bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1b study of selinexor, a first-in-class selective inhibitor of nuclear export (SINE) compound, in combination with doxorubicin in patients (pts) with locally advanced or metastatic soft tissue sarcoma (STS).
Authors: Malone Eoghan Ruadh , Lewin Jeremy Howard , Al-Ezzi Esmail Mutahar , Gupta Abha A. , Pedersen Pernille , Ng Michelle , Wang Lisa , Rodriguez Angela , Abdul Razak Albiruni Ryan 
Published: May 2019

3123 Background: Selinexor is a first-in-class SINE compound with single-agent activity in STS. We undertook this study to determine the safety, tolerability and efficacy of selinexor in combination with doxorubicin in pts with incurable STS. Methods: This phase 1b study was conducted using a bayesian model (modified toxicity probability index). Patients with locally advanced or metastatic STS received selinexor at either 60 or 80mg weekly PO plus doxorubicin (75mg/m2 IV q21 days, max 6 cycles). Pts with stable disease (SD) or better (per RECIST 1.1 criteria) after 6 cycles of combination treatment received selinexor monotherapy until disease progression or unacceptable toxicity. Disease assessments were made with standard imaging after every 2 cycles. Results: 24 pts (19F/5M, ECOG 0/1: 12/12, median age 58.5 years [range 34-74]) were enrolled. Disease subtypes included leiomyosarcoma (n = 6), malignant peripheral nerve sheath tumor (n = 3) and other sarcomas (n = 15). Three pts at 60mg selinexor and 21 pts at 80mg selinexor were treated. The most common G3 drug related adverse events were hematological, neutropenia n = 13 (54%), anemia n = 6 (25%). There were 4 dose-limiting toxicities (2 febrile neutropenia, 1 vomiting and 1 unresolved fatigue) all at the 80mg dose level, but does not satisfy criteria for maximum tolerated dose. Two patients had clinically significant and relevant drop in ejection fraction, presenting with cardiac symptoms. Of the 24 evaluable pts 4 (17%) had a partial response, 16 (67%) had SD as best response and SD > 16 weeks was seen in 13 pts (54%). PK analysis of selinexor did not demonstrate changes compared to single agent profile. The estimated median PFS and OS are 5.5 (95% CI:4.1-7.0) and 9.4 (6.6-13.8) months. Conclusions: Our initial data demonstrate that the combination of selinexor at 80mg with doxorubicin is tolerable and is associated with clinical benefit. Longer term follow up of available patients will be needed to understand toxicity profile. Clinical trial information: NCT03042819.
Measuring phospho-MET by multiplex immunofluorescence to aid in selection of patients with MET activation in tumors.
Authors: Navas Tony , Srivastava Apurva K. , Govindharajulu Jeevan P , Evrard Yvonne A. , Borgel Susanne , Carter John , Chen Li , Das Biswajit , Divelbiss Raymond , Karlovich Chris , Patidar Rajesh , Radzyminski Marianne , Stottlemyer Jesse , Williams Paul M. , Hollingshead Melinda G. , Bottaro Donald , Doroshow James H. , Parchment Ralph E. 
