines was perceived as easy to use, valuable to improve communication between care teams and helpful at easing documentation burdens.
Prognosis impact of serous metastases (SMs) in clear cell renal cell carcinoma patients in the GETUG-AFU-26 NIVOREN phase II trial.
Authors: Florian Bardet, Cécile Dalban, Christine Chevreau, Sylvie Negrier, Brigitte Laguerre, Gwenaelle Gravis, Marine Gross-Goupil, Stephane Oudard, Philippe Barthélémy, Jean Marc Ferrero, Antoine Thiery-Vuillemin, Hakim Mahammedi, Berangere Narciso, Lionnel Geoffrois, Florence Tantot, Bernard Escudier, Sylvain Ladoire, Laurence Albiges
Journal: Journal of Clinical Oncology (2021)

e16566 Background: Nivolumab monotherapy (N) is a standard of care for patients with metastatic clear cell renal cell carcinoma (ccRCC) after failure of antiangiogenic therapies. IMDC criteria is the established prognostic model in anyline of systemic treatment including with N. While liver, bone and brain have been reported to convey a dismal prognosis, little is known about the pejorative prognostic impact of serous metastatic sites (pleura, peritoneum, pericardium) in patients receiving anti-PD (L) -1 treatment. Methods: We aimed to assess survival, and activity of N in patients included in the GETUG-AFU 26 NIVOREN phase II prospective trial ( NCT03013335 ), according to serous metastases (SMs). Results: Overall, 720 patients with metastatic ccRCC, and treated with N. Baseline RECIST metastases data were available for 708 patients included in this analysis. Among them, 142 (20%) had SMs (pleura, n=91 ; peritoneum, n=50 ; pericardium, n=1). Median PFS (4.5 vs 2.6 mo ; HR :1.31 ; p=0.0079), and OS (26.1 vs 15 mo ; HR :1.67 ; p&lt;0.0001) were significantly lower in patients with SMs. The dismal prognostic impact was observed both with pleura and peritoneum SMs. These 2 sites were not significantly associated. Using multivariate Cox models, SMs remained significantly associated with poor survival, independently of IMDC category, gender, age, and number of previous lines of therapy. Objective response rate in patients with SMs was not significantly different from others patients (16.4 vs 22.1%; p=0.147). SMs were not statistically associated with known poor prognosis metastatic sites (cerebral, bone, and liver.) Conclusions: SMs are a strong independent prognostic impact in patients receiving N for metastatic ccRCC Poor prognostic metastatic sites should be considered when assessing the prognosis of patients with metastatic ccRCC
RARE-17. HIGH-THROUGHPUT SCREEN IDENTIFIES POTENTIAL CHEMOTHERAPIES FOR CHOROID PLEXUS CARCINOMA TREATMENT USING INTRAARTERIAL STRATEGY
Authors: Brice Martin, Craig Thomas, Tyler Garman, Daisy Lin, Nadia Dahmane, Mark Souweidane
Journal: Neuro-Oncology (2021)

