tbuckley/cabot-search huggingface dataset:
The SINTART 1 study: A phase II trial of induction chemotherapy (IC), surgery, photon-, proton-and carbon ion-based radiotherapy (RT) integration in locally advanced operable sinonasal epithelial tumors patients (pts).
Authors: Carlo Resteghini, Paolo Castelnuovo, Piero Nicolai, Ester Orlandi, Paolo Bossi, Barbara Vischioni, Alberto Schreiber, Nicola Alessandro Iacovelli, Paolo Battaglia, Davide Mattavelli, Nadia Facchinetti, Simone Gambazza, Giuseppina Calareso, Marco Ravanelli, Carla Facco, Tiziana Tartaro, Andrea Pietro Sponghini, Fabio Pagella, Luigi Mariani, Lisa F. Licitra
Journal: Journal of Clinical Oncology (2021)

6066 Background: Sinonasal epithelial tumors are rare diseases with several histotypes and poor prognosis. Multimodal approach including surgery is widely used, although no standard therapy has been established in prospective trials. This study assessed activity and safety of an innovative integration of multimodality treatment - IC, surgery and RT - modulated by histology, molecular profile and response to IC. Methods: Pts with untreated, operable squamous cell carcinoma (SCC), p53 wild type intestinal type adenocarcinoma (ITAC), sinonasal undifferentiated and neuroendocrine carcinoma (SNUC, SNEC) were enrolled in a single-arm, phase II, multicenter clinical trial from 2014 to 2018. Pts was treated with up to 5 IC cycles, whose regimen was selected according to histotype, followed either by curative radio-chemotherapy (CRT) (pts with ≥80% reduction of initial tumor volume (TV)) or surgery and adjuvant (C)RT. Photon and/or proton/carbon ion-based RT was employed according to disease site and stage. Primary endpoint was 5 years PFS, secondary endpoints were OS, IC ORR per RECIST 1.1 and safety. Results: Out of 39 enrolled pts, 35 pts were evaluable for primary endpoint. Two pts were only considered for safety analyses because definitive diagnosis on surgical specimen did not meet the study entry criteria; other two pts were screening failure due to inoperable disease. Five-year PFS was 38% (95% CI, 21 – 69), with a median PFS of 26 months. Five-year OS was 46% (95% CI, 28 – 75), with a median OS of 36 months. Responses to IC are reported in table. Globally, 15 pts avoided surgery. Overall treatment safety was in line with multimodality intensive head and neck cancer treatments (5% of pts with G3-4 adverse event during IC). One sudden cardiac death was recorded. At a median follow up of 27 months, 5 G3-4 RT related late adverse events have been recorded (1 G3 neurotoxicity, 2 G3 hearing impairment, 2 G3 xerostomia). Three-year PFS - OS for pts achieving PR/CR vs SD/PD to IC were 49.8% - 56.7% vs 43.2% - 53%, respectively. Conclusions: Treatment of advanced SNC with histology-driven IC followed by locoregional therapy tailored to response to IC was safe and showed survival rate similar to surgery containing case series. In the first prospective study, a surgery sparing multimodal approach proved feasible and effective in IC responsive pts. Clinical trial information: NCT02099175. [Table: see text]
Pancreatic hormones response-generated machine learning model to help distinguish sporadic pancreatic cancer from new-onset diabetes cohort.