Published: May 2019

3131 Background: Currently, patient selection criteria for clinical testing of MET inhibitors are limited. Robust studies selecting patients based on MET protein expression, MET gene amplification, or mutations have not met their efficacy goals. Development of microscopy-based assays to quantify levels of phospho-MET (pMET) in tumors has been hampered by poor antibody specificity. Here, we present the development and validation of a robust, highly specific multiplex immunofluorescence assay (IFA) that measures pY1235-MET and total MET in tumor tissue. Methods: This assay utilizes antibodies to pY1235-MET (NCI-23111), total MET (D1C2), and plasma membrane (PM) marker Na+/K+-ATPase, each conjugated to a different Alexa Fluor dye. We used tumor tissue from crizotinib-treated SNU5 xenograft models to demonstrate pY1235-MET assay fitness-for-purpose and cross-platform assay concordance with our validated pMET ELISA. In addition, this IFA was validated by phospho-peptide competition using custom tissue microarrays (TMA) derived from patients with colorectal carcinoma (CRC). Finally, we developed quantitative algorithms to assess pY1235 MET levels in the plasma membrane and nucleus using PM and DAPI masks, respectively. Patient-derived xenograft models (PDX) were obtained from NCI’s Patient-Derived Models Repository (www.pdmr.cancer.gov). Results: The prevalence of high pY1235-MET expression in CRC patient specimens was greater than expected; of the 64 TMA cores evaluated, 29 (45%) and 19 (29%) had high pY1235-MET and total MET levels, respectively, as defined by mean marker area of ≥ 30 μm2/cell. To address the potential utility of pY1235-MET as a diagnostic biomarker, we examined 15 CRC PDX models by pMET ELISA and IFA. Two CRC tumor models were positive for pY1235-MET expression in both assays. The pY1235-MET IFA results and gene expression data were used to select PDX models for ongoing preclinical trials of potent MET inhibitors. Conclusions: This novel pY1235-MET IFA will enable clinicians to address the utility of activated MET as a biomarker for patient selection and/or prediction of response in clinical trials of MET inhibitors. Funded by NCI Contract No. HHSN261200800001E.
Machine learning methods with salivary metabolomics for breast cancer detection.
Authors: Murata Takeshi , Yanagisawa Takako , Kurihara Toshiaki , Kaneko Miku , Ota Sana , Enomoto Ayame , Tomita Masaru , Sugimoto Masahiro , Sunamura Makoto , Hayashida Tetsu , Kitagawa Yuko , Jinno Hiromitsu 
Published: May 2019

3135 Background: Saliva is non-invasively accessible and informative biological fluid which has high potential for the early diagnosis of various diseases. The aim of this study is to develop machine learning methods and to explore new salivary biomarkers to discriminate breast cancer patients from healthy controls. Methods: We conducted a comprehensive metabolite analysis of saliva samples obtained from 101 patients with invasive carcinoma (IC), 23 patients with ductal carcinoma in situ (DCIS) and 42 healthy controls, using capillary electrophoresis and liquid chromatography with mass spectrometry to quantify hundreds of hydrophilic metabolites. Saliva samples were collected under 9h fasting and were split into training and validation data. Conventional statistical analyses and artificial intelligence-based methods were used to access the discrimination abilities of the quantified metabolite. Multiple logistic regression (MLR) model and an alternative decision tree (ADTree)-based machine learning methods were used. The generalization abilities of these mathematical models were validated in various computational tests, such as cross-validation and resampling methods. Results: Among quantified 260 metabolites, amino acids and polyamines showed significantly elevated in saliva from breast cancer patients, e.g. spermine showed the highest area under the receiver operating characteristic curves (AUC) to discriminate IC from C; 0.766 (95% confidence interval [CI]; 0.671 – 0.840, P < 0.0001). These metabolites showed no significant difference between C and DICS, i.e., these metabolites were elevated only in the samples of IC. The MLR yielded higher AUC to discriminate IC from C; 0.790 (95% CI; 0.699 – 0.859, P < 0.0001). The ADTree with ensemble approach showed the best AUC; 0.912 (95% CI; 0.838 – 0.961, P < 0.0001). In the comparison of these metabolites in the analysis of each subtype, seven metabolites were significantly different between Luminal A-like and Luminal B-like while, but few metabolites were significantly different among the other subtypes. Conclusions: These data indicated the combination of salivary metabolomic profiles including polyamines showed potential ability to screening breast cancer in a non-invasive way.
The whole genome landscape of adult metastatic sarcoma.
