tbuckley/cabot-search huggingface dataset:
AcornFusion: A novel tool to detect gene fusion events in DNA-Seq data.
Authors: Lifang Yao, Haijun Wang, Yanrui Zhang, Wenping Wang, Yongfang Dong, Wang Wang, Huina Wang, Jing Guo, Feng Lou, Shanbo Cao, Shumei Wei
Journal: Journal of Clinical Oncology (2019)

e14650 Background: Gene fusions, resulting from chromosomal breakage and rearrangement, play a critical role during oncogenesis. Recently, a growing number of gene fusions are being considered as important therapeutic targets in oncology, for instance, Anaplastic lymphoma receptor tyrosine kinase (ALK) fusion, which confer exquisite sensitivity to ALK tyrosine kinase inhibitors (TKIs). However, available methods are inadequate for unbiased identification of potentially targetable fusions. Hence, we developed a novel fusion gene analyzing method named AcornFusion by DNA-seq data. Methods: The method is purely based on the mapping results of soft-clipped reads and the distribution of the positions where the candidate breakpoints locate, which is significantly different from the traditional methods with assembly of short reads and efficient way to do the detection. 309 patients with advanced non-small cell lung cancer (NSCLC) were enrolled. Formalin-fixed, paraffin embedded (FFPE) samples were used to DNA extracting and analyzed by AcornFusion method. Immunohistochemistry (IHC) and Reverse transcriptase polymerase chain reaction (RT-PCR) platform were also applied. Results: Of 309 pts, 17 patients were identified as fusion-positive cases by AcornFusion. 15 patients were EML4-ALK fusion positive and 1 patient was HIP-ALK fusion positive, which were all confirmed by IHC. 1 patient was ROS1 rearrangement positive, which was validated by Reverse transcriptase polymerase chain reaction (RT-PCR) method. Conclusions: With this advantage of high consistency with IHC and RT-PCR, AcornFusion can be a useful tool for investigating gene fusion events in clinical settings.
Genetic variants in RNA binding protein (RBP) to predict outcome in metastatic colorectal cancer (mCRC): Data from FIRE-3, TRIBE, and MAVERICC trials.
Authors: Hiroyuki Arai, Shu Cao, Fotios Loupakis, Sebastian Stintzing, Ryuma Tokunaga, Francesca Battaglin, Jae Ho Lo, Shivani Soni, Wu Zhang, Christoph Mancao, Bodour Salhia, Shannon M Mumenthaler, Daniel J Weisenberger, Gangning Liang, Chiara Cremolini, Volker Heinemann, Alfredo Falcone, Joshua Millstein, Heinz-Josef Lenz
Journal: Journal of Clinical Oncology (2019)

3545 Background: RNA binding proteins (RBPs) post-transcriptionally regulate gene expression by stabilizing or destabilizing target messenger RNA. Although alteration of RBPs affects many steps of cancer development, its clinical implication in mCRC remains unclear. Methods: We analyzed data from mCRC patients (pts) enrolled in three first-line randomized trials (FIRE-3, TRIBE, and MAVERICC). Genomic DNA from blood samples of pts was genotyped through the OncoArray, a custom array manufactured by Illumina. Candidate 30 SNPs in 10 RBP genes (MSI1, MSI2, ELAVL1, RBM3, LIN28A, LIN28B, IGF2BP1, IGF2BP2, IGF2BP3, ZFP36) were tested on association with progression-free survival (PFS) and overall survival (OS). To evaluate prognostic effects and heterogeneities across treatment arms, meta-analysis approach using the METASOFT software was conducted. We also tested interaction between each SNP and treatment within each trial, i.e. FIRE-3 cohort (FOLFIRI+cetuximab (Cet) vs FOLFIRI+bevacizumab (Bev)) and MAVERICC cohort (FOLFIRI+Bev vs FOLFOX6+Bev). For multiple testing, p values were adjusted by the false discovery rate (FDR) method. Results: A total of 884 pts’ SNPs data were available (FIRE-3: n = 236, TRIBE: n = 324, and MAVERICC: n = 324). Meta-analysis combining three trials showed RBM3 rs926152 (adjusted p = 0.045) and RBM3 rs2249585 (adjusted p = 0.016) were significantly prognostic for PFS. Whereas, in terms of OS, only LIN28B rs314277 (adjusted p = 0.045) was significant, and RBM3 rs926152 (adjusted p = 0.057) and RBM3 rs2249585 (adjusted p = 0.059) had a trend. Interaction test showed several SNPs were potentially predictive (raw p &lt; 0.05), although without any significance after FDR adjustment: in FIRE-3 cohort, MSI2 rs1822381, RBM3 rs926152, LIN28B rs221635, IGF2BP1 rs2969 for OS; in MAVERICC cohort, MSI1 rs1179442 and MSI2 rs3826301 for OS, ELAVL1 rs4804244 for PFS. Conclusions: Our results indicate prognostic potential of SNPs in RBP genes, such as RBM3 and LIN28B, in mCRC. However, we find no distinct evidence that these SNPs can predict differential effect between Cet and Bev, or between oxaliplatin- and irinotecan-based chemotherapy.
Clinical efficacy and toxicity data on phase I study of fosbretabulin in combination with everolimus in neuroendocrine tumors.
Authors: Aman Chauhan, Susanne M. Arnold, Jianrong Wu, Rashmi T Nair, Stacey A. Slone, Emily Van Meter Dressler, Heather Flynn, Val R. Adams, Heidi Weiss, Mark Evers, Lowell Brian Anthony
Journal: Journal of Clinical Oncology (2019)

