tbuckley/cabot-search huggingface dataset:
Phase I/II clinical trial of NY-ESO-1-specific TCR-engineered T-cell transfer combined with a novel T-cell stimulator CHP:NE1 for patients with refractory soft tissue sarcoma.
Authors: Mikiya Ishihara, Hiroyoshi Hattori, Eisuke Arai, Yoshihiro Nishida, Kohichi Takada, Makoto Emori, Akira Kawai, Takafumi Ueda, Makoto Endo, Yoshihiro Matsumoto, Tetsuro Sasada, Eiichi Sato, Tomomi Yamada, Akihiko Matsumine, Yasuhiro Nagata, Naozumi Harada, Hiroshi Shiku, Shinichi Kageyama
Journal: Journal of Clinical Oncology (2019)

TPS11074 Background: Combination therapy to enhance the efficacy of T cell receptor (TCR)-engineered T cells (TCR-T) has received increasing attention. We found that a combination therapy of TCR-T and a long peptide vaccine with CpG adjuvant without lymphodepletion regimen caused regression of immune checkpoint inhibitor-resistant sarcoma in a preclinical mouse model. Based on this finding, we initiated a clinical trial of TBI-1301 combined with CHP:NE1 without lymphodepletion for the patients with NY-ESO-1-expressing advanced soft tissue sarcoma. TBI-1301 is an NY-ESO-1 157–165 /HLA-A*02:01- or -A*02:06-specific TCR-T engineered to reduce endogenous TCR mRNA expression. CHP:NE1 is a novel T cell stimulator consisting of NY-ESO-1 long peptide antigen, cholesteryl pullulan (CHP) nanogel, and CpG oligoDNA. CHP nanogel is used for efficient delivery of long peptide antigen into the lymph nodes. CpG oligoDNA is a TLR9 agonist and used as an adjuvant. CHP:NE1 is expected to reinforce TBI-1301 T cells in the lymph nodes. Methods: This is an investigator-initiated multi-institutional first-in-human phase I/II clinical trial. TBI-1301 is infused at 5×10 9 cells one day after subcutaneous injection of CHP:NE1. CHP:NE1 is injected again 7 days after TBI-1301 infusion. This cycle is repeated once more. Lymphodepletion using cyclophosphamide and/or fludarabine is not performed. Key inclusion criteria include: refractory soft tissue sarcoma with NY-ESO-1 antigen expression, HLA-A*02:01- or HLA-A*02:06- positive, ECOG Performance Status 0 or 1, and adequate organ function. The primary objective is to assess the safety and efficacy in the phase 1 and 2 parts, respectively. The secondary objective is to assess the efficacy and immune response (blood concentration, immunophenotype and activity of TBI-1301) in the phase 1 part and the safety and immune response in the phase 2 part. Enrollment in this study is currently ongoing. Clinical trial information: JMA-IIA00346.
P14.113 The role of maintenance high-dose methotrexate chemotherapy in elderly primary CNS lymphoma patients with complete response to induction immunochemotherapy
Authors: K Mishima, M Shirahata, J Adachi, T Suzuki, T Fujimaki, R Nishikawa
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND The addition of high-dose methotrexate (HD-MTX)-based chemotherapy to whole brain irradiation (WBRT) has improved the prognosis of primary central nervous system lymphoma (PCNSL). However, the high neurotoxicity rates observed, especially in the elderly, raised interest in chemotherapy-only treatments. Withholding radiotherapy substantially decreases the risk of neurotoxicity, however, disease control may be compromised. Therefore, developing a novel treatment for the elderly PCNSL patients (ePCNSL) is crucial. In the elderly who cannot tolerate WBRT as a consolidation, maintenance treatment may serve as a feasible approach after an initial response. We treated ePCNSL with induction immunochemotherapy with rituximab (RIT) and HD-MTX, maintenance chemotherapy with HD-MTX and deferred WBRT. Here, we retrospectively investigated the prognosis for ePCNSL that became CR after the induction chemotherapy. MATERIAL AND METHODS Newly diagnosed ePCNSL (median age: 74 years) received biweekly RIT/ HD-MTX (375 mg/m2/dose; 3.5g/m2/dose) for 6 cycles (induction) followed by monthly RIT/MTX for 2 cycles (consolidation) and then were treated differently according to the radiological response. With CR patients, HD-MTX was continued with every 3 months (maintenance) for 2 years. Patients who did not obtain consent for maintenance therapy were followed up. RESULTS Of the 42 ePCNSL (median age 74 years), 26 had CR after induction and consolidation, of which 18 cases were carried out maintenance (M +) and 8 cases were followed up (M-). The median age was 74 and 76, respectively. Median progression-free survival (mPFS) was 73 months in the M+ group and 24.6 months in the M- group. Median overall survival (mOS) is 92.5 months versus 27.6 months, respectively. Both mPFS (P= 0.025) and mOS (P =0.0003) were significantly prolonged by maintenance therapy. In addition, ePCNSL with tumors involvement of deep brain structure had a poor prognosis. CONCLUSION It was suggested that maintenance treatment with HD-MTX may improve the prognosis for ePCNSL that reached complete response after induction therapy.
Assessment of Deep Learning Using Nonimaging Information and Sequential Medical Records to Develop a Prediction Model for Nonmelanoma Skin Cancer
Authors: Hsiao-Han Wang, Yu-Hsiang Wang, Chia-Wei Liang, Yu-Chuan Li
Journal: JAMA Dermatology (2019)

