tbuckley/cabot-search huggingface dataset:
Effect of immunotherapy of triple negative breast cancer with ROR1 CAR T cells in combination with the TGF-ß receptor I kinase inhibitor SD-208.
Authors: Tanja Stüber, Razieh Monjezi, Achim Woeckel, Hermann Einsele, Joerg Wischhusen, Michael Hudecek
Journal: Journal of Clinical Oncology (2018)

e15050 Background: CAR T cells are genetically engineered T cells equipped with a tumor specific chimeric antigen receptor (CAR). They are highly effective in haematological malignancies, but a proof of concept in solid tumors is still pending. In preclinical models ROR1 CAR T cells destroy ROR1+ triple negative breast cancer (TNBC). However, we hypothesized that immunosuppressive TGF-ß might be the major culprit for the loss of CAR T cell efficacy in solid tumors. We hence analyzed if pharmacological blockade of TGF-ß signaling by the TGF-ß receptor I kinase inhibitor SD-208 can augment CAR T cell function. Methods: CD4+ and CD8+T cells (n = 3 donors) were isolated and transduced with ROR1 lentivirus. ROR1+ CAR T cells were pretreated with 5 ng/ml TGF-ß alone or in combination with 1 µM SD-208 for 24 hours prior to functional testing against breast cancer cells. Results: We confirmed that TGF-ß receptor II is highly expressed on CD4+ and CD8+ ROR1+ CAR T cells. Coculturing CAR T cells with TGF-ß led to activation of the TGF-ß signaling pathway and increased the phosphorylation of SMADS (pSMADS). The killing potency of CAR T cells was significantly decreased after treatment with TGF-ß (77 % vs. 51 % target lysis; p = 0.01). In concordance, the intracellular levels of perforin, GM-CSF and IFN-γ were significantly decreased. Moreover, TGF-ß impaired proliferation of CAR T cells. Co-incubation with SD-208 prevented the immunosuppressive effects of TGF-ß which was also confirmed by the absence of pSMADs. SD-208 fully reconstituted tumor specific lysis. Similarly, cytokine production and proliferative activity of CAR T cells were improved by SD-208. Conclusions: Our data demonstrate that TGF-ß suppresses cytolytic capacity, cytokine production and proliferation of CAR T cells against TNBC in vitro. The immunosuppressive effects can be neutralized by TGF-ß receptor I kinase inhibitor SD-208. These data encourage the evaluation of ROR1+ CAR T cells against TNBC in combination with a TGF-ß inhibitor.
Patient-reported outcomes (PRO) from a global phase 3 randomized controlled trial (RCT) of inotuzumab ozogamicin (InO) vs standard care (SC) for relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).
Authors: Hagop M Kantarjian, Yun Su, Helen Bhattacharyya, Eric Yan, Mark Shapiro, Joseph C Cappelleri
Journal: Journal of Clinical Oncology (2016)

7027 Background: InO, an anti-CD22 antibody-calicheamicin conjugate, has demonstrated superior clinical activity vs SC (intensive chemotherapy) for R/R ALL in the ongoing phase 3 INO-VATE trial (DeAngelo, European Hematology Society 2015 meeting [LB2073]). The PRO results are reported herein. Methods: Patients (pts) were randomized to InO (max 1.8 mg/m2/cycle [ ≤ 6 cycles]) or SC (fludarabine/cytarabine [ara-C]/granulocyte colony-stimulating factor, ara-C + mitoxantrone, or high-dose ara-C [ ≤ 4 cycles]) and completed the European Organization for Research and Treatment of Cancer Questionnaire (EORTC QLQ-C30) and EuroQoL 5 Dimensions questionnaire (EQ-5D) at baseline, day 1 of each cycle, and end of treatment. Treatment differences in PRO measures over time were assessed in the intent-to-treat population using longitudinal mixed-effects models with random intercepts and slopes. Analyses were supportive and no multiplicity adjustments were made. Results: 141 and 138 pts were randomized to InO or SC; PROs completion rates were 85% and 64%, respectively. Overall, pts receiving InO reported numerically better quality of life (QoL), functioning and symptom scores at each cycle vs SC, with statistically significant differences in least squares mean Physical and Role Functioning (7.6 and 11.5, respectively; P< 0.02). Mean treatment differences in favor of InO in EQ-VAS, Global Health Status/QoL, Social Functioning, Dyspnea, Appetite Loss, and Fatigue exceeded or approached 5 (generally considered the minimally important difference [MID] to be clinically meaningful), although without statistical significance. Other dimensions directionally favored InO, except Emotional Functioning, Constipation, and Pain, but none approached MID. Conclusions: This is the first time that PROs are reported in a large RCT of ALL. QoL, functioning, and symptoms in R/R ALL patients receiving InO appeared generally better than those receiving SC. These data support the favorable benefit risk ratio of InO for R/R ALL treatment, with superior clinical efficacy that does not compromise patients’ QoL. Clinical trial information: NCT01564784.
Global history and clinical experiences of gene therapy: A brief review.
Authors: Yi Li
Journal: Journal of Clinical Oncology (2017)