Abstract Choroid plexus carcinoma is a rare infantile brain tumor with an aggressive clinical course.1 There is no optimal treatment and survival is poor. Gross total surgical removal is the single most important predictor of survival.1 Gross total surgical removal rates are inconsistent and associated with significant morbidity owing to the hemorrhagic nature of these tumors compounded by a small circulating blood volume. Neoadjuvant systemic chemotherapy with “second look surgery” helps to achieve gross total surgical removal2 but has an inefficient pharmacokinetic profile and exposes children to dose- limiting toxic side effects. Hence, there is a strong need to identify and develop new agents and strategies to improve current choroid plexus carcinoma (CPC) treatment. Here, we report a high-throughput drug screening using a CPC cancer tissue-originated from a 7-year-old male patient and procured (Children’s Cancer Hospital Egypt) to identify new potent drugs. The selected candidates have been used as single agent and combination agent chemotherapy to propose a relevant study (e.g pharmacokinetics, toxicity, biodistribution, anticancer efficacy) for improving CPC treatment using a pre-existing intraarterial chemotherapy. A genetically engineered model has been developed by Shannon et al by breeding RosamTmG with Nestin-Cre to generate Nestin-cre/Rosa mTmG reporter mice overexpressing c-Myc, which provides a fully penetrant model of CPC in the lateral ventricle CP and 4th ventricle CP.3 This mice model will be used to explore in vivo the newly discovered drug combinations to treat the CPC tumor. 1. Hosmann, A. et al. Management of choroid plexus tumors—an institutional experience. Acta Neurochir. (Wien). 161, 745–754 (2019) 2. Schneider, C. et al. Neoadjuvant chemotherapy reduces blood loss during the resection of pediatric choroid plexus carcinomas *christian. J. Neurosurg. Pediatr. Pediatr. 16, 126–133 (2015) 3. Shannon, M. L. et al. Mice Expressing Myc in Neural Precursors Develop Choroid Plexus and Ciliary Body Tumors. Am. J. Pathol. 188, 1334–1344 (2018)
Association of total neoadjuvant therapy with major pathologic response and survival in localized pancreatic cancer: A multi-institutional analysis of 504 patients.
Authors: Jashodeep Datta, Amber Collier, Joshua Kronenfeld, Gregory Wilson, Ugwuji Maduekwe, Rebecca A Snyder, Sharon M. Weber, William G. Hawkins, Hong Jin Jin Kim, Alexander A. Parikh, Chet Hammill, David A. Kooby, Daniel Abbott, Shishir K. Maithel, Peter Joel Hosein, Syed A. Ahmad, Nipun B. Merchant
Journal: Journal of Clinical Oncology (2021)

4145 Background: Despite increased utilization of neoadjuvant therapy for pancreatic cancer (PC), a substantial proportion of patients never receive adjuvant therapy. We examined if total neoadjuvant therapy (TNT) would facilitate delivery of all prescribed (≥6 months) non-surgical therapy (NST: chemotherapy ± radiation) to improve oncologic outcomes. Methods: Patients receiving neoadjuvant FOLFIRINOX or gemcitabine/nab-paclitaxel ±radiation followed by pancreatectomy at 7 centers were reviewed. Patients receiving TNT (≥6 months NST pre-resection) were compared to those receiving &lt; 6 months ( &lt; TNT). Primary outcomes were major (complete/near-complete) pathologic response (MPR) and overall survival (OS). Results: Of 504 patients, 105 (21%) were selected for TNT. TNT and &lt; TNT patients had similar performance status and rates of borderline resectable/locally advanced disease (82% vs. 80%). TNT patients were significantly more likely to receive ≥6 months NST (100% vs. 31%; p &lt; 0.001) vs. &lt; TNT. While selection of chemotherapy regimen (FOLFIRINOX or gemcitabine/nab-paclitaxel) did not differ between TNT and &lt; TNT cohorts, TNT patients were more likely to receive neoadjuvant radiation (44% vs. 25%, p &lt; 0.001). Rates of vascular resection, postoperative complications, and mortality were similar between groups. TNT was associated with decreased rates of lymphovascular/perineural invasion (p = 0.002) and nodal positivity (p = 0.001), and increased rates of MPR (41% vs. 23%; p = 0.001) and pathologic complete response (13% vs. 6%; p = 0.02). TNT was associated with improved OS compared with &lt; TNT (median 38 vs. 30 months; p = 0.039). Both MPR (median 38 [MPR] vs. 28 [limited response] months; p = 0.002) and ≥6 months NST (TNT or peri-operative) (median 38 [≥6m] vs. 26 [ &lt; 6m] months; p = 0.001) were associated with improved OS. Addition of radiation was not associated with MPR or OS. Conclusions: The TNT approach allows more patients with localized PC to receive ≥6 months NST and is associated with improved rates of MPR and OS. TNT should be considered for all patients with operable PC when possible.
Correlation of Trop-2 expression with clinicopathological characteristics, sTILs, AR expression and outcome in primary TNBC.
Authors: Hava Izci, Kevin Punie, Lise Waumans, Annouschka Laenen, Hans Wildiers, Freija Verdoodt, Christine Desmedt, Jan Ardui, Ann Smeets, Sileny N. Han, Ines Nevelsteen, Patrick Neven, Giuseppe Floris
Journal: Journal of Clinical Oncology (2021)