A prediction model for new-onset nonmelanoma skin cancer could enhance prevention measures, but few patient data-driven tools exist for more accurate prediction.To use machine learning to develop a prediction model for incident nonmelanoma skin cancer based on large-scale, multidimensional, nonimaging medical information.This study used a database comprising 2 million randomly sampled patients from the Taiwan National Health Insurance Research Database from January 1, 1999, to December 31, 2013. A total of 1829 patients with nonmelanoma skin cancer as their first diagnosed cancer and 7665 random controls without cancer were included in the analysis. A convolutional neural network, a deep learning approach, was used to develop a risk prediction model. This risk prediction model used 3-year clinical diagnostic information, medical records, and temporal-sequential information to predict the skin cancer risk of a given patient within the next year. Stepwise feature selection was also performed to investigate important and determining factors of the model. Statistical analysis was performed from November 1, 2016, to October 31, 2018.Sensitivity, specificity, and area under the receiver operating characteristic (AUROC) curve were used to evaluate the performance of the models.A total of 1829 patients (923 women [50.5%] and 906 men [49.5%]; mean [SD] age, 65.3 [15.7] years) with nonmelanoma skin cancer and 7665 random controls without cancer (3951 women [51.5%] and 3714 men [48.4%]; mean [SD] age, 47.5 [17.3] years) were included in the analysis. The 1-year incident nonmelanoma skin cancer risk prediction model using sequential diagnostic information and drug prescription information as a time-incorporated feature matrix could attain an AUROC of 0.89 (95% CI, 0.87-0.91), with a mean (SD) sensitivity of 83.1% (3.5%) and mean (SD) specificity of 82.3% (4.1%). Carcinoma in situ of skin (AUROC, 0.867; -2.80% loss) and other chronic comorbidities (eg, degenerative osteopathy [AUROC, 0.872; -2.32% loss], hypertension [AUROC, 0.879; -1.53% loss], and chronic kidney insufficiency [AUROC, 0.879; -1.52% loss]) served as more discriminative factors for the prediction. Medications such as trazodone, acarbose, systemic antifungal agents, statins, nonsteroidal anti-inflammatory drugs, and thiazide diuretics were the top-ranking discriminative features in the model; each led to more than a 1% decrease of the AUROC when eliminated individually (eg, trazodone AUROC, 0.868; -2.67% reduction; acarbose AUROC, 0.870; -2.50 reduction; and systemic antifungal agents AUROC, 0.875; -1.99 reduction).The findings of this study suggest that a risk prediction model may have potential predictive factors for nonmelanoma skin cancer. This model may help health care professionals target high-risk populations for more intensive skin cancer preventive methods.
Guidelines Insights: Hepatobiliary Cancers, Version 2.2019
Authors: Al B. Benson, Michael I. D’Angelica, Daniel E. Abbott, Thomas A. Abrams, Steven R. Alberts, Daniel A. Anaya, Robert Anders, Chandrakanth Are, Daniel Brown, Daniel T. Chang, Jordan Cloyd, Anne M. Covey, William Hawkins, Renuka Iyer, Rojymon Jacob, Andreas Karachristos, R. Kate Kelley, Robin Kim, Manisha Palta, James O. Park, Vaibhav Sahai, Tracey Schefter, Jason K. Sicklick, Gagandeep Singh, Davendra Sohal, Stacey Stein, G. Gary Tian, Jean-Nicolas Vauthey, Alan P. Venook, Lydia J. Hammond, Susan D. Darlow
Journal: Journal of the National Comprehensive Cancer Network (2019)