Authors: Jiantong Bao, Chenyu Sun, Yidi Zhang, Ling Li, Stephen Jacob Pandol, Kelly Kozma
Journal: Journal of Clinical Oncology (2021)

e16235 Background: Diabetes mellitus (DM), a paraneoplastic phenomenon, can develop earlier than other symptoms in pancreatic cancer (PaC) patients. Enhanced surveillance is encouraged on all elderly patients with new-onset DM. However, it is a challenge to differentiate newly developed PaCDM from type 2 DM (T2DM). Thus, we investigated the differences of pancreatic hormones responses and functions between PaCDM and T2DM patients, and developed discriminative model by machine learning algorithms. Methods: PaC patients with normal blood glucose (PaCNG) or with new-onset DM (PaCDM) were recruited. For each case, age and gender matched newly developed T2DM patients and healthy volunteers were selected as controls. After ≥10 hours fasting, all participants underwent a mixed meal stimulation test (MMTT). Blood samples were collected at 0, 15, 30, 60 and 120 min to measure insulin, C-peptide, glucagon, and pancreatic polypeptide (PP). Indices of insulin sensitivity (HOMA-IS, HOMA-IR) and insulin secretion (HOMA-β, insulinogenic index 30’ and 120’) were calculated. Increases in hormone levels were compared among groups with repeated measure analysis. Four machine learning algorithms (Random Forest, Logistic Regression, Support Vector Machines, Naïve bayes) were used to develop quadri-separated discriminative models of PaCDM based on baseline characteristics, pancreatic hormones and insulin indices listed above. Results: Insulin and C-peptide responses to MMTT were blunted in PaCDM patients compared to T2DM. The AUC of insulin were comparatively lower in PaCDM; between-group differences were observed at the fasting (197.15 ± 16.59 pg/mL to 537.96 ± 118.69 pg/mL; P = 0.040) and 15 min (523.94 ± 81.15 pg/mL to 1182.51 ± 219.35 pg/mL; P = 0.036) time-points. No statistical differences among groups were found for glucagon. The mean peak PP concentration after MMTT in PaCDM group (466.67 ± 79.05 pg/mL) was higher than control group (258.54 ± 31.36 pg/mL, P = 0.034), but not statistically different to T2DM patients (452.34 ± 62.96 pg/mL, P = 0.892). PaCDM patients had lower insulin secretion capacity but better insulin sensitivity compared to T2DM patients. Eight indices (age, HbA1c, CA19-9, peak concentration of glucose, area above basal of PP, HOMA-IR, HOMA-IS, HOMA-β) were recruited for model development. And the discriminative model generated by random forest algorithm obtained best performance (AUC = 1.000, CA = 0.963, F-1 = 0.941, Precision = 0.889, Recall = 1.000, Specificity = 0.947; model verified). Conclusions: PaCDM patients tend to present with lower β-cell function and better insulin resistance compared to T2DM patients. As our model based on machine learning algorithm generates a good result for discrimination, the above findings may help with early screening for sporadic PaC in new-onset DM. Clinical trial information: ChiCTR1800018247.
LGG-06. COMPREHENSIVE GENOMIC CHARACTERIZATION AND INTEGRATED CLINICAL ANALYSIS OF LOW-GRADE GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1
Authors: Michael Fisher, David Jones, Yimei Li, Xiaofan Guo, Poonam Sonawane, Angela Waanders, Joanna Phillips, William Weiss, Adam Resnick, Sara Gosline, Jineta Banerjee, Justin Guinney, Astrid Gnekow, Daniela Kandels, Nicholas Foreman, Andrey Korshunov, Marina Ryzhova, Luca Massimi, Sri Gururangan, Mark Kieran, Zhihong Wang, Maryam Fouladi, Mariko Sato, Ingrid Øra, Stefan Holm, Stephen Markham, Pengbo Beck, Natalie Jäger, Andrea Wittmann, Alexander Sommerkamp, Felix Sahm, Stefan Pfister, David Gutmann
Journal: Neuro-Oncology (2021)