e12558 Background: Trophoblast cell-surface antigen-2 (Trop-2) is a transmembrane calcium signal transducer highly expressed in multiple tumor types including breast cancer. Trop-2 overexpression is associated with poor survival. Given the approval of sacituzumab govitecan in advanced triple-negative breast cancer (TNBC), Trop-2 emerges as an important target for antibody-drug conjugates. Limited data exist about correlations of Trop-2 expression with clinicopathological characteristics and outcome in early TNBC. Methods: We included 127 patients with early TNBC, treated with primary surgery at UZLeuven from 2005-2017. Trop-2 expression was determined with IHC (ab227689, Abcam) on whole slide tumor sections from resection specimens and assessed as continuous (H-score 0-300) and categorical (high 201-300, medium 100-200 and low &lt; 100) variables. Stromal tumor infiltrating lymphocytes (sTIL; low, intermediate and high), mitotic score and androgen receptor (AR) expression (1% or 10%-cutoff) were scored. We assessed associations between Trop-2 expression and age, BMI, BRCA status, tumor grade and size, lymphovascular invasion (LVI), DCIS, nodal status, sTILs, AR, mitotic index and outcome (Invasive disease free survival and breast cancer specific survival). Results: The median age at diagnosis was 51y (range 26-80y) and the median follow-up 8.5y. Low, medium and high Trop-2 expression was seen in 50%, 37% and 13% of cases. AR was positive in 32% of cases (10%-cutoff). Higher Trop-2 expression was correlated with age (ρ = 0.192, p = 0.03) and inversely correlated with mitosis/mm² (ρ = -0.2, p = 0.02). Patients with high Trop-2-expression were older compared to patients with low Trop-2-expression (median 58 vs 47 years, p = 0.02). LVI was more frequent in Trop-2-high (65%) compared to TROP-2-medium (15%) or -low (16%) (p &lt; 0.001). Median mitosis/mm² was higher in Trop-2-low (14) compared to Trop-2-medium (10) and -high (8) (p = 0.004). Patients in Trop-2-high subgroup had more nodal involvement (53%) compared to Trop-2-medium (23%) and -low (21%) (p = 0.03). There was no correlation between Trop-2 expression and sTILs, AR or outcome. Conclusions: In this patient cohort with TNBC treated with upfront surgery, higher Trop-2 expression was correlated with older age, with more LVI and nodal involvement, while mitosis/mm² were higher in tumors with low Trop-2 expression. Trop-2 expression was not correlated with sTILs, AR or outcome. Limited numbers of events warrant caution in interpretation.
Retinoic acid receptor responder1 promotes development of glomerular diseases via the Nuclear Factor-κB signaling pathway
Authors: Katja Möller-Hackbarth, Dina Dabaghie, Emmanuelle Charrin, Sonia Zambrano, Guillem Genové, Xidan Li, Annika Wernerson, Mark Lal, Jaakko Patrakka
Journal: Kidney International (2021)

Inflammatory pathways are activated in most glomerular diseases but molecular mechanisms driving them in kidney tissue are poorly known. We identified retinoic acid receptor responder 1 (Rarres1) as a highly podocyte-enriched protein in healthy kidneys. Studies in podocyte-specific knockout animals indicated that Rarres1 was not needed for the normal development or maintenance of the glomerulus filtration barrier and did not modulate the outcome of kidney disease in a model of glomerulonephritis. Interestingly, we detected an induction of Rarres1 expression in glomerular and peritubular capillary endothelial cells in IgA and diabetic kidney disease, as well as in ANCA-associated vasculitis. Analysis of publicly available RNA data sets showed that the induction of Rarres1 expression was a common molecular mechanism in chronic kidney diseases. A conditional knock-in mouse line, overexpressing Rarres1 specifically in endothelial cells, did not show any obvious kidney phenotype. However, the overexpression promoted the progression of kidney damage in a model of glomerulonephritis. In line with this, conditional knock-out mice, lacking Rarres1 in endothelial cells, were partially protected in the disease model. Mechanistically, Rarres1 promoted inflammation and fibrosis via transcription factor Nuclear Factor-κB signaling pathway by activating receptor tyrosine kinase Axl. Thus, induction of Rarres1 expression in endothelial cells is a prevalent molecular mechanism in human glomerulopathies and this seems to have a pathogenic role in driving inflammation and fibrosis via the Nuclear Factor-κB signaling pathway.