tbuckley/cabot-search huggingface dataset:
Identification of predictive markers of clinical activity from a phase II trial of single agent pertuzumab (rhuMab 2C4), a HER dimerization inhibitor, in advanced ovarian cancer (OC)
Authors: L. Amler, M. S. Gordon, A. Strauss, N. Rabbee, M. K. Derynck, K. Krueger, D. A. Eberhard, D. Matei, B. Y. Karlan
Journal: Journal of Clinical Oncology (2006)

3001 Background: Pertuzumab (P), a humanized HER2 antibody, represents a new class of targeted agents called HER dimerization inhibitors (HDIs). P inhibits dimerization of HER2 with EGFR, HER3 and HER4, and subsequently inhibits signaling through MAP and PI3 kinases. Interim data from a phase II trial suggested that P has activity in OC, especially in a subset of tumors with activated HER2 (Abstract #5051 ASCO 2005). Methods: 123 pts with relapsed OC were treated with P. Cohort 1 was treated with 840mg followed by 420mg and cohort 2 with 1050mg every 3 weeks. Fresh tissue biopsies were mandated from Cohort 1, and archival formalin fixed paraffin tissue (FFPET ) were obtained from both cohorts. Molecular expression studies from FFPET and fresh tissue were conducted. Results: From final data of 117 evaluable pts, 5 pts had objective partial responses (RR = 4.3%). Eight pts (6.8%) had SD for ≥ 6 months, and an additional 4 pts (3.4%) had SD with CA-125 reduction of ≥50%. Overall rate of activity = 14.5%. Of the 65 fresh tumor biopsies, 28 were evaluable and 8 (28.6%) were positive for phosphorylated HER2 (pHER2) by ELISA. Among pts who had pHER2 status determined, TTP was 20.9 weeks for pHER2+ pts (n=8), compared to 5.8 weeks for pHER2- (n = 20). Data from microarray expression profiling were analyzed with respect to pHER2 status from the same tumors. The expression levels of HER2, EGFR and HER3 in combination with the expression of certain HER ligands may be predictive of pHER2 status. We have extended these analyses to qRT-PCR from macrodissected FFPET of HER receptors and ligands. This was analyzed with respect to clinical outcome. Preliminary analyses of expression data suggest that HER receptors and ligands may be promising candidates for diagnostic markers. Updated data in 78 OC pts will be presented. Conclusions: Clinical activity was observed in 14.5% of pts with heavily pretreated OC (PRs, SD ≥ 6 months, and SD with CA-125 reductions of ≥50%). This study suggests that P may be active in OC, and that specific HER receptors and ligands may be promising diagnostics for identifying tumors responsive to P. [Table: see text]
circMYBL2, a circRNA from MYBL2, regulates FLT3 translation by recruiting PTBP1 to promote FLT3-ITD AML progression
Authors: Yu-Meng Sun, Wen-Tao Wang, Zhan-Cheng Zeng, Tian-Qi Chen, Cai Han, Qi Pan, Wei Huang, Ke Fang, Lin-Yu Sun, Yan-Fei Zhou, Xue-Qun Luo, Chengwei Luo, Xin Du, Yue-Qin Chen
Journal: Blood (2019)
White Matter in Schizophrenia Treatment Resistance
Authors: Peter Kochunov, Junchao Huang, Song Chen, Yanli Li, Shuping Tan, Fengmei Fan, Wei Feng, Yunhui Wang, Laura M. Rowland, Anya Savransky, Xiaoming Du, Joshua Chiappelli, Shuo Chen, Neda Jahanshad, Paul M. Thompson, Meghann C. Ryan, Bhim Adhikari, Hemalatha Sampath, Yimin Cui, Zhiren Wang, Fude Yang, Yunlong Tan, L. Elliot Hong
Journal: American Journal of Psychiatry (2019)