Abstract Background Low-grade gliomas (LGGs) arising in children with neurofibromatosis type 1 (NF1) are usually not biopsied. To identify secondary genetic alterations or molecular features that may contribute to pathogenesis and correlate with clinical behavior, we initiated a comprehensive molecular and clinical analysis of pediatric NF1-LGGs. Methods NF1-LGGs were analysed by whole-genome sequencing (31), targeted gene panel sequencing (9), RNAseq transcriptomal profiling (33) and genome-wide DNA methylation analysis (67). Clinical annotation was available for 48 subjects. Results Most LGGs harbored bi-allelic NF1 inactivation as the sole genetic abnormality, but 11% had additional alterations (FGFR1 mutation, n=3; PIK3CA mutation, n=2; homozygous 9p21 deletion, n=2; MYB:QKI fusion, n=1; SETD2 mutation, n=1; EGFR amplification, n=1). FGFR1 mutation conferred additional growth advantage in multiple complementary murine Nf1 models. 88% of NF1-LGGs resembled sporadic pilocytic astrocytoma (PA) by methylation, higher than that based on histology. Non-PA methylation patterns included low-grade glial/glioneuronal tumors, rosette-forming glioneuronal tumors, MYB/MYBL1-altered glioma, and high-grade astrocytoma with piloid features (2 tumors histologically diagnosed as LGG). In total, 18% of samples were classified as non-PA and/or harbored an additional non-NF1 mutation. Non-PA methylation class tumors were more likely to harbor an additional non-NF1 mutation (p=0.005). 7.7% of optic pathway hypothalamic gliomas (OPHGs) had other mutations or were not classified by methylation as PA, compared with 20.6% of NF1-LGGs arising elsewhere. There was no difference based on age for the presence of an additional non-NF1 mutation or non-PA methylation class. Conclusions Given the overall low occurrence of non-NF1 mutations or non-PA methylation class tumors in this series, routine clinical biopsy of typically-appearing NF1-LGG may not be indicated, particularly for children with OPHG. Biopsy should be considered for non-OPHG tumors refractory to conventional treatment. As additional agents are developed and treatment strategies evolve, the rationale for biopsy of NF1-LGG may become stronger.
Overall survival throughout treatment course among patients diagnosed with small cell lung cancer.
Authors: Adina Estrin, Patricia Prince, Dylan Supina, Rami Ben-Joseph, Anne Boccuti, Kobby Asubonteng, Moshe Fridman, Badri Rengarajan, Raj Hanvesakul, Benjamin Taylor
Journal: Journal of Clinical Oncology (2021)

e20577 Background: Previous studies have investigated overall survival (OS) among small cell lung cancer (SCLC) patients with data through 2015. Using data through mid-2019, this study strives to make the body of studies more current, and to provide more recent data on the baseline characteristics and OS of treated SCLC patients, stratified by stage at diagnosis. Methods: This retrospective cohort study identified adult patients with confirmed SCLC between January 1, 2016 - December 31, 2018 that initiated anti-cancer treatment using real-world data from electronic medical records (ConcertAI, including data from CancerLinQ, an initiative of the American Society of Clinical Oncology). Exclusion criteria included evidence of other primary cancer at baseline, no initial stage recorded, death prior to diagnosis, or participation in a clinical trial. Patients entered the cohort upon receipt of their first anti-cancer treatment after SCLC diagnosis and were assigned up to three progression intervals to assess overall survival for each progression-based line of therapy. Patients were followed until death, end of data, or end of the study period (June 30, 2019). Kaplan-Meier analyses were conducted to assess median survival time as estimated by the survival curve. Results: Characteristics among the 82 limited stage (LS) and 217 extensive stage (ES) patients at 1L treatment were similar; however, LS patients were slightly older (mean age: LS = 67.5, ES = 66.4), and ES patients had a higher comorbidity score given their metastatic disease status (mean score: LS = 3.9, ES = 7.3). Both groups had very similar ECOG performance scores prior to 1L (ECOG: 0-1 ≅ 40%, 2+ ≅ 25%, Missing ≅ 35%). For the 299 patients that began 1L treatment (LS = 82, ES = 217), median OS time was 8.41 months (LS = 12.35 months, ES = 7.98 months). For the 124 of the 299 patients who progressed and were treated with 2L therapy, median OS time was 4.30 months. For the 44 of the 124 patients that progressed and were treated with 3L therapy, median OS time was 3.88 months. Of the 299 treated patients, 216 died before the end of the study period, representing 57% of the LS patients and 78% of the ES patients. Conclusions: These results reveal a difference in OS between LS and ES patients treated in 1L. The short survival time in patients with later lines of therapy highlights the need for new treatments in 2L and 3L.[Table: see text]
n-3多価不飽和脂肪酸と心房細動の関係。EPA/DHAの高濃度は,孤立性心房細動の危険因子か?
