tbuckley/cabot-search huggingface dataset:
Coexpression patterns of IDO-1, PD-L1 and EGFR in non-small cell lung cancer.
Authors: Weili Wang, Chen Zhang, Liang Cheng, Jianyue Jin, Feng-Ming Spring Kong
Journal: Journal of Clinical Oncology (2019)

e14279 Background: Indoleamine-2, 3-dioxygenase (IDO), a well-established immune suppressor, may offset efficacy of immune checkpoint inhibitors (ICIs) such as programmed death receptor ligand-1(PD-L1) by inducing unfavorable tumor microenvironment. The unpredictability of one ICI response may partially due to the concomitant presence of other ICIs. Therefore, increasing interest has been focus on the dual ICIs or the combination of ICIs with conventional treatment modalities such as radiotherapy, chemotherapy as well as target therapy. This study aimed to study the coexpression patterns and significance of IDO-1, PD-L1 and epidermal growth factor receptor (EGFR) in non-small cell lung cancer (NSCLC). Methods: Patients with newly diagnosed NSCLC enrolled in three prospective surgery clinical trials were included in this study. The expressions of IDO-1, PD-L1 and EGFR were evaluated by immunohistochemistry (IHC). For positive cases, the percentile score and H-score were generated respectively from two independent pathologists. The descriptive analysis of Crosstab was used to compare the distributions of these biomarkers expression by pathological types. Results: A total of 117 patients (adenocarcinoma -54%, squamous cell carcinoma -32% and others -14%) with pretreatment tissue specimen available for IHC analysis were studied. Of these, 105 (90%) were from lung primary and 12 (10%) from distant metastasis sites. The expressions of IDO-1 (≥ 1%), PD-L1 ((≥ 1%) and EGFR (≥ 90% or intensity = 3) were identified in 43%, 40% and 52% of NSCLC patients. For IDO-1 and PD-L1, coexpression rates were 21% for co-positive and 37% for co-negative. However, there were still 42% patients showed isolated PD-L1 (20%) or IDO-1 expression (22%). The coexpression rates for EGFR and IDO-1 were 21% for co-positive and 26% for co-negative. The coexpression rates for EGFR and PD-L1 were 20% for co-positive and 25% for co-negative. 38% patients had a positive EGFR with either IDO-1 or PD-L1 positive. The expression patterns were not significant associated with clinical factors including pathological types and differentiation grades. Conclusions: IDO-1 and PD-L1 expression patterns may be useful in the selection of NSCLC patients for dual ICIs immunotherapy. The combinations of EGFR target therapy with immunotherapy may benefit some of NSCLC patients. However, testing expression status of EGFR and immune checkpoints becomes essential since majority of NSCLC patients exhibits EGFR positive with IDO-1 or PD-L1 negative patterns.
Combining neoadjuvant chemoradiation with adjuvant chemotherapy in multimodality treatment for patients with potentially curable esophageal carcinoma.
Authors: Ruta Arays, Albina Kibirova, Miklos L Auber, Gerald M. Higa, Shalu Pahuja
Journal: Journal of Clinical Oncology (2019)

e15574 Background: Optimal multimodality treatment followed by surgical resection results in cure for less than half of patients with operable adenocarcinoma of the lower esophagus or GEJ. The current standard of care is either neoadjuvant chemoradiation established by the CROSS trial or perioperative chemotherapy established by MAGIC trial. We aimed to investigate whether additional treatment beyond current standards of care might improve outcomes. Methods: We performed a phase II, single center, investigator initiated study assessing the combination of neoadjuvant chemoradiation followed by esophagectomy and adjuvant chemotherapy in patients with resected esophageal/GEJ cancer. All patients received neoadjuvant infusional 5-fluorouracil at 225mg/m2 for 5 days with concurrent radiation at a dose of 4500 cGy followed by esophagectomy and 6 cycles of adjuvant paclitaxel 200mg/m2 on day 1, carboplatin AUC 6 on day 1 and infusion 5-fluorouricil 225 mg/m2 on days 1-7 (PCF) on a 28-day cycle. Results: 27 patients with stage IIA-IIIB (AJCC7) esophageal/GEJ tumors were enrolled on the protocol between 1999 and 2007. There were 23 males and 4 females with a median age at diagnosis 58 years. Twenty-five patients had adenocarcinoma, 1 had squamous and 1 had adenosquamous histology with 14 tumors located in GEJ and 11 in lower 1/3 of esophagus. The time between the surgery to start of PCF was 2.4 months. Fifteen patients (55.6%) had an R0 resection margin at the time of surgery. Only 8 (30%) patients could complete all 6 cycles of planned adjuvant chemotherapy, median number of cycles of chemotherapy administered was 1. Patients were followed for 10 years. Median progression free and overall survival was estimated to be 11.9 and 18.8 months respectively. At present time only one patient is alive and free of disease. One patient passed from an unrelated malignancy. Conclusions: Inferior survival results in this small study may be attributed to difficulty delivering adjuvant chemotherapy after prior chemoradiation, extensive surgery and delayed recovery. Total neoadjuvant therapy may overcome these obstacles in management of esophageal/GEJ cancer patients and should be explored in future studies.
