tbuckley/cabot-search huggingface dataset:
Preliminary evaluation of a novel blood test to predict delayed nausea for breast cancer patients.
Authors: Kinjal Parikh, Yue Wang, Amy L Brady, Zonera A. Ali, Aarti Lothe Shevade, Erik L. Zeger, Paul Gilman, Margaretha Wallon
Journal: Journal of Clinical Oncology (2017)

e18210 Background: We have previously reported on glutathione recycling capacity (GRC) in red blood cells as a predictor of delayed nausea in cancer patients treated with platinum-based chemotherapies [1]. The test identifies individual variations in the efficiency to scavenge reactive oxygen species, produced by chemotherapy-induced cell-damage, which triggers release of serotonin – a know inducer of chemotherapy-induced nausea and vomiting. In this current study, we have examined if the GRC assay and/or changes in substance P (SP), another inducer of nausea, can predict delayed nausea among breast cancer patients receiving doxorubicin- or taxane-based therapies and thereby provide better guidance to individualized antiemetic therapies. Methods: Chemotherapy naïve breast cancer patients were asked to participate in this IRB-approved study. Consented patients donated a tube of blood prior to each treatment cycle. Commercial kits were used to measure GRC (OxPhos, Rockland Inc.) and Substance P (Parameter, R&amp;D Systems). On-set, duration and severity of nausea, and anti-emetics prescribed were documented by the medical staff. Results: Obtained GRC and SP values were compared to documented incidences of nausea. We found that 26.8% of taxane treated patients [N = 42] had moderate/severe nausea and demonstrated a similar GRC pattern to platinum-based induced nausea, i.e. low GRC results in more severe nausea. Among doxorubicin treated [N = 31] patients, 41.9% had moderate/severe nausea but showed no correlation with GRC. However, preliminary evaluation of these patients showed a continuous increase in SP levels (average 1.74 fold increase after one cycle). Conclusions: In this initial evaluation of our on-going study, we found that fewer patients had nausea in the taxane treated group with a similar GRC predictive pattern as previously reported. However, patients in the doxorubicin treated group were more likely to experience nausea with no correlation to GRC but with a steadily rising level of SP during the early part of their regimen. Using SP testing could help identify patients that might have a medical benefit from additional NK1 antagonist therapy. 1. Kutner, T., et al. Supprot Care Cancer (2017) 25:581-587.
Systemic treatment preferences for patients with advanced desmoid-type fibromatosis (DF) in Europe.
Authors: Thomas Van Cann, Annelies Requilé, Patrick Schoffski
Journal: Journal of Clinical Oncology (2017)

e22523 Background: The treatment of DF as a rare, benign mesenchymal tumor is poorly standardized and based on physician’s choice. Only a few clinical trials have assessed the different treatment options in DF and randomized evidence is virtually non-existing. We evaluated systemic treatment preferences for patients (pts) with advanced DF among European sarcoma experts, aiming to provide a reference for a generally acceptable control treatment for potential prospective randomized trials. Methods: A 7-item structured questionnaire was sent to physicians in Europe and Israel involved in the multidisciplinary care and experimental treatment of mesenchymal tumors, to assess their systemic treatment choices for DF. Results: The questionnaire was sent to 266 experts (117 institutions, 21 countries), 54 experts (52 institutions, 14 countries) responded. Wait and see was the most common primary approach for pts with advanced DF. (Symptomatic) Disease progression and failure or non-availability of local treatment options were cited as common reasons for considering systemic therapy. Treatment preferences for pts with sporadic vs hereditary DF were similar, with a tendency of earlier use of chemotherapy in hereditary DF. At least 28 different agents or regimens are used in DF. Tamoxifen +/- nonsteroidal anti-inflammatory agents (NSAIDs) or NSAIDs alone are most commonly used in first line, followed by methotrexate- or anthracycline-containing regimen. Tyrosine kinase inhibitors are often used in further lines; other drugs are sporadically used. Clinical trial activity in DF was restricted to only one country/one multi-centric study. Conclusions: DF pts in Europe and Israel have broad off label access to systemic agents, but only to a few clinical trials. Treatment approaches are diverse, poorly standardized and based on weak evidence. There is an urgent need for practice-defining, prospective randomized trials. Such trials should ideally select a homogeneous population of pts with well documented, progressive, symptomatic disease and/or functional impairment after wait and see and/or local treatments. NSAIDs +/- tamoxifen could be considered a generally accepted standard control treatment for clinical trials.
Third-line treatment: A randomized, double-blind, placebo-controlled phase III ALTER-0303 study—Efficacy and safety of anlotinib treatment in patients with refractory advanced NSCLC.
Authors: Baihui Han, Kai Li, Qiming Wang, Yizhuo Zhao, Li Zhang, Jianhua Shi, Zhehai Wang, Ying Cheng, Jianxing He, Yuankai Shi, Weiqiang Chen, Xiuwen Wang, Yi Luo, Kejun Nan, Faguang Jin, Baolan Li, Yinglan Chen, Jianying Zhou, Donglin Wang
Journal: Journal of Clinical Oncology (2017)