Authors: Zhao Eric Yang , Feng Xiaolan , Pleasance Erin D. , Ng Tony L. , Grewal Jasleen , Mohammad Nissreen , Taylor Sara Kristina , Simmons Christine E. , Srikanthan Amirrtha , Rassekh Shahrad Rod , Deyell Rebecca , Shen Yaoqing , Titmuss Emma , Lim Howard John , Renouf Daniel John , Gelmon Karen A. , Yip Stephen , Jones Steven J. M. , Marra Marco A. , Laskin Janessa J. 
Published: May 2019

3137 Background: Metastatic sarcomas represent a heterogeneous, difficult to treat family of cancers with poor median overall survival of 18 months. While global sequencing initiatives have catalogued genomic variation among primary sarcomas, metastatic sarcoma is less well understood. Genome-guided targeted therapy has made promising advances but is difficult to study in sarcomas due to heterogeneity and low prevalence. Whole genome and transcriptome analysis (WGTA) can help elucidate sarcoma oncogenesis, metastasis, and potential therapeutic targets. Methods: Using whole genome (80X) and transcriptome (200M read) sequencing of 43 metastatic sarcomas across 19 subtypes, we analyzed structural variants (SV), copy-number variants (CNV), mutation signatures, gene expression, and the immune microenvironment. All prior treatments were retrieved through chart review. Results: 17 patients (40%) attempted WGTA-informed therapy, of which 8 (47%) were classified as responders. Metastatic sarcomas demonstrated recurrent CNVs, with 17p11-p12 amplification in 42% of cases. Some recurrent expression outliers were associated with potential targets (e.g. MYOCD, PMP22, COPS3) while others (e.g. ADORA2B) have not been previously observed in sarcoma. Discovery of oncogenic fusions refined diagnoses in two cases with atypical histology. Clustering by mutation signatures distinguished histological subtypes, and two signatures were novel in sarcoma: (1) a strong base excision repair signature associated with NTHL1 loss and (2) a cisplatin-associated signature exclusive to platinum-treated cases. Frequent homologous recombination deficiency was observed and was associated with response to ifosfamide in three leiomyosarcomas. Of four immunotherapy-treated cases, the only responder demonstrated outlier CIBERSORT immune infiltration score, which did not correlate with PD-L1 expression. Conclusions: This is the first in-depth WGTA of metastatic sarcoma. We found recurrent and potentially targetable CNVs, expression outliers, mutation signatures, and immune markers. Our results suggest that clinical translation is promising using actionable insights obtained through WGTA.
Prediction of biomarker status, diagnosis and outcome from histology slides using deep learning-based hypothesis free feature extraction.
Authors: Klaiman Eldad , Gildenblat Jacob , Ben-Shaul Ido , Heller Astrid , Korski Konstanty , Kiermaier Astrid Christina , Gaire Fabien 
Published: May 2019

3140 Background: Recently, histological pattern signatures obtained from diagnostic H&E images have been found to predict mutation, biomarker status or outcome. We report here on a novel deep learning based framework designed to identify and extract predictive histological signatures. We have applied this framework in 3 experiments, predicting specifically the microsatellite status (MSS) of colorectal cancer (CRC), breast cancer (BC) micrometastasis in Lymph nodes (LN) and Pathologic Complete Response (pCR) in BC diagnostic biopsies. Methods: Our deep learning based algorithm was trained on histology images at 20X magnification. Algorithms were trained for binary classification for each of the three cohorts. We used 75% of the images for training and test our algorithm on the remaining 25% of the images. Cohort details are as follows: MSS for CRC: 94 patients’ H&E stained tissue images from the Roche internal CRC80 dataset (MSS n =24; MSI n = 70) were used. BC LN: 270 patients’ H&E stained tissue images from the CAMELYON16 dataset ( LN(+) n = 110 ; LN(-), n =160) were used. pCR for BC: 225 patients’ H&E stained tissue images from the Tryphaena Study BO22280, neoadjuvant, Trastuzumab/Pertuzumab chemotherapy combination trial. (pCR=111, non-pCR n=114). Results: We report and assess algorithm performance on each of the cohorts by Area Under the Curve (AUC). Prediction of MSS in the CRC80 status yielded AUC 0.9. Prediction of LN invasion on CAMELYON16 dataset yielded AUC 0.85. Prediction of pCR on the Tryphaena cohort yielded an AUC of 0.8. Conclusions: We present a new approach to generate predictive signatures based on conventional diagnostic H&E images and a novel machine learning framework. The CRC80 and CAMELYON16 cohorts served as a confidence building experiments with predictive features well known by clinicians and visually confirmed. The predictive algorithm for pCR in the Tryphaena cohort yielded both response prediction and the high predictive value FOVs. These included tissue patterns which have not until now been considered to influence on the prediction of pCR.