Case 7-1985
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, Betty U. McNeely, Robert Burakoff, Jose Jessurun
Journal: New England Journal of Medicine (1985)

Presentation of CaseAn 80-year-old woman was admitted to the hospital because of hematochezia.She was in a static state of health until five weeks earlier, when she passed fresh blood with a stool. Bleeding per rectum recurred twice during the next two weeks, and she was admitted to the hospital. On examination she was pale but alert and talkative. The blood pressure was 170/90 mm Hg supine and 150/70 mm Hg seated. The lungs were clear. The heart was not enlarged; a Grade 3 systolic ejection murmur was heard at the apex and base and was transmitted to both . . .
Updated results from a randomized phase II study of cabazitaxel (CAB) versus abiraterone (ABI) or enzalutamide (ENZ) in poor prognosis metastatic CRPC.
Authors: Kim N. Chi, Sinja Taavitsainen, Nayyer Iqbal, Cristiano Ferrario, Michael Ong, Deepa Wadhwa, Sebastien J. Hotte, Gregory Lo, Ben Tran, Arun Azad, Lori Wood, Joel Roger Gingerich, Scott A. North, Carmel Jo Pezaro, Joseph D. Ruether, Srikala S. Sridhar, Jack Bacon, Gillian Vandekerkhove, Matti Annala, Alexander William Wyatt
Journal: Journal of Clinical Oncology (2019)

5003 Background: The treatment for poor prognosis mCRPC includes taxanes and androgen receptor (AR) targeted therapy, however the optimal treatment is undefined. Methods: Patients (pts) with poor prognosis (liver metastases, early CRPC ( &lt; 12 months from ADT start), and/or &gt; 3 of 6 poor prognostic criteria (Chi et al, Annals of Oncol, 2016)) were randomized to receive CAB (Arm A) or AR targeted therapy (Arm B, ABI or ENZ by investigator choice) with cross over at progression. Primary objective was to determine the clinical benefit rate (CBR) (PSA decline ≥50% (PSA50), objective response (OR), or stable disease (SD) ≥ 12 weeks). Plasma was sampled serially for circulating tumour DNA (ctDNA). Results: 95 pts were randomized (Arm A: 45, Arm B: 50): 18% had liver mets, 88% early CRPC and 30% had &gt; 3 of 6 poor prognostic criteria. 52% of pts had prior docetaxel, half for castration sensitive disease. Table summarizes 1st-line therapy outcomes. Baseline ctDNA fraction &gt; 15% (median) was associated with shorter 1st-line progression-free survival (PFS) (median 2.8 vs 8.4 m, HR = 2.54, P &lt; 0.001) and overall survival (OS) (median 14.0 vs 38.7 m, HR = 2.64, P = 0.001). ctDNA alterations in AR, TP53, PI3K pathway, RB1 and DNA repair were detected in 53%, 45%, 31%, 23%, and 21% of pts. Shorter PFS and OS were associated with AR gain (HR 2.57 (95% CI 1.63-4.06); HR 3.59, (1.9-6.69), respectively) and TP53 defects (HR 2.62 (CI 1.65-4.15); HR 3.33 (CI 1.8-6.14), respectively). Pts with concurrent defects in TP53 and RB1 had a trend for worse PFS/OS than pts with TP53 defect alone. AR rearrangements predicted to disrupt the ligand binding domain were detected in 6% of pts and had a shorter PFS (HR = 2.60 (1.11 - 6.09)) with a trend for shorter OS (HR = 2.27 (0.89 - 5.81)). Conclusions: In this poor prognosis cohort, 1st-line treatment with CAB had a higher clinical benefit rate than treatment with ABI/ENZA. Elevated ctDNA and genomic alterations in AR and TP53 were prognostic. Supported in part by Sanofi. Clinical trial information: NCT02254785. [Table: see text]
The prognostic significance of magnetic resonance imaging (MRI) following neoadjuvant concurrent chemoradiation (NCCR) in patients with locally advanced rectal adenocarcinoma (LARA).