4114 Background: Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs). Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D), safety data and early clinical efficacy in metastatic GEPNET patients was conducted. Methods: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. RECIST 1.1 was used to evaluate radiological responses at 3 month. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had &gt; 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Conclusions: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Clinical trial information: NCT0301429.
Methylation profiling of EGFR mutant primary and metastatic lung cancer with brain metastasis.
Authors: Yasin Mamatjan, Michael Cabanero, Jessica Weiss, Jeffrey Zuccato, Hadas Sorotsky, Ming Sound Tsao, Kenneth D. Aldape, Gelareh Zadeh, Frances A. Shepherd
Journal: Journal of Clinical Oncology (2019)

e20574 Background: EGFR-mutant lung cancer is a key molecular subtype of lung cancer. In recent years there is clear recognition in the value of using methylation signature of cancer for improving diagnosis and predicting outcome as well as understanding the biology of cancer progression. Methods: In this study we chose to characterize the methylome signature of early stage surgically resected EGFR-mutant lung adenocarcinomas in the primary lung tumor. 90 NSCLC cases and 7 matched metastatic brain samples were profiled using Illumina Infinium MethylationEPIC Beadchip. We compared methylation profiles of 1) smokers versus lifetime non-smokers and 2) matched primary lung versus brain metastasis to identify methylation biomarkers. We performed supervised analysis and unsupervised clustering of the methylation data. Results: Unsupervised clustering of all lung and brain samples based on 10K most variable probes showed a similar methylation signature between metastatic brain samples and lung samples. The 7-matched brain and lung samples formed close cluster groups based on matching pairs for the most variable probes from 2.5K to 10K, reflecting the same cell of origin. Supervised analysis of smokers versus lifetime non-smokers did not show any significant methylation differences between the two groups, while unsupervised analysis did not create clusters of smokers and non-smokers based on various number of probe sets we analyzed. Conclusions: Lung tumors that metastasized to the brain share similar methylation features with primary lung tumors. Comprehensive methylation profiling demonstrated no difference between EGFR mutant tumors in smokers versus non-smokers, suggesting that the EGFR mutation is a stronger determinant of outcome independent of smoking.
[<sup>18</sup>F] Fluciclatide PET as a biomarker of clinical response to combination therapy of pazopanib and paclitaxel in patients with platinum-resistant or platinum-refractory advanced ovarian cancer: Results of a phase Ib study.
Authors: Rohini Sharma, Pablo Oriol Valls, Marianna Inglese, Suraiya Rahim Dubash, Michelle Chen, Hani Gabra, Ana Montes, Amarnath Challapalli, George Tharakan, Edward Chambers, Tom Cole, Jingky Lozano-kuehne, Tara Barwick, Eric Aboagye
Journal: Journal of Clinical Oncology (2019)