Reassignment of HER2 status for subgroups of breast cancer according to the 2018 updated American Society of Clinical Oncology and College of American Pathologists guidelines: The impact of combined immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) reflex testing in a large national reference laboratory.
Authors: Geiersbach Katherine , Meyer Reid G. , Kloft-Nelson Sara M. , Knutson Darlene L. , Knudson Ryan A. , Sukov William R. , Ketterling Rhett P. , Greipp Patricia T. , Jenkins Robert B. 
Published: May 2019

3144 Background: Updated ASCO/CAP Guidelines for HER2 testing in breast cancer have been most impactful on the resolution of certain challenging groups of FISH results. We review the change in assignment of HER2 status in a large series of breast cancers referred to a large national reference laboratory for FISH testing since the introduction of the 2018 updated guidelines. Methods: Patient samples submitted to the Mayo Clinic Cytogenetics Laboratory (N = 2208) were analyzed by FISH. Samples with Group 2, Group 3, or Group 4 FISH results were reflexed to immunohistochemistry (IHC) in our central laboratory; FISH slides for those cases with equivocal 2+ IHC results were re-scored in the regions of invasive cancer showing more intense membranous staining. A subset of 202 samples with Group 4 FISH results were also reflexed to the previously employed reflex FISH assay (HER2/D17S122), and these were also re-analyzed according to the new reflex IHC/FISH process. Results: 382 of 2208 breast cancer samples tested (17.3%) had FISH results categorized as Group 2 (N = 17, 0.8%), Group 3 (N = 34, 1.5%), or Group 4 (N = 331, 15%) and required reflex IHC testing, and of those, 75% were 2+ equivocal and required targeted re-analysis of the FISH slide according to the 2018 updated guidelines. Re-analysis of the FISH slide resulted in switching between Groups 1-5 in 19.4% of cases, but HER2 status was changed by FISH re-scoring in only 7.7% of cases re-scored (1.0% of all samples), generally due to only minor shifts in HER2 copy number and HER2/control ratios between the initial and IHC-guided reflex FISH scores. In the subset of 202 cases tested by both reflex methods, the previously employed HER2/D17S122 reflex probe set was positive in 123 cases (60.9%), whereas reflex IHC/FISH was positive in only 10 cases (7.9%). Including positive reflex IHC (0.4%) and positive reflex FISH results (2.1%), the overall assignment of positive HER2 status on our series of 2208 cases was 11.5%. Conclusions: Overall rates of HER2 positive FISH results have declined under the most recent ASCO/CAP guideline update as a consequence of new recommendations for reflex testing for Groups 2-4. This change is largely due to reassignment of Group 2 and Group 4 results as negative in the absence of positive IHC.
BRCA1 genetic variant to predict survival in metastatic colorectal cancer (mCRC) patients (pts) treated with FOLFIRI/bevacizumab (bev): Results from phase III TRIBE and FIRE-3 trials.