Authors: Yazan Fahmawi, Clayton Smith, Leander Grimm, Shikha Khullar, Paul Rider, John Hunter, Greire Iliff, Wadad Mneimneh, Kelly Roveda, Bin Wang, Pranitha Prodduturvar, Yesica Campos, Ansh Mehta, Ben McCormick, Moh'd M. Khushman
Journal: Journal of Clinical Oncology (2019)

e15166 Background: In patients with locally advanced rectal adenocarcinoma (LARA), the response to neoadjuvant concurrent chemoradiation (NCCR) correlates with long-term outcomes. Neoadjuvant rectal (NAR) score ([5 ypN - 3 (cT - ypT) + 12] 2 /9.61) is a novel short-term surrogate endpoint for disease free survival (DFS) and Overall survival (OS). The prognostic significance of magnetic resonance imaging (MRI) findings following NCCR is yet to be explored. Here, we evaluated the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. In addition, we calculated the post NCCR MRI NAR (mNAR) score using the MRI yT and yN ([5 yN - 3 (cT - yT) + 12] 2 /9.61) and explored its prognostic significance. Methods: Between 2014 and 2018, all patients with LARA were identified. Among those, 43 patients received NCCR, had post NCCR MRI and underwent surgical resection. Weighted Kappa was used to measure the agreement between post NCCR MRI yT and yN and pathological ypT and ypN. Paired t-test was used to compare the means between NAR and mNAR scores. NAR and mNAR scores were classified as low ( &lt; 8), intermediate (8-16) and high ( &gt; 16). DFS and OS were analyzed using Kaplan-Meier curves. Results: In our cohort, the agreement was slight between post NCCR MRI yT and Pathological ypT (p = 0.111), and fair between post NCCR MRI yN and pathological ypN (0.278). The mean NAR score was 16 and the mean mNAR score was 20 (p = 0.0079). Low-intermediate and high NAR scores were seen in 31 (72%) and 12 (28%) patients respectively. However, low-intermediate and high mNAR scores were seen in 20 (47%) and 23 (53%) patients respectively. The median DFS in patients with low-intermediate and high NAR scores was not reached and 30 months (p = 0.00063) respectively. The median OS in patients with low-intermediate and high NAR scores was not reached and 40 months (p = 0.00056) respectively. The median DFS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.058). The median OS in patients with low-intermediate and high mNAR scores was not reached in both groups (p = 0.15). Conclusions: Post NCCR MRI yT and yN had slight and fair agreements with ypT and ypN respectively. In our cohort, there was a difference between NAR and mNAR. NAR demonstrated prognostic significance for DFS and OS, while mNAR did not at the time of analysis.
Correlation of negative PD-L1 expression with TMB-H and MSI-H rates.