e17562 Background: Based on the theoretic and clinical development of modern medicine, gene therapy has been a promising treatment strategy for cancer and other patients. Methods: In the present paper, we reviewed the history and clinical experiences of gene therapy from the aspects of treatment protocol, administration cycle, dosage calculation and evaluation of therapeutic effects, in order to provide more information for the further development of this promising treatment. Results: although the development of gene therapy has not gone smoothly since the beginning of the clinical trials, the results showed that this was a promising treatment for the cancer patients. There are still a lot of researches needed to be done to further solve the theoretic and clinical issues, and to improve the therapeutic effects. Conclusions: In conclusion, although the development of gene therapy has not gone smoothly since the beginning of the clinical trials, the results showed that this was a promising treatment for the cancer patients. There are still a lot of researches needed to be done to further solve the theoretic and clinical issues, and to improve the therapeutic effects. But the future of the gene therapy will be bright, and it will become a new basic strategy to help more patients.
Assessment of actionability of cancer genomic testing panels based on a structured clinical trial knowledge base.
Authors: Mia Alyce Levy, Christine Micheel, Neha Jain, Kathleen F Mittendorf
Journal: Journal of Clinical Oncology (2017)

6533 Background: Today’s oncologist is responsible for choosing appropriate cancer genomics tests to inform patient treatment from multiple available platforms, weighing cost, availability, sensitivity and specificity, and clinical actionability. Knowledge-driven clinical decision support tools can assist clinicians in choosing the panel that is most informative in a given clinical space. Methods: Using a queryable knowledgebase of &gt;1800 active clinical trials containing structured eligibility criteria curations for diagnosis and genomic alterations, we compared two CLIA-regulated genomic panels for clinical actionability over the landscape of solid, breast, and lung cancer clinical trials. Results: The larger panel (73 genes) was more actionable than the smaller panel (62 genes) in the breast cancer (10x more trials returned) and solid tumor (2.7x more trials returned) clinical trial space, while the smaller panel returned 1.2x more trials in the lung cancer space (see table). Conclusions: This analysis demonstrates that patient diagnosis has a significant effect on the potential clinical actionability of a given genomic panel. Further, this analysis demonstrates the clinical utility of knowledge-driven clinical decision support tools for test selection, especially given the often-limited tumor sample available, cost of genomic panel testing, and continuously shifting trial landscape. [Table: see text]
Photochromotherapy for treatment of hemangiomas in children.
Authors: Elena A. Sheiko, Oleg Ivanovich Kit, Yuliya Yu. Kozel, Alla Ivanovna Shikhlyarova, Yury Valentinovich Przhedetskiy
Journal: Journal of Clinical Oncology (2016)