9053 Background: Anlotinib hydrochloride, an oral TKI targeting VEGFR, FGFR, PDGFR and c-Kit, showed promising efficacy in PhaseⅡstudy. Here, we evaluated the efficacy and safety of anlotinib as third-line treatment for advanced NSCLC, a randomized, double-blind, placebo-controlled Phase Ⅲtrial (ALTER-0303). Methods: Eligible ⅢB/Ⅳ NSCLC pts who progressed after at least 2 lines of prior therapies were randomized 2:1 to receive anlotinib or placebo (12 mg QD from day 1 to 14 of a 21-day cycle) till progression or intolerable toxicity. Enrolled pts harboring EGFR or ALK mutations must had failed in previous match-targeted therapies. The primary endpoint is OS; secondary endpoint includes PFS, DCR and ORR. Results: As of Aug 2016, total of 437 pts from 31 sites were randomized. The baseline characteristics of Anlotinib arm (N=294) and placebo arm (N=143) were well balanced in the age, gender, ECOG PS and gene states. With 292 OS events (66.82%), significant superiorities in OS, PFS, DCR and ORR were observed in Anlotinib arm according to investigator-assessed results. Grade ≥ 3 treatment-related AEs were hypertension, dermal toxicity and hypertriglyceridemia. There was no treatment–related death in either arm. (Data presented in the Table.) Conclusions: ALTER-0303 trial met its primary endpoint. Anlotinib significantly improved OS and PFS in advanced NSCLC with a manageable safety profile. The results strongly suggest that anlotinib should be considered as a candidate for the third-line treatment or beyond in advanced NSCLC. Clinical trial information: NCT02388919. [Table: see text]
Telemedical Interventional Management in Heart Failure II (TIM‐HF2), a randomised, controlled trial investigating the impact of telemedicine on unplanned cardiovascular hospitalisations and mortality in heart failure patients: study design and description of the intervention
Authors: Friedrich Koehler, Kerstin Koehler, Oliver Deckwart, Sandra Prescher, Karl Wegscheider, Sebastian Winkler, Eik Vettorazzi, Andreas Polze, Karl Stangl, Oliver Hartmann, Almuth Marx, Petra Neuhaus, Michael Scherf, Bridget‐Anne Kirwan, Stefan D. Anker
Journal: European Journal of Heart Failure (2018)
Strengthening the scientific backbone of the WPA
Authors: Thomas G. Schulze
Journal: World Psychiatry (2018)

As per WPA by-laws, the overarching aims of the Scientific Sections comprise the “collection, analysis, presentation, and dissemination of information concerning services, research, and training in the various fields of psychiatry and mental health and the advancement of scientific knowledge in these fields”. This is a lot, and may be considered quite ambitions by some. But, on the other hand, the Sections have become known as the “scientific backbone” of the WPA and, as such, they are meant to carry a lot of weight and provide a framework for our field, that is so diverse and deals with disorders that present with a combined lifetime prevalence of up to 40 percent. This diversity certainly is one of the reasons why the number of Sections has now grown to 72. Given this importance for WPA, the post of Secretary for Scientific Sections comes with a great deal of responsibility and calls for a continuous thought process on how to further develop the Sections and keep them engaged. These proposals will be tightly coordinated with the plans and work programs of the new Secretaries for Education and Scientific Publications, as well as the newly established Science Committee. Their implementation and integration in WPA's Action plan is currently discussed at the level of the WPA Executive Committee and Board. The Secretary for Scientific Sections welcomes any further suggestions as to the future work and visibility of the Sections, WPA's scientific backbone.
Comprehensive genomic sequencing for triple negative breast cancer in Japan.
Authors: Masayuki Nagahashi, Tetsu Hayashida, Yuko Kitagawa, Manabu Futamura, Kazuhiro Yoshida, Takashi Kuwayama, Seigo Nakamura, Chie Toshikawa, Hideko Yamauchi, Koji Kaneko, Nobuaki Sato, Junko Tsuchida, Kizuki Yuza, Yoshifumi Shimada, Hiroshi Ichikawa, Jennifer E. Ring, Stephen Lyle, Shujiro Okuda, Kazuaki Takabe, Toshifumi Wakai
Journal: Journal of Clinical Oncology (2017)