3070 Background: Angiogenesis has been shown to be a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum resistant/refractory ovarian cancer. Integrins α v β 3 and α v β 5 are both up-regulated in tumour-associated vasculature. [ 18 F]Fluciclatide is a novel PET tracer that has high affinity for integrins α v β 3/5 , and was used to assess the anti-angiogenic effect of pazopanib. Methods: We conducted an open-label, phase Ib study in patients with platinum resistant/refractory ovarian cancer. Patients received 1 week of single agent pazopanib (800mg daily) followed by combination therapy with weekly paclitaxel 80mg/m 2 . Following completion of 18 weeks of therapy, patients continued with single agent pazopanib until disease progression. Dynamic [ 18 F]Fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. Results: Fourteen patients were included in the intention-to-treat analysis. Complete and partial response was seen in 7 patients (54%). Median progression free survival (PFS) was 7.97 months, and overall survival (OS) was 18.5 months. A reduction in [ 18 F]fluciclatide uptake was observed following 1 week of pazopanib, and the reduction in uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and FGF were predictive of greater reduction in SUV 60,mean following pazopanib. Kinetic modelling indicated a reduction in K 1 and K i following pazopanib indicating reduced radiotracer delivery and retention. Conclusions: Combination therapy followed by maintenance pazopanib is effective and tolerable in patients with platinum resistant/refractory ovarian cancer. We have shown that [ 18 F]fluciclatide-PET uptake parameters alter with pazopanib therapy indicating an anti-angiogenic response. Clinical trial information: NCT01608009.
Effect of minimal lymphodepletion prior to ACT with TBI-1301, NY-ESO-1 specific gene-engineered TCR-T cells, on clinical responses and CRS.
Authors: Marcus O. Butler, Sam Saibil, Luisa Bonilla, Norman Franke, Sevan Hakgor, Sarah Boross-Harmer, Habeeb Majeed, Megan Nelles, Pamela S Ohashi, Kendra Ross, Adrian G. Sacher, Elizabeth Scheid, Valentin Sotov, Aileen Trang, Koosha Vakili, Brendan Van As, Shuichi Takahashi, Shinya Tanaka, Linh T. Nguyen, Naoto Hirano
Journal: Journal of Clinical Oncology (2019)

2537 Background: Adoptive transfer of T cell receptor (TCR) gene-engineered T cells can induce durable anti-cancer responses. Post-infusion cytokine release syndrome (CRS) has been associated with clinical utility. Pre-infusion lymphodepletion (LD) may influence CRS, graft persistence, and clinical responses. While the optimal LD regimen is not yet defined, most include both cyclophosphamide (CY) and fludarabine (FLU). TBI-1301 is a novel gene therapy produced by engineering autologous lymphocytes to express an NY-ESO-1-specific TCR using a retrovirus vector that encodes siRNA to silence endogenous TCR. Since less intensive LD may be sufficient with the use of this novel vector, we are conducting a study where patients are treated with TBI-1301 following LD with CY alone. Methods: Eligibility includes informed consent, HLA-A*02:01 or A*02:06 haplotype, and NY-ESO-1 expression by immunohistochemistry. Eligible patients undergo harvest of PBMC which are then processed locally to generate engineered TBI-1301 cells. The study design is to infuse 5x10 9 cells (day 0) to patients following LD with CY (750 mg/m 2 on day -3 and -2). Endpoints include safety, efficacy, and biological correlates for persistence of NY-ESO-1-specific T cells post infusion. Results: Thus far, 9 patients have been treated, and 8 have received the target dose. To date, 8 patients are evaluable for response and toxicity, and no DLTs have been observed. Despite LD with CY alone, all 4 patients with synovial sarcoma and 1 with melanoma experienced clinical and laboratory evidence of grade 1-2 CRS with increased CRP, ferritin, and IL-6 levels. CRS resolved spontaneously in all but one patient who required tocilizumab due to grade 2 nausea/vomiting. Two subjects experienced grade 3 tumor-associated pain. Other treatment-associated grade 3 or 4 toxicities included neutropenia and hypophosphatemia. Best overall response by RECIST is as follows: 2 partial responses, 5 stable disease, and 1 progressive disease. Biomarker analysis demonstrates persistence of transferred TBI-1301 cells, &gt; 100 days in some patients. Conclusions: TBI-1301 appears to be safe and to possess anti-tumor activity. Despite LD with CY alone, grade 1-2 CRS is induced. Additional cohorts to this study will examine the role of repeat infusions to enhance anti-tumor activity. Clinical trial information: NCT02869217.
The combined treatment of 150 kHz tumor treating fields (TTFields) and sorafenib inhibits hepatocellular carcinoma in vitro and in vivo.
Authors: Uri Weinberg, Shiri Davidi, Catherine Tempel- Brami, Mijal Munster, Karnit Gotlib, Einav Zeevi, Rosa S. Schneiderman, Tali Voloshin, Moshe Giladi, Adrian Kinzel, Eilon David Kirson, Yoram Palti
Journal: Journal of Clinical Oncology (2019)