Authors: Jun Dong, Xiaoni Zhang, Hongyue Qu, Shifu Chen, Ziyang Zhu, Tanxiao Huang, Da-Wei Ye, Long Bai, Xiuyu Cai
Journal: Journal of Clinical Oncology (2019)

e13162 Background: PD-L1 protein expression, tumor mutation burden (TMB) and microsatellite instability (MSI) are majorbiomarkers for PD-1/PD-L1 blockade therapy for solid tumors. We designed a study to evaluate the relevance of these biomarkers. Methods: From April 2018 to December 2018, 197 patients with lung cancer, colorectal cancer, andgastric cancer wereprospectivelyenrolled.Foreachpatient, afreshfrozentissuesampleor FFPE sample wascollected. Each sample was dividedinto3parts for next-generation sequencing (NGS), PD-L1 protein expression evaluation and MSI evaluation. The sequencing library was captured using a 605-gene panel and sequenced at~5,000×coverage.Mutationsinthe NGS datawereidentified,andTMB was then calculated. The PD-L1 protein expression was analyzedby immunohistochemistry, and the MSI was evaluated using a multiplex PCR comprising 5 loci(NR27, NR21, NR24, BAT25, and BAT26). Results: 18.78% (37/197) were detected with high PD-L1 expression (positive tumor cells ≥50%); 5.08% (10/197) ofpatientswere diagnosed as MSI-H; 4.06% (8/197) of patients had a TMB-H (TMB &gt; 20 mutations/Mb). Among the 37 PD-L1 positive patients, only one patientwith TMB-Hwas detected, and 3patients were MSI-H. In contrast, among the 14 patients with PD-L1 expression less than 1%, 8patients (57.14%) were detected with TMB-H or MSI-H (3 with TMB-H only, 3 with MSI-H only, and 2 with both). In addition, among all the 10patients with MSI-H, 4patients had TMB-H, indicating that MSI-H may be partly associatedwith high TMB. Conclusions: From our preliminary result, PD-L1 protein expression negative patients tend to have higher rates of TMB-H and MSI-H. For patients with negative PD-L1 expression, it issuggested to evaluate its TMB level and MSI status. This study is ongoing, and more data will be collected to verify these findings.
Circulating tumor DNA analysis (ctDNA) for genomic testing in NSCLC patients with isolated CNS progression.
Authors: Mihaela Aldea, Laura Mezquita, Lizza Hendriks, Edouard Auclin, Jordi Remon, David Planchard, Cecile Jovelet, Jose Carlos Benitez, Anas Gazzah, Pernelle Lavaud, Charles Naltet, Ludovic Lacroix, Clive D. Morris, Emma Green, Karen Howarth, Claudio Nicotra, Benjamin Besse
Journal: Journal of Clinical Oncology (2019)

2015 Background: Genomic DNA profiles are mandatory in advanced, treatment naive non-small cell lung cancer (NSCLC) patients (pts) and strongly recommended at progression (PD) on personalized treatment. In pts with PD limited to central nervous system (CNS), tissue biopsy is difficult and the performance of ctDNA is unknown. Methods: Clinical, molecular, imaging data of NSCLC pts included in 2 prospective studies from 01.2016 to 11.2018 at Gustave Roussy were collected. Inclusion criteria were: stage IV disease and any known tissue genomic alteration (GA) EGFR, ALK, BRAF, KRAS, HER2, ROS1, MET, PIK3CA, TP53. Plasma ctDNA collected at baseline/PD were analyzed by next-generation sequencing (NGS-InVisionFirst™-Lung) in 3 groups: pts with isolated CNS (iCNS), extra-CNS only (noCNS) or both combined (cCNS) disease. iCNS was defined as any PD to CNS, while stable/absent extra-CNS metastases (mts). ctDNA was considered positive if ≥1 GA was found. ctDNA in cerebrospinal fluid (CSF) were also collected. Results: Out of 245 pts with ≥1 ctDNA: 56 had iCNS (66 samples), 97 noCNS (127 samples) and 92 cCNS (107 samples). In this cohort, 60% were female, median age 60 years, 47% smokers; 92% had adenocarcinoma. The median number of mts sites was 3 in noCNS/cCNS groups. Proportions of tissue GA at baseline were (iCNS vs noCNS/cCNS): EGFR (50% vs 44%), ALK (30% vs 11%), BRAF (4% vs 12%), KRAS (5% vs 15%), HER2 (2% vs 5%), ROS1 (5% vs 4%). Tyrosine kinase inhibitors were used in 73% iCNS vs 61% noCNS/cCNS. Local brain treatments were performed in 43% (n = 24) vs 32% (n = 29) and leptomeningeal mts (LM) detected in 34% (n = 19) vs 8% (n = 9), in iCNS and cCNS, respectively. CtDNA was positive (+) in 52% in iCNS vs 84% in noCNS and 92% in cCNS (p &lt; 0.0001). In iCNS, there was a non-significantly higher proportion of + ctDNA in pts with LM vs only brain disease (59 vs 48%, P = 0.44). 12/56 pts of iCNS group had serial ctDNA, being collected also at time of cCNS. In 25% of cases, a negative ctDNA at time of iCNS shifted to + at time of cCNS. In 12 iCNS pts, ctDNA was + in 6 (50%) plasma and in 10 (83%) paired CSF (p = 0.193). Conclusions: Detection of GA by plasma ctDNA is lower in NSCLC pts with isolated CNS PD. Alternative strategies (as CSF analysis) should be explored.