e23187 Background: This study aims to analyze the clinical effects of noncoherent monochromatic red light emitting diodes on infantile hemangiomas (IH) in children from the new-born to one-and-a half year old for the period from 2004 to 2015. Methods: We investigated the effect of PCT (photochromotherapy) of red spectrum λ = 635 nm with irradiation dose 3·86-3·96 J/cm2 to 2010 children with IH. Results: The results showed a significant regression in 100% of simple IH, in 92% of mixed ones and 84.5% of cavernous forms after PCT. Progression of IH was seen only in 1 patient (0.95%) subjected to tumor destruction. After the first course of PCT, regression of simple and mixed IH forms was registered in half of the patients (49.4 and 50.2% respectively), in cases of cavernous IH – only in 15% of children. Ultrasound control demonstrated reduction of tumors' size in 46-71%, decrease of blood flow in 11-22% and formation of capsule in 40% of the cases. After the second and the third courses of PCT proportion of the patients with regression of IH continued to increase. Decrease of tumors' size was found in 98%, blood flow was weak or absent in 96% of cases, clear borders or capsule were determined in 96% of cases, absence of the tumor-feeding vessels – in 80 cases. VEGF levels in sera of patients with IH before the treatment were 221.1±12 pg/ml, which was 3.1 times higher than in healthy children (72.6±3.2 pg/ml). After effective PCT VEGF levels in patients' sera became close to normal (68.9±2.0 pg/ml). In cases of ulcerative complications of IH the positive local effect of PCT on suppuration and inflammation was observed. The clinical PCT practice allowed the effects of wound healing just after the first course (10 procedures). After the second and third courses (about 25-30 procedures), the significant decrease in tumor size up to the regress and formation of scar was observed. Ultrasound control confirmed the absence of tumor feeding vessels. Conclusions: PCT resulted in wound healing by improving the reduced exudative and epitelisation phases; significant decrease in tumor size up to regress was observed.
Tumor-infiltrating lymphocytes (TILs) and PDL1 expression in ovarian cancer (OC): Evolution with neoadjuvant chemotherapy (NCT) and prognostic value.
Authors: Soizick Mesnage, Catherine Genestie, Aurelie Auguste, Erwann Pain, Sebastien Gouy, Philippe Morice, Enrica Bentivegna, Catherine Lhomme, Patricia Pautier, Ariane Dunan, Audrey Le Formal, Julien Adam, Alexandra Leary
Journal: Journal of Clinical Oncology (2016)

5512 Background: Lymphocytic infiltration at diagnosis is prognostic in OC, however how TILs or PDL1 expression change with NCT is unknown. Methods: We identified OC patients (pts, N = 113) treated with NCT from 2002-2014. Stromal TILs (sTILs) were evaluated according to the International TILs Working Group 2014 (Salgado 2015) and intra-epithelial (ieTILs) semi-quantitatively scored (0-3) on whole sections. Cutoffs for analysis were: high sTILs ≥ 50%, high ieTILs ≥ 2, sTILs change post- vs pre-NCT ≥ 10% absolute increase or decrease. PDL1 (E1L3N clone, Cell Signaling) was positive (+) if ≥ 5% immune cells had membranous staining, AFA fixed samples were excluded. Results: In pre-NCT tumors, the level of sTILs varied (range: 2%-90%, median 20%), with 22% (25/113) showing high sTILs. Among evaluable paired samples, sTILS increased significantly post-NCT (median sTILs: 20% vs 30%, P 0.05) with 42/83 (52%) of pts showing increased sTILs after NCT, 21/83 decreased, and 20/83 stable. In pre-NCT tumors median ieTILs score was 1 (0-3), with high ieTILs in 24% of pts. Among pts with paired samples evaluable for PDL1, 63% (17/27) of post-NCT samples were PDL1+ vs only 30% (8/27) of pre-NCT (p = 0.04), and 63% (12/19) went from PDL1- to PDL1+ after NCT. Median follow-up was 52 months (95%CI 41-61). In univariate analysis, every 10% increase in sTILs levels in pre- or post-NCT tumors, resulted in a 12% (HR 0.88, 95%CI 0.79-0.97, P 0.01) or 9% (HR 0.91, 95%CI 0.83-1.0, P 0.04) decrease in relapse event, respectively. As a binary variable, pts with high sTILs pre- or post-NCT had a HR for relapse of 0.46 (95%CI 0.25-0.84, p 0.01) and 0.53 (95%CI 0.32-0.89, P 0.02), respectively. In multivariate analysis controlling for complete resection, grade and BRCA-status, high sTILs pre-CT remained an independent positive prognostic factor (HR 0.49, 95%CI 0.26-0.90 P 0.02). ieTILs and PDL1 expression were not prognostic. Conclusions: In OC, sTILs levels are prognostic at diagnosis and remain prognostic after NCT. TILs and PDL1 increase in more than half of pts following NCT. Evaluation of immune parameters in the post-NCT tumor, may inform appropriate selection of pts for novel maintenance immune strategies.
PET scan-directed chemoradiation (CRT) for esophageal squamous cell carcinoma (ESCC): No benefit for salvage chemo in PET non-responders (PETnr).
Authors: Megan Greally, Joanne F. Chou, Daniela Molena, Valerie W. Rusch, Manjit S. Bains, Bernard J. Park, Abraham Jing-Ching Wu, David Paul Kelsen, Yelena Yuriy Janjigian, David H. Ilson, Geoffrey Yuyat Ku
Journal: Journal of Clinical Oncology (2018)