e15653 Background: Hepatocellular carcinoma (HCC) is the third cause of cancer related mortality and the primary cause of cancer death. Tumor Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. Sorafenib, an oral multikinase inhibitor is approved for patients with advanced HCC, yet its survival benefit is still limited. In this work we explored the potential of the use of TTFields alone and in combination with Sorafenib as a treatment for HCC. Methods: HepG2 and Huh-7D12 cells were treated with various TTFields frequencies for 72 hours using the inovitro system. Efficacy of the combined treatment of TTFields and Sorafenib (36-3000 nM) was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, induction of apoptosis, cell cycle and clonogenic potential were determined. TTFields (1.2 V/cm) and Sorafenib (10 mg/kg) were applied for 6 days to rats injected to the liver with N1S1 HCC cells. Tumor growth was followed using MRI. Results: The optimal TTFields frequency was 150 kHz for both cell lines. TTFields application (1.0 - 1.7 V/cm, 72 hours) at 150 kHz led to 36-40% reduction in cell counts and to additional reduction of over 70% in the clonogenic potential. The combined treatment of TTFields and Sorafenib led to a significant reduction in the number of cells (p &lt; 0.001) as compared to each treatment alone. The averaged tumor volume fold increase of the combination treatment group was significantly lower than the one observed in the: control group, the TTFields group and the Sorafenib group. Conclusions: The results presented in this work demonstrate that TTFields can be an effective treatment against HCC cells and that the combination with Sorafenib may further enhance treatment efficacy.
Association between pretreatment Fusobacterium nucleatum and cancer pain at six months postsurgery in newly diagnosed colorectal cancer patients: Results from the ColoCare Study.
Authors: Anita Roselyn Peoples, Biljana Gigic, Jennifer Ose, Andreana Natalie Holowatyj, Patrick M. Mallea, Christy A. Warby, W. Zac Stephens, Sheetal Hardikar, Petra Schrotz-King, Julie Ryan-Wolf, Alexis B. Ulrich, Eric A. Swanson, Martin Schneider, Christopher I. Li, David Shibata, Erin M. Siegel, Jane C. Figueiredo, Adetunji T. Toriola, June Round, Cornelia M. Ulrich
Journal: Journal of Clinical Oncology (2019)

3581 Background: Pain is a prevalent, debilitating symptom in more than half of cancer patients. Accumulating evidence suggests a bi-directional relationship between gut microbiota and pain, potentially via inflammation and oxidative stress. Fusobacterium nucleatum (Fn), a pro-inflammatory anaerobic bacterium, is frequently detected in colorectal cancer (CRC) patients. To date, no study has identified a relationship between Fn and cancer pain in CRC patients. We investigated the associations between pre-treatment Fn and cancer pain at 6 months post-surgery in CRC patients. Methods: We utilized pre-surgery stool samples collected from 80 prospectively followed, newly diagnosed CRC patients recruited from the German site of the international ColoCare Study. Eligible patients were neo-adjuvant treatment naïve and did not use antibiotics for at least 1 month before stool collection. Fn DNA was assessed via quantitative real-time polymerase chain reaction. Patients were median split into Fn-high (&gt;17.27; n=40) or Fn-low (≤17.27; n=40). Cancer pain was assessed using the 2 pain symptom items from the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core-30 (lower score=lower pain) at pre- and 6 months post-surgery. Results: Before surgery, 48% of all patients reported any pain. At 6 months post-surgery, we observed a decrease in cancer pain by 33% for Fn-low, while there was an increase in cancer pain by 41% for Fn-high. After controlling for pre-surgery cancer pain in ANCOVA model, we observed significantly higher mean cancer pain at 6 months post-surgery in the Fn-high group vs. the Fn-low group (24.07 vs. 13.44; effect size, ES=0.45; p=0.04). These results were maintained even after controlling for age, sex, tumor stage and site, adjuvant chemotherapy, BMI, physical activity, and any pain medications (29.11 vs. 16.55; ES=0.53; p=0.03). Conclusions: These findings suggest that high Fn is an independent predictor of cancer pain at 6 months post-surgery in colorectal cancer patients. Further research is needed to confirm and understand the mechanisms of these results. Funding: NCI U01 CA206110.
Case 22-1987
Authors: Richard C. Cabot, Robert E. Scully, Eugene J. Mark, William F. McNeely, Betty U. McNeely
Journal: New England Journal of Medicine (1987)