e23122 Background: Breast cancer is the leading cancer among women both in US and Japan. Triple negative breast cancer (TNBC) is the subset of breast cancers that are negative for estrogen receptor (ER), progesterone receptor, and HER2. While the selective ER modulator tamoxifen or anti-HER2 therapy for breast cancer patients with ER positive or HER2 protein overexpression are the most successful examples of targeted therapies, only limited therapies are available for patients with TNBCs, which are associated with a poor prognosis. Advance in next-generation sequencing enables us to identify actionable driver mutations that can be potentially treated by targeted therapies in each cancer patient. The aim of this study is to examine actionable driver mutations in TNBCs in Japan by comprehensive genomic sequencing (CGS) with 435 gene panel, and compare the driver events in Japan with TCGA database to validate the utility of CGS. Methods: We examined all exons of 435 known cancer genes in Japanese TNBC patients (N = 53) by CGS and evaluated for concordance among independent data obtained from The Cancer Genome Atlas-TNBC whole exome sequencing database (N = 123). Results: Oncogenic driver mutations were identified in 51 of 53 Japanese patients (96%) with TNBC and 36 of 53 patients (67%) harbored mutations in genes associated with FDA-approved targeted therapies, indicating the potential clinical utility of a large gene panel for evaluating patients with TNBC. Among 80 total genetic alterations, frequently mutated genes ( &gt; 10% patients) were TP53, PIK3CA and PTEN. Overall, the mutation spectrum of the Japanese patients is similar to that of the TCGA population, except amplification of MYC. Conclusions: Use of a CGS panel of 435 genes can reliably identify all of the critical mutations in TNBC patients, which are similar as TCGA data. The information derived from CGS can be used to determine the optimal treatment for TNBC patients.
Subsequent malignant neoplasms (SMNs) among non-irradiated survivors of childhood cancer treated with chemotherapy in the Childhood Cancer Survivor Study.
Authors: Lucie Marie Turcotte, Qi Liu, Yutaka Yasui, Tara O. Henderson, Todd M. Gibson, Wendy Leisenring, Michael A. Arnold, Rebecca M. Howell, Daniel M. Green, Gregory T. Armstrong, Leslie L. Robison, Joseph Philip Neglia
Journal: Journal of Clinical Oncology (2018)

10509 Background: In recent treatment eras radiotherapy (RT) use decreased while chemotherapy (CT) increased. RT is an established risk factor for SMNs. Limited data exist on how CT increases risk for SMNs > 5 years after childhood cancer. Methods: SMNs were evaluated in 5-year survivors diagnosed < 21 years of age between 1970-99, treated with CT and not RT (N = 7447, 138,008 person-years follow-up). 30-year cumulative incidence and 95% confidence intervals (CI) and standardized incidence ratios (SIRs) for SMNs were estimated. SIRs were estimated for chemotherapy exposures [alkylator: 0, 1-3999, 4000-7999, ≥8000 mg/m2; platinum: 0, 1-400, 401-750, > 750 mg/m2; anthracycline: 0, 1-100, 101-300, > 300 mg/m2; epipodophyllotoxin: 0, 1-1000, 1001-4000, > 4000 mg/m2]. Results: There were 154 SMNs among 139 survivors. Cumulative incidence for SMNs at 30 years was 4.5% (95% CI 3.4-5.6) and risk for SMN was 3-fold greater than the general population. Survivors of leukemia, lymphoma, and sarcomas had increased risk for SMNs (Table), whereas, survivors of Wilms tumor, neuroblastoma and CNS cancer did not. Exposure to moderate- to high-dose alkylator (≥4000 mg/m2) or platinum ( > 400 mg/m2) or high-dose anthracycline ( > 300 mg/m2) or epiodophyllotoxin ( > 4000 mg/m2) therapy had SIRs of ≥4.0. A combination of alkylators and platinum, one of the two being high-dose and the other being moderate or high-dose, had a SIR of 13.0 (95% CI 6.5-23.2). Conclusions: Non-RT exposed survivors are at increased risk for SMN and should be counseled regarding the potential for genetic predisposition and the need for increased surveillance for early detection of subsequent cancers. SIRs (95% CI) for SMNs by childhood cancer diagnosis. Primary Cancer SMN All SMNs (n = 154) Leukemia/ Lymphoma (n = 21) Breast (n = 34) Soft tissue sarcoma (n = 14) Thyroid (n = 20) Melanoma (n = 15) All diagnoses 3.1 (2.6-3.6) 2.9 (2.4-3.4) 6.3 (4.4-8.9) 4.1 (2.2-6.8) 3.5 (2.2-5.5) 3.4 (2.1-5.3) Leukemia/lymphoma (n = 4309) 2.7 (2.2-3.4) 2.1 (1.2-3.4) 6.3 (3.7-10.1) 1.5 (0.3-4.3) 2.6 (1.2-5.0) 4.1 (2.3-6.9) Sarcoma (n = 1484) 3.8 (3.0-4.9) 2.5 (1.0-5.1) 7.1 (4.1-11.3) 10.0 (4.8-18.4) 5.6 (2.6-10.7) 3.2 (1.2-7.0)
Elucidation of distinct mutational patterns between diffuse large B cell lymphoma subtypes utilizing circulating tumor DNA.
Authors: Joanne Soo, David Matthew Kurtz, Florian Scherer, Alexander F.M. Craig, Michael C. Jin, Jason R. Westin, Davide Rossi, Gianluca Gaidano, Ranjana H. Advani, Maximilian Diehn, Ash A. Alizadeh
Journal: Journal of Clinical Oncology (2017)