Authors: Hata Takeki, Tomita Takeshi, Aizawa Kazunori, Kasai Hiroki, Kumazaki Setsuo, Tsutsui Hiroshi, Koyama Jun, Yazaki Yoshikazu, Kinoshita Osamu, Ikeda Uichi
Journal: Circulation (2007)
Study of copper-cysteamine based X-ray induced photodynamic therapy and its effects on cancer cell proliferation and migration in a clinical mimic setting
Authors: Xiangyu Chen, Jiayi Liu, Ya Li, Nil Kanatha Pandey, Taili Chen, Lingyun Wang, Eric Horacio Amador, Weijun Chen, Feiyue Liu, Enhua Xiao, Wei Chen
Journal: Bioactive Materials (2021)

Copper-cysteamine as a new generation of sensitizers can be activated by light, X-rays, microwaves, or ultrasound to produce reactive oxygen species. X-ray induced photodynamic therapy (X-PDT) has been studied extensively; however, most of the studies reported so far were conducted in the laboratory, which is not conducive to the clinical translation conditions. In this contribution, for the first time, we investigated the treatment efficiency of copper-cysteamine (Cu-Cy) based X-PDT by mimicking the clinical conditions with a clinical linear accelerator and building deep-seated tumor models to study not only the effectiveness but also its effects on the cell migration and proliferation in the level of the cell, tissue, and animal. The results showed that, without X-ray irradiation, Cu-Cy nanoparticles (NPs) had a low toxicity in HepG2, SK-HEP-1, Li-7, and 4T1 cells at a concentration below 100 mg/L. Interestingly, for the first time, it was observed that Cu-Cy mediated X-PDT can inhibit the proliferation and migration of these cell lines in a dose-dependent manner. Antigen markers of migration and cell proliferation, proliferating cell nuclear antigen (PCNA) and E-cadherin, from tumor tissue in the X-PDT group were remarkably different from that of the control group. Furthermore, the MRI assessment showed that the Cu-Cy based X-PDT inhibited the growth of deeply located tumors in mice and rabbits (p < 0.05) without any obvious toxicities in vivo. Overall, these new findings demonstrate that Cu-Cy NPs have a safe and promising clinical application prospect in X-PDT to improve the efficiency of radiotherapy (RT) for deep-seated tumors and effectively inhibit tumor cell proliferation and migration.
Possible immunologic predictors of the PD-1/PD-L1 checkpoint inhibitors' efficiency in lung cancer patients.
Authors: Elena Yu. Zlatnik, Oleg I. Kit, Elena S. Bondarenko, Aleksandr B. Sagakyants, Maria A. Teplyakova, Liubov Yu Vladimirova, Anna E. Storozhakova, Inna A. Novikova, Natalia A. Abramova, Irina L. Popova, Ludmila A. Ryadinskaya, Aza A. Agieva, Faina V. Alieva, Kristina A. Novoselova, Natalia M. Tikhanovskaya, Elena A. Kalabanova, Sergey N. Kabanov, Anna V. Tishina, Yuriy N. Lazutin
Journal: Journal of Clinical Oncology (2021)

e21035 Background: Immunotherapy with PD-1/PD-L1 check-point inhibitors (CPI) is a new trend in oncology. Their effect significantly depends on the patients` immune status. The aim of the study was to search the immunologic parameters of lung cancer (LC) patients receiving immunotherapy as factors that could predict their effect. Methods: 20 patients (12 male and 8 female) with LC had adenocarcinoma – 15 (75%), squamous cell carcinoma – 5 (25%). PD-1/PD-L1 CPI were used: 9 patients received atezolizumab (43%), 9 (43%) – pembrolizumab and 3 (14%) – nivolumab. The effect of therapy was evaluated according to imRECIST v.1.1. Factors of cell-mediated immunity were assessed by flow cytometry before treatment including immunotherapy. CD8+CD279+, CD4+CD279+, TLR2, TLR4, TLR3, TLR8 were studied. Results: Complete response was observed in 2 (9%) patients, partial response in 5 (24%), stabilization