Presentation of Case A 58-year-old woman was admitted to the hospital because of right-sided and left-sided congestive heart failure. There was a lifelong history of a systolic murmur, without symptoms. Five years before admission a new murmur of aortic regurgitation was noted, and an x-ray film of the chest showed cardiac enlargement. Four years before entry easy fatigability developed, and a physician heard a pericardial friction rub. The patient was admitted to another hospital. Physical examination showed that the temperature was 37.9°C. A Grade 3 holosystolic murmur was heard along the left sternal border and at the cardiac apex, and . . .
Evidence that neoadjuvant anthracycline based combination chemotherapy (NACT) in breast cancer (BC) induces phenotypical changes which guides the optimal adjuvant therapy.
Authors: Tarek Mohamed Ahmed Abdel-Fatah, Rebekah Webb, Ruizhe Li, Xin Chen, Elisabetta Giannotti, Dorothee Auer, Jennifer Walker, Paul M Moseley, A. Graham Pockley, Graham Ball, Ian O. Ellis, Emad Rakhah, Zsolt Hodi, Andrew Lee, Arlene Chan, Stephen Chan
Journal: Journal of Clinical Oncology (2019)

590 Background: We hereby evaluated the histopathological and radiological alterations of tumor characteristics after receiving NACT and the clinical significance of the changes of adjuvant therapy based on these findings. Methods: A pathological assessment of tumor features including ER, PR, HER2 and proliferation markers (Ki67 and SPAG5) status in pre and post NACT tumors tissue have been centrally evaluated in two cohorts [Nottingham University Hospital (NUH; n=850) and Australian cohort (n=250 patients)]. Since 2013 any change in the ER and HER2 status from negative (-) [in the pre NACT biopsies] to positive (+) [in the post NACT surgical specimens] received additional adjuvant therapy (Endocrine therapy (ET) for ER+ and Trastuzumab for HER2+ cases) in NUH. MRI volumetric and texture changes have been assessed in 400 cases. The primary end point was disease free survival (DFS; median follow-up = 62 months). Results: 10% of pre NACT HER2- cases had been converted to post NACT HER2+ and those cases who subsequently received adjuvant Trastuzumab had achieved 92% 5-year DFS compared to those who remained HER- in post NACT specimens (58% 5-year DFS); (HR (95% CI)= 0.25 (0.08-0.80); p=0.016). While 13% of pre NACT HER2+ tumors were converted into HER2- in post NACT surgical specimens and had similar 5-year DFS to those who remained post NACT HER2+ (5-year DFS= 94% vs., 87%; p=0.613). Loss of PR in the residual disease of pre NACT ER+ BC was associated with shorter 5-year DFS after ET compared to those who remained post NACT PR+ (HR (95% CI)=2.1 (1.25-3.46); p=0.005). After NACT, 40% of pre NACT SPAG5+ cases were converted into post NACT SPAG5- and these patients had prolonged DFS compared to those who remained SPAG5+ in post NACT specimens (27%) [5-year DFS=84% vs 49%; (HR (95% CI)= 3.8 (2.1-6.9); p&lt;0.0001). A prognostic model has been generated including factors in table (AUC = 0.854 (95% CI) = 0.777-.0.931; p= 0.00000001]. Conclusions: We hereby showed evidences a change of treatment strategy based on the changes in the tumor post NACT phenotype gives the optimal choice of treatment eg., the introduction of HER2 targeting therapy for the conversion of HER2– to HER2+ phenotype after NACT improved DFS. Multivariate Cox regression model for 5-year DFS. [Table: see text]