7538 Background: Patients with diffuse large B cell lymphoma (DLBCL) exhibit significant differences in clinical outcome based on cell-of-origin (COO). Patients are categorized as having germinal-center-like (GCB) or activated-B-cell-like (ABC) disease based on RNA microarray and histopathological analyses of tumor biopsies. We recently described an accurate sequencing-based method for determination of COO in DLBCL utilizing stereotyped differences in mutations (Scherer et al., 2016). Here, we further explore the mutational patterns in patients with differing molecular subtypes of DLBCL based on sequencing of circulating tumor DNA. Methods: We applied cancer personalized profiling by deep sequencing (CAPP-Seq) to pretreatment plasma samples and matched germline from a cohort of 115 patients with DLBCL. We then identified somatic alterations, which were used to determine COO molecular subtypes as previously described. Finally, we compared mutational patterns in patients with GCB and non-GCB DLBCL. Results: We detected a significantly greater number of total mutations (GCB: 1766 ± 160 mutations per Mb of targeted sequencing; non-GCB: 1364 ± 150 mutations per Mb of targeted sequencing; p &lt; 0.05) and coding mutations (GCB: 145 ± 21 mutations per Mb of targeted sequencing; non-GCB: 28 ± 8.5 mutations per Mb of targeted sequencing; p &lt; 0.001), particularly in immunoglobulin (Ig) regions (p &lt; 0.05). In addition, GCB and non-GCB samples exhibited distinct mutational patterns within Ig regions. GCB samples were enriched for mutations in regions of switch mu (Sμ) (p &lt; 0.01) and IGHV2-70 (p &lt; 0.01), while non-GCB samples were enriched for mutations in regions of IGHG3 (p &lt; 0.03), IGHV4-34 (p &lt; 0.03), and IGLL5 (p &lt; 0.05). GCB samples were also significantly enriched for coding mutations in SOCS1 (p &lt; 0.01), a gene not included in our original COO classifier. Conclusions: Patients with GCB and non-GCB DLBCL exhibit distinct mutational patterns across both Ig and non-Ig loci of the genome. These differences in mutational patterns can be used to classify molecular subtypes noninvasively, potentially providing further utility to noninvasive genotyping and liquid biopsies.
Simultaneous characterization of tumor cellularity and the Warburg effect with PET, MRI and hyperpolarized <sup>13</sup>C-MRSI
Authors: Christian Hundshammer, Miriam Braeuer, Christoph A. Müller, Adam E. Hansen, Mathias Schillmaier, Stephan Düwel, Benedikt Feuerecker, Steffen J. Glaser, Axel Haase, Wilko Weichert, Katja Steiger, Jorge Cabello, Franz Schilling, Jan-Bernd Hövener, Andreas Kjær, Stephan G. Nekolla, Markus Schwaiger
Journal: Theranostics (2018)