Failure of antipsychotic medications to resolve symptoms in patients with schizophrenia creates a clinical challenge that is known as treatment resistance. The causes of treatment resistance are unknown, but it is associated with earlier age at onset and more severe cognitive deficits. The authors tested the hypothesis that white matter deficits that are involved in both neurodevelopment and severity of cognitive deficits in schizophrenia are associated with a higher risk of treatment resistance.The study sample (N=122; mean age, 38.2 years) included schizophrenia patients at treatment initiation (N=45), patients whose symptoms were treatment responsive (N=40), and patients whose symptoms were treatment resistant (N=37), as well as healthy control subjects (N=78; mean age, 39.2 years). White matter regional vulnerability index (RVI) was tested as a predictor of treatment resistance and cognitive deficits. Higher RVI is indicative of better agreement between diffusion tensor imaging fractional anisotropy across the brain in an individual and the pattern identified by the largest-to-date meta-analysis of white matter deficits in schizophrenia.Patients with treatment-resistant symptoms showed the highest white matter RVI (mean=0.38 [SD=0.2]), which was significantly higher than the RVI among patients with treatment-responsive symptoms (mean=0.30 [SD=0.02]). At the onset of treatment, schizophrenia patients showed significantly higher RVI than healthy control subjects (mean=0.18 [SD=0.03] and mean=0.13 [SD=0.02], respectively). RVIs were significantly correlated with performance on processing speed and negative symptoms.Schizophrenia affects white matter microstructure in specific regional patterns. Susceptibility to white matter regional deficits is associated with an increased likelihood of treatment resistance. Developments to overcome schizophrenia treatment resistance should consider white matter as an important target.
Abstract 4798: Genetically engineered mouse models of proliferative C5 high grade serous ovarian cancer
Authors: Clare L. Scott, Gwo Y. Ho, Elizabeth E. Lieschke, Olga Kondrashova, Ronny Drapkin, David Bowtell, Matthew J. Wakefield
Journal: Cancer Research (2017)

Abstract Introduction: High-grade serous ovarian cancer (HGSOC) can be divided into four subgroups based on molecular characteristics1,2. The proliferative/C5 subgroup is defined by MYCN-pathway activation and may be associated with stem cell-like behavior3. The majority of HGSOC originate from the secretory cells of the fallopian tube (FT), with both tumours and secretory cells characterised by PAX8 expression4. We have developed pre-malignant C5 sub-type Genetically Engineered Mouse Models (GEMM) to characterise key molecular events in the initiation of this sub-type and to provide an immune-competent model for testing therapeutics. Methods: We have generated independent GEMM with p53 dysfunction (p53lsl-R172H knock-in5) and over-expression of the MYCN-pathway, using either lsl-MYCN or lsl-lin28b transgenes6 directed by the doxycycline-inducible PAX8 promoter. Murine FT were harvested following two-weeks of transgene activation. One FT was harvested en bloc and paraffin embedded for analysis by H&amp;E and immunohistochemistry for the presence of pre-malignant tubal lesions. The contralateral FT was macro-dissected into distal/mid-FT, which were snap frozen for analysis of gene expression by qRT-PCR and RNAseq. As mice with PAX8-directed expression of oncogenes (±MYCN/lin28b overexpression) developed enlarged kidneys due to renal tubular adenomata, for alternate mice, the mid/distal FT tissue was implanted into the bursae of wild-type CBA/nu mice for observation and later analysis. Results: FT were harvested from twelve p53lsl-R172H/lsl-lin28b mice and from ten p53lsl-R172H/lsl-MYCN mice (including relevant control mice). Dysplastic lesions were observed in a subset of p53lsl-R172H/lsl-MYCN or lsl-lin28b FT and not in controls. MYCN pathway activation was demonstrated by qRT-PCR analysis. Conclusion: Over-expression of the MYCN-pathway can drive FT epithelial dysplasia in the presence of p53 dysfunction. RNASeq analysis is being performed to elucidate early genetic events in dysplastic FT. Mice are now being harvested after eight-weeks of doxycycline activation to determine whether more advanced pre-malignant change occurs. CRISPR guides deleting relevant genes including p53, PTEN, Nf1 or Rb1 were generated to delete additional genes in MYCN pathway-transgenic FT, followed by implantation for observation of tumourigenesis. Note: This abstract was not presented at the meeting. Citation Format: Clare L. Scott, Gwo Y. Ho, Elizabeth E. Lieschke, Olga Kondrashova, Ronny Drapkin, David Bowtell, Matthew J. Wakefield. Genetically engineered mouse models of proliferative C5 high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4798. doi:10.1158/1538-7445.AM2017-4798
Efficacy and safety of anlotinib in advanced soft tissue sarcoma: results from one of multi-centers in a phase IIB trial (ALTER0203).
Authors: Lina Tang, Yonggang Wang, Jianjun Zhang, Wenxi Yu, Yujing Huang, Yang Yao
Journal: Journal of Clinical Oncology (2019)