Outcome of Severe Vaso Occlusive Crisis in Sickle Cell Disease Adults Admitted to Referral Centers in Africa and Europe. Preliminary Results from the Presev 2 Study
Authors: Dapa Diallo, Mehdi Khellaf, Gonzalo De Luna, Sandrine Dautheville, Louis Affo, Stephanie Ngo, Tatiana besse-Hammer, Yvon Segbena, jean Benoit Arlet, François Lionnet, Sylvain le-Jeune, Anoosha Habibi, Bertrand Godeau, Frédéric Galactéros, Pablo Bartolucci
Journal: Blood (2017)
Changes in DNA hydroxymethylation for the detection of multiple cancers in plasma cell-free DNA.
Authors: Anna Bergamaschi, Francois Collins, Chris Ellison, Yuhong Ning, Gulfem Guler, Tierney Phillips, Erin McCarthy, Wendy Wang, Michael Antoine, Jeremy Ku, Aaron Scott, Paul Lloyd, Alan Ashworth, Samuel Levy
Journal: Journal of Clinical Oncology (2019)

3058 Background: Methylation and hydroxymethylation of cytosines enable the epigenomic regulation of gene suppression and activation. 5-hydroxymethyl-cytosine (5hmC) is globally decreased in tumor tissue. However, genome-wide analysis using precise 5hmC labelling techniques reveals more nuanced changes upon tumorigenesis and raises the possibility that this loss could be exploited for developing a cancer biomarker. This suggests that 5hmC profiles might enable discrete classification of not only tumor tissue but also of tumor cell-free DNA (cfDNA). We sought to identify genome-wide 5hmC changes in plasma based cfDNA from cancer patients representing multiple disease types, stages and clinical characteristics in comparison with non-cancer patients. Methods: cfDNA was isolated from plasma, enriched for the 5hmC fraction using chemical labelling, sequenced, and aligned to the genome to determine 5hmC counts per genomic feature. Regularized regression models were constructed to classify cancer samples (age matched or corrected for smoking status) on non-overlapping training (80% of all samples) and test sample sets (20% of all samples). Results: 226 non-cancer patients and 278 cancers across four cancer types (breast, colorectal, lung-squamous and pancreas) were included in this study, where more than 60% of cancer samples were early stage disease (I or II). Upon comparison with non-cancer samples, 5hmC peaks have reduced enrichment in exons in breast, colorectal and lung cancer but not in pancreatic cancer. Further, 5hmC peaks in pancreas show different patterns of enrichment in 3’UTR, translational termination sites, promoters and LTR. Overall 5hmC signal density was reduced in late stage cancers across all four diseases. The ability to classify non-cancer versus cancer patients was evaluated via cross-validation of out of fold prediction in the training set with AUC &gt; 0.84 for all four cancer types. Further, test set sensitivity across all four cancer types was found to be &gt; 66% with 98% specificity. Conclusions: These findings suggest that 5hmC changes in plasma cfDNA enable classification of early stages of breast, colorectal, lung-squamous and pancreas cancer and are promising biomarkers for disease detection.
Artificial intelligence (AI) to improve patient outcomes in community oncology practices.