in 4 (19%) and progression in 8 (38%). In one patient the treatment was cancelled due to the development of immune-mediated complication (Guillain-Barre syndrome). The factors studied varied depending on different effect. In cases of LC stabilization/progression the initial amount of CD8+CD279+ cells were twice lower than in cases with complete/partial response. In the first group CD8+CD279+ cells` level before the treatment was 0,1-3,4%, while in the other group 4,1-9% (7,0±1,16%). In patients with stabilization/progression CD4+CD279+ cells` level before the immunotherapy was 0,1-3,3 and in patients with response to treatment 1,4-7,8% (3,4±0,8%) of total CD4+ lymphocytes. Besides, the LC patients with different effect of treatment had different initial amount of CD4+ Tem cells: stable response to CPI developed in patients with their higher levels (40,8±3,9%) vs 15,3±3,9% in cases of tumor progression (p &lt; 0.05). Initial high expression of TLR2 and TLR4 as well as low expression of TLR3 and TLR8 on monocytes in patients with response to immunotherapy suggests the contribution of innate immunity to its effect. Conclusions: Complete or partial response should be expected in cases of initially high per cent of T lymphocytes (CD4+, CD8+) CD4+ Tem cells and TLR2+, TLR4+ as well as low amount of TLR3+ and TLR8+ monocytes. These factors should be studied in future as predictive factors for effectiveness of CPI.
A risk stratification model for toxicities in phase 1 immuno-oncology (P1-IO) trials.
Authors: Alberto Hernando-Calvo, Abdulazeez Salawu, Marc Oliva Bernal, Daniel Vilarim Araujo, Zhihui (Amy) Liu, Rachel Chen, Lillian L. Siu
Journal: Journal of Clinical Oncology (2021)

2648 Background: Despite an exponential increase in the number of potential targets in the immuno-oncology (IO) field, lack of risk models to predict toxicities remains a challenge in early drug development. We proposed a risk stratification strategy and investigated whether different IO classes may be associated with incremental risk of toxicities. Methods: A systematic search for IO studies from 01/2014 to 10/2020 was conducted. Among the 12053 abstracts screened, 254 reporting phase I-IO trials were selected. Type of IO treatment (IO monotherapy [mono] vs IO combination [comb]), therapeutic class (e.g. IO, molecularly targeted agents [MTA]), and dose escalation method (rule-based, model-based and model-assisted) were collected. A risk scoring model was developed after expert consensus: treatment-related deaths (1:yes, 0:no), incidence of G3/G4 treatment related adverse events (TRAE) or treatment emergent adverse events (TEAE) (0 if 1-29%,1 if ≥30-49%, 2 if ≥50%), incidence of ≥G2 cytokine release syndrome (1:yes, 0:no), incidence of ≥G2 encephalopathy (1:yes 0:no) and incidence of dose-limiting toxicity (DLT) (0:no, 1:lab, 2:clinical). Risk categories were defined by summing all points (0 = low, 1-2 = intermediate, 3+ = high) and were correlated with type of IO treatment, therapeutic class and dose escalation method. Results: Of 254 P1-IO trials reviewed, 228 (90%) were scorable, 26 were not (25 due to lack of AE data). Up to 10/26 (38%) of non-scorable studies were cell therapies. Among the 228 scorable studies, 120 (53%) scored 0, 65 (28%) scored 1-2, 43 (19%) scored 3+; 24 (11%) and 125 (55%) did not provide no. of pts with G3/G4 TRAEs or TEAEs respectively. A significant association was observed between risk categories and therapeutic class (p&lt;0.001) (see table). Additionally, IO-MTA and IO-IO were both associated with an increased risk of toxicity as compared to IO-mono (OR=3.91 (95%CI 1.7-9.2), p=0.002) and (OR=2.79 (95%CI 1.2-6.5), p=0.02) respectively. There was no association between dose escalation method and risk of toxicity (p=0.95), but 182 (92%) used rule-based methods. Conclusions: Our results suggest that different IO classes are associated with different risks of toxicity. This risk classification strategy may guide future clinical trial design. Additionally, standards for reporting toxicities in P1-IO trials are urgently needed.[Table: see text]