e22518 Background: There is no standard therapy for soft tissue sarcoma (STS) patients progressing after first-line chemotherapy. Anlotinib significantly prolonged PFS in advanced STS patients in the earlier results of ALTER0203. In view of regional differences, we further analysis results from Affiliated Sixth People’s Hospital, Shanghai Jiaotong University, one center in this IIB trial. Methods: Patients aged from 18 to 70 with advanced STS, progressing after anthracycline-based chemotherapy (not adapted to alveolar soft part sarcoma (ASPS) and clear cell sarcoma (CSC)), angiogenesis inhibitor naive, at least one measurable lesion according to RECIST 1.1, were eligible. Patients were randomised in a 2:1 ratio to receive anlotinib (12 mg per day 2 weeks on and 1 week off) or placebo. Primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate (ORR), disease control rate (DCR). Results: This center of ALTER0203 enrolled 48 eligible patients who received either anlotinib (n = 32) or placebo (n = 16). Leiomyosarcoma (LMS) (13/48), ASPS (12/48), synovial sarcoma (SS) (11/48) were major subtypes. The median PFS was 1.57 months (95% CI: 1.19-1.95) for placebo versus 6.27 months (95% CI: 1.89-10.65) for anlotinib ( P= 0.009). ORR was 0% (0/16) for placebo versus 18.75% (6/32) for anlotinib ( P= 0.16); DCR was 18.75% (3/16) for placebo versus 56.25% (18/32) for anlotinib ( P= 0.02). The most common adverse events (AEs) were hypertension, elevated TSH, hypertriglyceridaemia (HTG). The most common Grade ≥3 AEs were menstrual disorder, hypertension, gamma glutamyl transferase (GGT) elevation and lipase elevation. Conclusions: The efficacy and safety of anlotinib is further confirmed in advanced STS patients regarding regional differences. Clinical trial information: NCT02449343. [Table: see text]
Stage III non-small cell lung cancer: Who passes the threshold?
Authors: Magda Palka, Andrea Ruiz-Valdepeñas, Bernard Gaston Doger de Speville, Patricia Ibeas, David Perez Callejo, Elena Almagro, Miriam Huelves, Miriam Mendez, Constanza Maximiano, Mariano Provencio-Pulla
Journal: Journal of Clinical Oncology (2012)

e17502 Background: Objective: The objective of the study is to indentify the patients diagnosed of stage III non-small cell lung cancer (NSCLC) in Puerta de Hierro Madrid Hospital (Spain) between 2000 and 2008, who had longer overall survival rates (more than 24 months) and longer time to progression after completing initial treatment. Methods: We revised all cases of NSLC seen in our hospital, and of those, selected 147, the ones diagnosed, treated and followed completely in our hospital. We reviewed the age at diagnosis, initial staging, modalities of treatment received in each case, time to progression, site of development of metastasis, time to relapse and overall survival. The time of monitoring was from date of diagnosis until death date or, until transferral to palliative care clinics. Results: We revised 966 histories of patients, of which 147 were diagnosed stage III, treated and followed in our hospital. Most common hystological type were Epidermoid Carcinomas (54.3% versus 21.7% of adenocarcinomas), and were diagnosed at older ages. 45.6% underwent surgery, most of them (41.2%) were treated before with neoadyuvant chemo or radiotherapy, with a median survival of 32.4 months, with an overall survival interval very wide, from 20 days until more than 8 years. Among these patients were the ones who survived more than 24 moths after diagnosis, and those had Ps 0 -1 at diagnosis, less comorbidities and had the same proportion of stage IIIA and IIIB stages. 53% of patients were only treated with cisplatin-based chemotherapy or radiotherapy at 60Gy, and in these cases, the median overall survival was shorter: 9.5 months Conclusions: In our study, neoadyuvant therapies and the protocols used are the most accepted in international guidelines. The patients who underwent chemotherapy and surgery lived much more and they had better Performance Status at diagnosis, so we can conclude that chemotherapy and surgery, if possible, are a good treatment option with longer global survival. Definitive chemotherapy and radiotherapy should be better reserved for those patients who are not candidates for surgery.
Erythropoietin Level and Percentage of Urinary Albumin Are Important for Renal Recovery in Patients with Multiple Myeloma Receiving Novel Agents
Authors: Hiroki Kobayashi, Yoshiaki Abe, Daisuke Miura, Kentaro Narita, Akihiro Kitadate, Masami Takeuchi, Kosei Matsue
Journal: Blood (2018)
Medical encounters, cardiac arrests and deaths during a 109 km community-based mass-participation cycling event: a 3-year study in 102 251 race starters—SAFER IX
Authors: Jannelene Killops, Martin Schwellnus, Dina Christina Janse van Rensburg, Sonja Swanevelder, Esme Jordaan
Journal: British Journal of Sports Medicine (2019)