Authors: John Frownfelter, Sibel Blau, Ray D. Page, John Showalter, Kelly Miller, Jonathan Kish, Amy W. Valley, Chadi Nabhan
Journal: Journal of Clinical Oncology (2019)

e18098 Background: Artificial Intelligence(AI) for predictive analytics has been studied extensively in diagnostic imaging and genetic testing. Cognitive analytics adds by suggesting interventions that optimize health outcomes using real-time data and machine learning. Herein, we report the results of a pilot study of the Jvion, Inc. Cognitive Clinical Success Machine (CCSM), an eigen vector-based deep learning AI technology. Methods: The CCSM uses electronic medical record (EMR) and publicly available socioeconomic/behavioral databases to create a n-dimensional space within which patients are mapped along vectors resulting in thousands of relevant clusters of clinically/behaviorally similar patients. These clusters have a mathematical propensity to respond to a clinical intervention which are updated dynamically with new data from the site. The CCSM generates recommendations for the provider to consider as they develop a care plan based on the patients’ cluster. We tested and trained the CCSM technology at 3 US oncology practices for the risk (low, intermediate, high) of 4 specific outcomes: 30 day severe pain, 30 day mortality, 6 month clinical deterioration (ECOG-PS), and 6 month diagnosis of major depressive disorder (MDD). We report the accuracy of the CCSM based on the testing and training data sets. Area under the curve (AUC) was calculated to show goodness of fit of classification models for each outcome. Results: In the training/testing data set there were 371,787 patients from the 3 sites: female = 61.3%; age ≤ 50 = 21.3%, 51-65 = 26.9%, &gt; 65 = 51.9%; white/Caucasian = 43.4%, black/African American = 5.9%, unknown race = 43.4%. Cancer types were unknown/missing for 66.3% of patients and stage for 90.4% of patients. AUC range per vector: 30 day severe/recurrent pain = 0.85-0.90; 30-day mortality = 0.86-0.97; 6-month ECOG-PS decline of 1 point = 0.88-0.92; and 6-month diagnosis of MDD = 0.77-0.90. Conclusions: The high AUC indicates good separation between true positives/negatives (proper model specification for classifying the risk of each outcome) regardless of the degree of missing data for variables including cancer type and stage. Following testing, a 6 month pilot program was implemented (06/2018-11/2018). Final results of the pilot program are pending.
Ingenol mebutate to treat lentigo maligna of the head (face and scalp): A prospective and multicenter single-arm phase 2 trial.
Authors: Henri Montaudié, Florence Le Duff, Catherine Butori, Veronique Hofman, Eric Fontas, Coralie Roger, Philippe Bahadoran, Jena-Luc Perrot, Eve Desmedt, Delphine Legoupil, Thierry Passeron, Jean-Philippe Lacour
Journal: Journal of Clinical Oncology (2019)

e21051 Background: Ingenol mebutate gel is indicated for the treatment of actinic keratoses. In vitro, it has been shown that ingenol mebutate can induce the apoptosis of melanoma cells, but robust clinical data are missing with only few case reports reported.The objectives of the current study was to assess the efficacy and safety of ingenol mebutate for the treatment of lentigo maligna (LM). Methods: We conducted a prospective, multicentre, and single-arm phase 2 trial (NCT02723721), from June 2016 to November 2017. This trial was planned according to Simon’s optimal two-stage design for a total sample size of 23 subjects. Adults with LM of the head were included. Ingenol mebutate gel 150 µg/g was applied daily for 3 consecutive days (one cycle). For patients having no remission or only partial remission at 2 months, a second cycle was done. Patients were evaluated 2 months after the (re)treatment and then every 3 months for 36 months if a complete response (CR) was obtained. The primary endpoint was the CR, defined as the complete clearing of the LM evaluated at 2 months clinically and histologically. Results: Twelve patients with a median age of 73 years were recruited. Only 2 achieved a CR; one patient relapsed during the first year following the treatment. Forty-seven adverse events related to ingenol mebutate were declared. Most were grade 3-4 (66%), but all were resolved without any sequelae. The mean maximum local skin reaction score was 12 (min: 3 – max: 22). These results should be interpreted with caution, because this study has limitations, such as the lack of a comparative arm and the heterogeneity of LM (size and localization). Conclusions: To our knowledge, we report the first prospective study evaluating the efficacy and safety of IM in patients with LM of the head. Unfortunately ingenol mebutate is not an effective treatment of LM in this indication at the concentration of 150 µg/g. Its use with a more intense regimen (more cycles and/or highest concentration (500 µg/g)) is also limited by a poor safety profile. Clinical trial information: NCT 02723721.