Modern oncology aims at patient-specific therapy approaches, which triggered the development of biomedical imaging techniques to synergistically address tumor biology at the cellular and molecular level. PET/MR is a new hybrid modality that allows acquisition of high-resolution anatomic images and quantification of functional and metabolic information at the same time. Key steps of the Warburg effect-one of the hallmarks of tumors-can be measured non-invasively with this emerging technique. The aim of this study was to quantify and compare simultaneously imaged augmented glucose uptake and LDH activity in a subcutaneous breast cancer model in rats (MAT-B-III) and to study the effect of varying tumor cellularity on image-derived metabolic information. Methods: For this purpose, we established and validated a multimodal imaging workflow for a clinical PET/MR system including proton magnetic resonance (MR) imaging to acquire accurate morphologic information and diffusion-weighted imaging (DWI) to address tumor cellularity. Metabolic data were measured with dynamic [18F]FDG-PET and hyperpolarized (HP) 13C-pyruvate MR spectroscopic imaging (MRSI). We applied our workflow in a longitudinal study and analyzed the effect of growth dependent variations of cellular density on glycolytic parameters. Results: Tumors of similar cellularity with similar apparent diffusion coefficients (ADC) showed a significant positive correlation of FDG uptake and pyruvate-to-lactate exchange. Longitudinal DWI data indicated a decreasing tumor cellularity with tumor growth, while ADCs exhibited a significant inverse correlation with PET standard uptake values (SUV). Similar but not significant trends were observed with HP-13C-MRSI, but we found that partial volume effects and point spread function artifacts are major confounders for the quantification of 13C-data when the spatial resolution is limited and major blood vessels are close to the tumor. Nevertheless, analysis of longitudinal data with varying tumor cellularity further detected a positive correlation between quantitative PET and 13C-data. Conclusions: Our workflow allows the quantification of simultaneously acquired PET, MRSI and DWI data in rodents on a clinical PET/MR scanner. The correlations and findings suggest that a major portion of consumed glucose is metabolized by aerobic glycolysis in the investigated tumor model. Furthermore, we conclude that variations in cell density affect PET and 13C-data in a similar manner and correlations of longitudinal metabolic data appear to reflect both biochemical processes and tumor cellularity.
Neoadjuvant (neo) immune checkpoint blockade (ICB) in patients (Pts) with high-risk resectable metastatic melanoma (MM).
Authors: Rodabe Navroze Amaria, Sangeetha Meda Reddy, Hussein Abdul-Hassan Tawbi, Michael A. Davies, Merrick I. Ross, Isabella Claudia Glitza, Janice N. Cormier, Carol M. Lewis, Wen-Jen Hwu, Ehab Y. Hanna, Adi Diab, Michael K.K. Wong, Richard Eldon Royal, Neil D. Gross, Randal S. Weber, Stephen Yenzen Lai, Richard A. Ehlers, Elizabeth M. Burton, Michael T. Tetzlaff, Jennifer Ann Wargo
Journal: Journal of Clinical Oncology (2018)

9510 Background: Nivolumab (nivo) and combination ipilimumab (ipi) + nivo are highly active in pts with unresectable and stage IV MM. Nivo is also safe and effective adjuvant treatment for MM pts with resected stage III disease. Preclinical studies demonstrate that neo ICB may be more effective than adjuvant treatment, but the safety and efficacy of neo ICB in pts is unknown. We designed a randomized trial to assess the safety and activity of neo nivo +/- ipi ICB in pts with high-risk, resectable MM. Methods: We conducted a non-comparative randomized phase II study for pts with resectable, clinically detectable stage III or oligometastatic stage IV MM. Pts were randomized to receive neo nivo 3mg/kg IV every 2 weeks for up to 4 doses (Arm A) or neo ipi 3mg/kg + nivo 1mg/kg IV every 3 weeks for up to 3 doses (Arm B) prior to surgery, then nivo 3mg/kg IV every 2 weeks for 13 doses (Arms A and B) after surgery (NCT02519322). Planned total accrual was 40 pts (1:1 randomization) with stratification by stage and PD-L1 status. The primary endpoint was pathologic complete response (pCR) rate. Results: The trial was closed after 23 pts were enrolled (12 to Arm A, 11 to Arm B). Neo nivo achieved 25% pCR and 25% radiographic response rate (RR), but 17% were unable to undergo surgery due to rapid disease progression during neo therapy. All pts on neo ipi + nivo underwent surgery, and the pCR and RR rates were 45% and 73%, respectively. Grade 3 treatment related adverse events occurred in 8% of pts on Arm A and 73% on Arm B. Conclusions: Neo treatment with nivo +/- ipi can produce pCR in high-risk resectable MM. While neo nivo was well tolerated, RRs were lower than observed in stage IV pts and some pts experienced rapid progression that precluded surgery. Neo ipi + nivo achieved higher RRs but with high toxicity. This data provides a foundation for further optimization and testing of neo ICB. Clinical trial information: NCT02519322.