There are few data on medical encounters, including deaths during mass-participation cycling events.To determine the incidence and nature of medical encounters during a community-based mass-participation cycling event.Cross-sectional study across three annual events.2012-2014 Cape Town Cycle Tour (109 km), South Africa.102 251 race starters (male=80 354, female=21 897).Medical encounters (moderate, serious life-threatening, sudden cardiac arrest/death), using the 2019 international consensus definitions, were recorded on race day for 3 years as incidence rates (IR per 1000 starters; 95% CI). Overall illness-related (by organ system) or injury-related (by anatomical region) encounters, and severity were recorded.We recorded 539 medical encounters (IR 5.3; 4.8 to 5.7). The IR was 3.2 for injuries (2.9 to 3.6), 2.1 for illnesses (1.0 to 2.4) and 0.5 for serious life-threatening medical encounters (0.4 to 0.7). In the 3-year study, we encountered three cardiac arrests and one death (2.9 and 1.0 per 100 000 starters, respectively). Injury IRs included upper limb (1.9; 1.6 to 2.1), lower limb (1.0; 0.8 to 1.0) and head/neck (0.8; 0.6 to 1.0). Illness IRs included fluid/electrolyte abnormalities (0.6; 0.5 to 0.8) and the cardiovascular system (0.5; 0.4 to 0.6).In a 109 km community-based mass-participation cycling event, medical encounters (moderate to severe) occurred in about 1 in 200 cyclists. Injury-related (1/300 cyclists) encounters were higher than illness-related medical encounters (1 in about 500). Serious life-threatening medical encounters occurred in 1/2000 cyclists. These data allow race organisers to anticipate the medical services required and the approximate extent of demand.
Usability testing of the PRO-CTCAE measurement system in patients with cancer.
Authors: Maria R. Fawzy, Amy Pickar Abernethy, Martin W. Schoen, Lauren J. Rogak, Tito R. Mendoza, Diane C. St. Germain, Diane B. Paul, Paul Baumgartner, Vinay Gangoli, Ram Chilukuri, Sandra A. Mitchell, Bryce B. Reeve, Kathleen M. Castro, Eve Shalley, Ethan M. Basch
Journal: Journal of Clinical Oncology (2013)

e17560 Background: Use of electronic Patient-Reported Outcomes (ePROs) are increasingly employed in patient care and oncology research. However, these systems can be difficult to use, preventing adoption and deployment. The objective is to evaluate the patient usability of the National Cancer Institute’s (NCI) Patient Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) Measurement System. Methods: PRO-CTCAE is an item bank of 124 questions evaluating 78 symptomatic adverse events, as well as a software system that includes a web-based and interactive voice response system [IVRS] to administer these items to patients, and electronic features to customize survey creation, schedule survey administration, export data, and generate alerts and reports. A protocol was developed for two rounds of usability testing to evaluate understanding and ease of navigation reported by patients undergoing cancer treatment. Software was refined between rounds and retested. Patients were asked to login and complete PRO-CTCAE items either in clinic or at home, then were immediately debriefed (semi-scripted) by a trained interviewer. Results: 173 patients at 3 cancer centers and affiliated community network sites were enrolled in the study between 1/11-5/12 (45% male; 32% non-white; 26% high school or less). Usability issues identified in Round 1 (N=37) included difficulty in using radio buttons, absence of survey progress indicators, and problems with system login. Modifications included increasing size of buttons, improving the progress bar feature, and simplifying the interface to focus users on survey questions. In Round 2 (N=136), remaining issues were related to general difficulty with Internet use, such as navigating to the URL. IVRS testing indicated high scores of ease of use and completion of items, but users had difficulty adding unique symptoms to the system. Conclusions: Iterative usability testing identified improvements to web-based and IVRS for patient self-reporting and achieved a more favorable user experience. The feasibility of integrating PRO-CTCAE into trials to gather symptomatic adverse events directly from patients is currently being evaluated in the cancer cooperative groups.
Tolerability of split-dose oprozomib (ONX 0912) in patients with advanced refractory or recurrent solid tumors.
Authors: Kyriakos P. Papadopoulos, David S. Mendelson, Anthony W. Tolcher, Howard A. Burris, Michael S. Gordon, Darrin Bomba, Heidi H. Gillenwater, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2012)