Recent applications of electrical, centrifugal, and pressurised emerging technologies for fibrous structure engineering in drug delivery, regenerative medicine and theranostics
Authors: Prina Mehta, Manoochehr Rasekh, Mohammed Patel, Ekhoerose Onaiwu, Kazem Nazari, I. Kucuk, Philippe B. Wilson, Muhammad Sohail Arshad, Zeeshan Ahmad, Ming-Wei Chang
Journal: Advanced Drug Delivery Reviews (2021)
EPCT-05. A PHASE 1/2 STUDY OF AVAPRITINIB FOR KIT- OR PDGFRA-MUTANT PEDIATRIC RELAPSED/REFRACTORY SOLID TUMORS
Authors: Susan Chi, Antony Hsieh, Megan Foley, Hongliang Shi, Preethi Swamy, Jill Rodstrom, Marc Rudoltz
Journal: Neuro-Oncology (2021)

Abstract Prognosis for pediatric patients with advanced relapsed/refractory (R/R) solid (including central nervous system [CNS]) tumors is poor; targeted therapies achieve response rates of only ~15%. Germ cell tumors and high-grade glioma (HGG) are the most common with KIT mutations; sarcoma and HGG are the most common tumors with platelet-derived growth factor receptor alpha (PDGFRA) mutations. Two-year overall survival is &amp;lt;10% for pediatric patients with diffuse intrinsic pontine glioma, often driven by PDGFRA mutations. No KIT/PDGFRA targeted therapies are currently approved for pediatric patients with R/R solid tumors. The selective KIT and PDGFRA inhibitor, avapritinib, demonstrated potent activity against KIT activation-loop (exon 17), juxtamembrane (exon 11), and extracellular-domain (exon 9) mutants (IC50 &amp;lt;2 nM), and PDGFRA activation-loop (D842V) mutants (IC50=0.24 nM). CNS penetration in preclinical models (brain-to-plasma ratios at steady-state ranging from 0.74–1.00) demonstrated potential for activity against CNS tumors. Avapritinib is approved for the treatment of adults with unresectable/metastatic gastrointestinal stromal tumors (GIST) harboring PDGFRA exon 18 mutations (including D842V) in the USA based on an overall response rate ³84% with 59% response durations &amp;gt;6 months, and in the EU for adults with unresectable/metastatic GIST harboring a PDGFRA D842V mutation. The objectives of this 2-part phase 1/2 multicenter, open-label study, anticipated to enroll 31 patients from Q3 2021, are to assess avapritinib safety, preliminary efficacy, and pharmacokinetics in pediatric patients with KIT/PDGFRA-mutant solid R/R tumors. Eligible patients are aged 2 to &amp;lt;18 years with no alternative treatment options. Part 1 will enroll ≥6 patients; primary endpoint is confirmed age and body surface area physiologically-based pharmacokinetic modeling dose to provide equivalent exposure to the 300 mg adult avapritinib dose. Part 2 will enroll ≥25 patients at the recommended modeled avapritinib dose from Part 1; primary endpoint is overall response rate. Avapritinib once-daily will be administered in continuous 28-day cycles.
Abstract 15633: Whole Exome Sequencing and Monogenic Hypertension in a Multiethnic Cohort of 28,000 Individuals
Authors: Ishan Paranjpe, Kipp W Johnson, Steven Coca, Lili Chan, John C He, Barbara Murphy, Ron Do, Jagat Narula, Girish Nadkarni
Journal: Circulation (2019)

Background: Hypertension (HTN) is a major cause of morbidity and mortality and a subset may be caused by monogenic mutations and influence treatment decisions and prognosis. Methods: In 27,972 indi...