4055 Background: Pre-operative or definitive CRT is standard for locally advanced (LA) ESCC. We previously showed that PET response after induction chemo and prior to CRT and surgery strongly predicts outcomes (Cancer 118:2820; 2012). The CALGB 80803 study also revealed a benefit for changing chemo during CRT in PETnr with E adenocarcinoma (J Clin Oncol 35:1, 2017 [abstr]). Methods: We retrospectively reviewed all pts with LA ESCC who received induction chemo and CRT; all had PET scan pre- and post-induction chemo. Survival was calculated from date of repeat PET using Kaplan-Meier analysis and compared between groups using the log-rank test. Results: 113 pts were identified, median age 64, median KPS 80%, 75% had uN+ disease. 63 (56%) received induction chemo with platinum/paclitaxel, 43 (38%) with platinum/irinotecan, 6 (5%) with docetaxel/irinotecan +/- cisplatin and 1(1%) with capecitabine/oxaliplatin. 72 pts (64%) were PET responders (PETr; ³35% decrease in mSUV of tumor) and 41 (36%) were PETnr; <35% decrease). All PETr received same chemo during RT. Of PETnr, 16 continued same chemo and 25 were changed to alternate chemo during RT. Of 106 pts evaluable for clinical complete response (cCR), 88% of PETr achieved cCR vs 57% of PETnr/no chemo change vs 60% of PETnr/chemo change (p<0.01 for PETr vs PETnr). The cCR rate was not significantly different in the PETnr/chemo change vs PETnr/no chemo change groups (p=0.86). 31 pts had resection, 30 R0; 8 had pathologic CR (7 were PETr and 1 was a PETnr/chemo change). Median progression-free (PFS; 62.1 vs. 7.1 mos, p<0.01) and overall survival (OS; 72.2 vs. 17.3 mos, p<0.01) were significantly better for PETr vs. PETnr. Median PFS and OS for PETnr/chemo change vs. PETnr/no chemo change were 6.4 vs 8.3 mos (p=0.48) and 14.2 vs 17.2 mos (p=0.79) respectively and not significantly different. Conclusions: PET scan after induction chemo highly predicts for outcomes in ESCC pts who received CRT. However, PETnr pts did not benefit from changing chemo during RT, likely reflecting underlying poor biology. Next generation sequencing is ongoing. Future trials should utilize PET after induction chemo to select PETnr pts to receive experimental therapies.
What oncologists, patients, and families want from published clinical trials and office visits.
Authors: Kenneth Robert Hoffman
Journal: Journal of Clinical Oncology (2017)