Authors: Naseem Madiha , Cao Shu , Stintzing Sebastian , Loupakis Fotios , Berger Martin D. , Puccini Alberto , Tokunaga Ryuma , Battaglin Francesca , Barzi Afsaneh , Soni Shivani , Millstein Joshua , Salem Mohamed E. , Cremolini Chiara , Zhang Wu , Heinemann Volker , Falcone Alfredo , Lenz Heinz-Josef 
Published: May 2019

3145 Background: BRCA muts in CRC are associated with a higher tumor mutation burden irrespective of microsatellite instability, which highlights the possibility of using PARP-inhibitors(i) in CRC in the future. Early phase studies have shown that combination of PARP-i with oxaliplatin or irinotecan enhances tumor lysis in CRC. In this study, we investigated the influence of mutations in the Homologous Repair Pathway genes on survival outcomes among mCRC pts treated with oxaliplatin or irinotecan-based regimens. Methods: The impact of selected SNPs within 4 genes (BRCA1, BRCA2, RAD51, BARD1) on OS/PFS was analyzed through the OncoArray, a custom array manufactured by Illumina, on genomic DNA from blood samples of 431 pts enrolled in 2 randomized trials. TRIBE FOLFIRI/bev arm (n = 215, mPFS/OS: 9.7/26.2 mo) served as discovery cohort, FIRE-3 FOLFIRI/bev arm (n = 107, mPFS/OS: 11.5/31.4 mo) as validation and TRIBE FOLFOX/bev arm (n = 109, mPFS/OS: 10.8/26 mo) as control. Results: Significant associations were found among carriers of BRCA1 rs8176318 SNP, where C > A base change is known to reduce BRCA1 expression among CRC cells. In the discovery cohort, pts with A/A had shorter OS (22.4 vs 27.3 mo, P = .009) and PFS (7.5 vs 10.5 mo, P = .0006) compared to carriers of any C allele in both univariate and multivariate analysis. Same results were observed in pts with left-sided CRCs (PFS-7.5 vs 11 mo, P = .005; OS- 25.6 vs 32.3, P = .034) and among males (PFS- 7.5 vs 10.3 mo, P = .008; OS- 25.7 vs 31.3 mo, P = .008) in both uni and multivariate analysis. These results were also seen in the validation cohort: A/A carriers in left-sided CRCs had poor OS (26.1 vs 36.0 mo, P = .027) and PFS (9.5 vs 11.7 mo, P = .002. Males with A/A genotype also had poor OS (24.7 vs 32.5 mo, P = .028) and PFS 96.9 vs 12.2 mo; P = .0002). In the control cohort, A/A genotype carriers had poor tumor response in overall (P = .011) and left-sided disease (P = .034). These outcomes were independent of KRAS mutation status. No significant relationship was observed among females with mCRC. Conclusions: This is the first study to report that BRCA1 mut influence survival outcomes among mCRC pts, particularly among males and those with left-sided disease. Prospective trials are warranted to assess the utility of routine BRCA mut testing and the role of PARP-i in improving survival outcomes in this pt population.
Randomized phase III study comparing FOLFOX + bevacizumab versus folfoxiri + bevacizumab (BEV) as 1st line treatment in patients with metastatic colorectal cancer (mCRC) with ≥3 baseline circulating tumor cells (bCTCs).