e13077 Background: Oprozomib (ONX0912), a structural analog of carfilzomib, is an orally bioavailable proteasome inhibitor that irreversibly binds to its target and is being evaluated in hematologic malignancies and solid tumors (ST). In a dose-escalation study of once-daily (qd) ONX0912, the maximum tolerated dose (MTD) was 150 mg/d. The protocol was subsequently amended to investigate the effects of a split-dose schedule. Presented here are the interim results from this patient (pt) group. Methods: This is an ongoing, phase 1 study in pts with advanced refractory or recurrent ST. The primary objective is to evaluate the safety and tolerability of ONX0912 and determine the MTD. ONX0912 is administered for 5 consecutive days in 14-day cycles. For pts under the amended regimen, treatment is initiated at 60 mg BID, with 4–6 h between doses. Daily doses are escalated in 30 mg increments in successive groups of 3 pts. Groups are expanded to include 6 pts in the event of a dose-limiting toxicity (DLT) or if the MTD is reached. All AEs, including serious AEs (SAEs), are defined per protocol and collected from screening to 30 days after the last dose. Results: 13 pts received a split dose of ONX0912 (4 pts: 60 mg BID; 3 pts: 90/60 mg; 6 pts: 90 mg BID). At least 1 dose reduction was required by 1 pt in the 90/60 mg group and 2 pts in the 90 mg BID group. 9 pts reported treatment-related GI AEs (vomiting, n=9; nausea, n=8; diarrhea, n=5). 2 SAEs, arthralgia and mental status change, were reported at 60 mg BID. 2 SAEs resulting in a dose delay were reported at 90/60 mg (Grade 3/4 anemia [ongoing, also required a dose reduction] and reversible fatigue). There was 1 DLT at 90 mg BID (Grade 3 reversible hypophosphatemia), and this cohort was therefore expanded. Treatment-related vomiting led to discontinuation for 1 patient at 60 mg BID. No AEs led to early withdrawal, and no deaths have been reported in the study. Conclusions: With qd administration, the MTD of ONX0912 was established at 150 mg/d. However, the MTD has not been reached on the split-dose regimen at cumulative doses up to 180 mg/d (90 mg BID). GI AEs were the most common treatment-related AEs. Based on these preliminary observations, split-dose ONX0912 may improve tolerability over qd dosing.
Abstract 1193: S100A proteins play immune regulatory roles in tumor microenvironment
Authors: Nobuyuki Tanaka, Natsumi Kodake, Naoko Ogama
Journal: Cancer Research (2019)

Abstract S100A proteins are Ca2+ binding multifunctional molecule in different cellular compartments. Dysregulated expression of S100A is often observed in many types of human cancers, and is assoiciated with cancer pathogenesis. Inside a cell, S100A proteins respond to various stimuli, and some typical intracellular functions such as cytoskeleton control and motility have been extensively studied. Extracellular functions of S100A proteins have recently emerged, and they bind innate immune receptors such as TLR4 and RAGE. Nevertheless, the mode of S100A secretion has been obscure. We designed a secretion system to induce spontaneous S100A release from the cell, and examined their roles towards tumor microenvironment. We found S100A proteins are included in exosomes, and the stability of S100A contributes to their extracellular functions. Using a syngeneic tumor model, we investigated some S100A proteins show immune regulatory functions on tumor-associated macrophages. These results suggest that S100A secretion affects tumor immune environment. Note: This abstract was not presented at the meeting. Citation Format: Nobuyuki Tanaka, Natsumi Kodake, Naoko Ogama. S100A proteins play immune regulatory roles in tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1193.
Induction Therapy for AML with 90 Mg/m² Daunorubicin Results in Higher Troponin T Serum Levels in Comparison to Treatment with 60 Mg/m² Daunorubicin
Authors: Stefan D Dendorfer, Michael Kramer, Katharina Schmidt-Brücken, Friedrich Stoelzel, Regina Herbst, Richard Noppeney, Zdenek Racil, Jiri Mayer, Björn Steffen, Tilman Bochtler, Alwin Krämer, Carsten Müller-Tidow, Kerstin Schäfer-Eckart, Andreas Burchert, Andreas Neubauer, Claudia D. Baldus, Christoph Schliemann, Martin Kaufmann, Edgar Jost, Ralph Naumann, Sebastian Scholl, Andreas Hochhaus, Hubert Serve, Wolfgang E. Berdel, Gerhard Ehninger, Martin Bornhäuser, Christoph Rollig
Journal: Blood (2017)