e18192 Background: When oncology-related professionals &amp; patients are reading their publications such words as: "may, possibly, might, could, hopefully &amp; perhaps" are used to describe potential improvements in treatment &amp; outcome. Similarly the terms "significant inprovement" &amp; "approval" have different meanings to professionals &amp; their patients &amp; toxicity issues are often not clearly defined. This often leads to misunderstandings about treatment. Methods: To better understand these issues, 4 round table discussions with 16 community oncologists &amp; 4 discussions with 26 patients or family member were held. The basic question was "what's missing" to help make a better treatment decison? Results: From physicians: a lack of clarity on the order of treatment, especially dealing with non-chemotherapy agents was seen. Issues of how &amp; when to judge response to therapy &amp; whether treatment should continue, stop or be changed were clear. There was much confusion as to when &amp; what to order to evaluate diagnostic, prognostic&amp; therapeutic options. Questions on proper randomization based on solid tumor load &amp; location (quality &amp; quantity of disease) and the aggressiveness of supportive care for patients on study vs "standard of care" led to questions on the comparability of reported results &amp; their own clinical practice. Discussing "statistical" vs "clinical" significance &amp; FDA drug "approval" was confusing in discussions with patients. The cost &amp; reimbursement of drugs, whether oral or IV was problematic. From patients &amp; their families, similar concerns were raised. Their frustration was seen by unknown "out of pocket" financial costs &amp; the "hidden costs" of treatment, like supportive care issues, transportation &amp; psychosocial support to the family. However, what the patients and their families wanted more than anything else was for them to be respected: appointments kept on time, empathy &amp; honesty in their discussions with &amp; from caregivers. Conclusions: Clinical articles should have a summary section with information on how to treat today's patients &amp; when possible, treatment costs should be included to help with these discussions. Patients need to be seen as a person with a disease rather than as a disease attached to a person.
Next generation sequencing (NGS) in wild type GISTs.
Authors: Haibo Qiu, Wei Zhuang, Ting Wu, Min Huang, Zhiwei Zhou, Xueding Wang
Journal: Journal of Clinical Oncology (2017)

e22507 Background: The majority driven mutation of GIST are located in KIT and PDGFRA. A proportion of the remaining 10% of GIST without KIT or PDGFRA mutations called wild type GIST (wt-GIST). It is poor response to imatinib, sunitinib or regorafenib in these wt-GIST patients. It is lack of precise drug target of wt-GIST. We analyzed next generation exome sequencing (NGS) results in wt-GISTs. Methods: Whole exome sequencing was performed on freezing tumor tissue and peripheral blood DNA with 100X sequencing depth. The low frequency somatic mutation was confirmed by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) and Sanger sequencing. This study was approved by the ethical committee of Sun Yat-Sen University Cancer Center. Results: A total of 11 wt-GIST samples were analyzed. ROS1 (ROS Proto-Oncogene 1, Receptor Tyrosine Kinase) was mutated in one CD117 negative patients with 5.3% mutation frequency of c. 364G &gt; A (p. A122T). Sanger sequencing couldn’t found the ROS1 mutated in tumor tissue. But this low frequency somatic mutation was verified by MALDI-TOF. Conclusions: This is the first report showed a new ROS1 somatic mutation in wt-GIST. Our results indicated that ROS1 could be a new possible driven mutation in wt-GIST. ROS1 rearrangement have been described in a subset of non-small-cell lung cancers (NSCLC). Crizotinib shows a potent curative effect in ROS1 rearrangement NSCLC. Therefore, crizotinib might be an appropriate drug to GIST patients with mutated ROS1.
High, durable minimal residual disease negativity (MRD–) with venetoclax + rituximab (VenR) in relapsed/refractory (R/R) CLL: MRD kinetics from phase 3 MURANO study.
Authors: Peter Hillmen, Arnon P. Kater, John Francis Seymour, Anton W Langerak, Barbara Eichhorst, Carolyn Owen, Sarit E. Assouline, Ann Janssens, Paula Marlton, Xavier C. Badoux, Rogier Mous, Brenda Chyla, Rod Humerickhouse, Michelle Boyer, Kathryn Humphrey, Yanwen Jiang, Elizabeth Punnoose, Jue Wang, Qun Jenny Wu, Mehrdad Mobasher
Journal: Journal of Clinical Oncology (2018)