Authors: Sastre Javier , Vieitez Jose María , Gomez-España Maria Auxilidora , Gil Calle Silvia , Salud Salvia Antonieta , Suárez Begoña Graña , Garcia-Alfonso Pilar , Martinez de Castro Eva , Quintero Aldana Guillermo Alfonso , Reina-Zoilo Juan José , González Flores Encarnación , Fernández Mercedes Salgado , Guillen Carmen , Garcia-Carbonero Rocio , Safont Maria Jose , La Casta Munoa Adelaida , García de Paredes Beatriz , Lopez Rafael , Aranda Enrique , Díaz-Rubio Eduardo ,   Spanish Cooperative Group for the Treatment of Digestive Tumors (TTD)
Published: May 2019

3507 Background: FOLFOXIRI+BEV has demonstrated a survival benefit compared with FOLFIRI plus BEV (TRIBE Lancet Oncol 2015) in first-line mCRC. Nevertheless, due to its safety profile, this schedule is not recommended for all pts. In addition, we have showed that the detection of ≥3 bCTCs is a poor prognostic factor for survival (MACRO The Oncologist 2012). The VISNU-1 trial compares FOLFOX + BEV vs FOLFOXIRI + BEV in pts with mCRC and ≥3 bCTCs. Progression-free survival (PFS) is the primary endpoint. Secondary endpoints included overall response rate (ORR) and overall survival (OS). Methods: This is an open, multicentric, randomized phase III trial. Patients with mCRC younger than 70 years, ECOG 0-1 were randomized to FOLFOX+BEV (arm A) or FOLFOXIRI+BEV (arm B), stratified per KRAS mutation (mutated vs WT) and number of involved organs (1 vs >1). Results: 349 pts were included in the ITT population; 177 in group A and 172 in group B. Characteristics of the pts, molecular profiling and safety analysis have been previously presented at ASCO 2018 and showed that this schedule had an acceptable toxicity profile. Efficacy analysis in the ITT population is shown in the table. Conclusions: In this population with very bad prognosis, our study met its primary endpoint. Pts who received FOLFOXIRI + Bev benefit for a statistically significative PFS and ORR. OS showed a trend of benefit in the experimental arm. According to these results, FOLFOXIRI-Bev could be considered an adequate treatment option for pts with mCRC and ≥3 bCTCs. Clinical trial information: 2012-000846-37. [Table: see text]
A randomized controlled trial of the conventional technique versus the no-touch isolation technique for primary tumor resection in patients with colon cancer: Primary analysis of Japan Clinical Oncology Group study JCOG1006.
Authors: Takii Yasumasa , Mizusawa Junki , Kanemitsu Yukihide , Komori Koji , Shiozawa Manabu , Ohue Masayuki , Nishimura Yoji , Ikeda Satoshi , Takiguchi Nobuhiro , Kobatake Takaya , Ike Hideyuki , Sato Toshihiko , Tomita Naohiro , Ota Mitsuyoshi , Masaki Tadahiko 
Published: May 2019

3515 Background: The no-touch isolation technique (NTIT) aims to reduce cancer cells flowing from the primary tumor site to the liver and other organs by first ligation of blood vessels that feed the primary tumor. The efficacy of NTIT has not been proved in previous studies. To acquire the answer of an unsolved problem more than 60 years, we conducted a phase III trial to confirm the superiority of NTIT in patients with cT3/T4 colon cancer. This is the primary analysis of the disease-free survival (DFS) as the primary endpoint. Methods: Eligibility criteria included histologically proven colon cancer; tumor located in the cecum, ascending, transverse, descending, sigmoid or rectosigmoid colon; clinical T3 or T4, N0-2, M0; patients age 20-80 years. Patients were randomized preoperatively to either conventional technique (CoT) arm or NTIT arm. Operation was performed in open surgery. Patients with pathological stage III received adjuvant chemotherapy with capecitabine. The primary endpoint was DFS. Planned sample size was 850 to detect a hazard ratio (HR) of 0.732 in DFS with one-sided alpha of 5% and power of 80%. Results: A total of 853 patients were randomized (CoT: 427, NTIT: 426) between January 2011 and November 2015. The 3-year DFS were 77.3% and 76.2% in the CoT arm and NTIT arm,respectively. The HR was 1.029(95% CI 0.800-1.324); thus the superiority of NTIT was not confirmed (p = 0.59). The 3-year overall survival (OS), 3-year recurrence-free survival (RFS) and 3-year liver-recurrence-free survival (LRFS) are shown in the Table. Conclusions: The superiority of NTIT to CoT was not confirmed. NTIT does not improve the DFS or OS, RFS, LRFS in the patents with stage II and III colon cancer. Clinical trial information: UMIN000004957. [Table: see text]