7508 Background: Survival with chemoimmunotherapy is associated with MRD–, but the importance of MRD with targeted agents and in R/R setting remains unclear, mostly due to low MRD– rates. In MURANO, VenR showed superior PFS (hazard ratio 0.17) and peripheral blood (PB) and bone marrow (BM) MRD– vs bendamustine + R (BR) in R/R CLL pts. We now report MRD kinetics. Methods: Pts randomized to VenR for 6 mo. followed by single-agent Ven ≤1.5 y, or BR for 6 mo. PB samples serially collected and BM at end of combination treatment (EOCT; Mo. 9) or at best response; MRD analyzed centrally by ASO-PCR and/or flow cytometry; MRD–: < 1 CLL cell/104 leukocytes. Results: Higher concordance in MRD– between BM and PB in VenR (45/50 [90%]) vs BR (3/10 [30%]) in pts with paired samples. Thus, we focus on PB MRD and outcome. Best MRD– rates were higher with VenR (84% vs 23% in BR), and were independent of high-risk factors only for VenR: del(17p), IGVH unmutated and mutated TP53 (present vs non-present: 83% vs 87%, 82% vs mutated 89% and 73% vs unmutated 88% respectively). PB MRD kinetics for VenR are shown in Table. Among 121/194 (62%) pts on VenR and MRD– at EOCT: 100 (83%) maintained MRD– and were PFS free at median follow-up (f/u) of 13.8 (5.6–23.0) mo.; 2 developed PD; 2 died (unrelated); 2 developed Richter’s (with one MRD+ directly before); and 15 (12%) converted to confirmed MRD+ (2 serial assay positive) at median MRD+ f/u of 5.6 (0.03–11.2) mo. (1 MRD ≥10-2 with PD, 14 MRD 10-4– < 10-2 with 2 PD, 1 death and 11 PFS free). MRD kinetics by arm will be presented graphically. Conclusions: Robust PB MRD and high concordance with BM MRD with VenR confirms value of PB MRD for correlation with clinical outcome. VenR achieves high, early, deep, durable PB MRD–regardless of risk features, unlike BR. Some reemergence of MRD+, mainly intermediate level, is seen only in a small number of pts, and may not lead to clinical PD, consistent with PFS benefit observed. Clinical trial information: NCT02005471.VenR MRD kinetics. N = 194, % Assessment timepoint, mo. 4* 9† 12 15 18 Negative: < 10-4 45 62 60 57 60 Positive Intermediate: 10-4– < 10-2 25 19 16 10 18 ≥10-2 6 5 4 4 5 Assay failure 2 1 1 10 1 Missing or progressive disease/death/withdrew 22 13 19 19 16 *1st assessment †EOCT
Abstract 14105: Does Venous Thromboembolism (VTE) Prophylaxis Impact Hospital-Acquired VTE Events for Patients on Dual Antiplatelet Therapy (DAPT)
Authors: Michael Riordan, Kai Ha, Abhishek Sarkar, Laura Willett, James Prister
Journal: Circulation (2017)

Introduction: Though there are specific guidelines for Venous Thromboembolism (VTE) prophylaxis in medical and surgical patients, the guidelines do not explicitly address patients on DAPT. We aim t...
TCT-84 Percuatenous Extracorporeal membrane oxygenation (ECMO) utilization in Real World All Comers Population with Refractory Cardiac Arrest
Authors: Sachin Kumar, Bindu Akkanti, Sriram Nathan, Marwan Jumean, Manish Patel, Mehmet Akay, Kriti Taneja, Igor Gregoric, Biswajit Kar
Journal: Journal of the American College of Cardiology (2018)
Association of Trauma Type, Age of Exposure, and Frequency in Childhood and Adolescence With Psychotic Experiences in Early Adulthood
Authors: Jazz Croft, Jon Heron, Christoph Teufel, Mary Cannon, Dieter Wolke, Andrew Thompson, Lotte Houtepen, Stanley Zammit
Journal: JAMA Psychiatry (2018)

Cross-sectional and longitudinal studies have consistently reported associations between childhood trauma and psychotic experiences and disorders. However, few studies have examined whether the age of exposure or specific trauma types are differently associated with the risk of developing psychotic experiences.