The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel’s discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.
T Cell Dysfunction in Epstein-Barr Virus-Associated Lymphoma
Authors: Huihui Liu, Xinan Cen, Lihong Wang, Bingjie Wang, Yujun Dong, Yongjin Shi, Bo Tang, Yang Zhang, Wenjun Mao, Junhui Xu, Ye Shen, Hanyun Ren
Journal: Blood (2018)
The Evolution of Reverse Gyrase Suggests a Nonhyperthermophilic Last Universal Common Ancestor
Authors: Ryan J Catchpole, Patrick Forterre
Journal: Molecular Biology and Evolution (2019)

Abstract Reverse gyrase (RG) is the only protein found ubiquitously in hyperthermophilic organisms, but absent from mesophiles. As such, its simple presence or absence allows us to deduce information about the optimal growth temperature of long-extinct organisms, even as far as the last universal common ancestor of extant life (LUCA). The growth environment and gene content of the LUCA has long been a source of debate in which RG often features. In an attempt to settle this debate, we carried out an exhaustive search for RG proteins, generating the largest RG data set to date. Comprising 376 sequences, our data set allows for phylogenetic reconstructions of RG with unprecedented size and detail. These RG phylogenies are strikingly different from those of universal proteins inferred to be present in the LUCA, even when using the same set of species. Unlike such proteins, RG does not form monophyletic archaeal and bacterial clades, suggesting RG emergence after the formation of these domains, and/or significant horizontal gene transfer. Additionally, the branch lengths separating archaeal and bacterial groups are very short, inconsistent with the tempo of evolution from the time of the LUCA. Despite this, phylogenies limited to archaeal RG resolve most archaeal phyla, suggesting predominantly vertical evolution since the time of the last archaeal ancestor. In contrast, bacterial RG indicates emergence after the last bacterial ancestor followed by significant horizontal transfer. Taken together, these results suggest a nonhyperthermophilic LUCA and bacterial ancestor, with hyperthermophily emerging early in the evolution of the archaeal and bacterial domains.
Targeted Protein Delivery: Supramolecular Toxin Complexes for Targeted Pharmacological Modulation of Polymorphonuclear Leukocyte Functions (Adv. Healthcare Mater. 17/2019)
Authors: Astrid Johanna Heck, Theresa Ostertag, Leonie Schnell, Stephan Fischer, Bikram Keshari Agrawalla, Pia Winterwerber, Eva Wirsching, Michael Fauler, Manfred Frick, Seah Ling Kuan, Tanja Weil, Holger Barth
Journal: Advanced Healthcare Materials (2019)

Excessive recruitment of polymorphonuclear neutrophils (PMNs) into injured tissues after traumatic injuries can be highly detrimental to patients and remains a significant source of morbidity and mortality. In article number 1900665 by Seah Ling Kuan, Tanja Weil, Holger Barth, and co-workers, the authors develop supramolecular protein complexes for pharmacological modulation of PMNs. In this way, a novel therapeutic approach is formulated by fusing PMN-binding peptides to a Rho-inhibiting enzyme on a supramolecular platform.
OS10.2 Effectiveness and tolerability of lacosamide as add-on therapy in patients with brain tumor-related epilepsy: results from a prospective, non-interventional study in European clinical practice
Authors: R Rudà, S Hellot, M De Backer, J Chan, L Joeres, I Leunikava, R Grant
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Data on the use of lacosamide (LCM) for the treatment of brain tumor-related epilepsy (BTRE) are limited. The objective of this study was to evaluate the effectiveness and tolerability of LCM added to 1 or 2 antiepileptic drugs (AEDs) in the treatment of patients with epilepsy due to low-grade primary brain tumor. MATERIAL AND METHODS Prospective, multicenter, single-arm, non-interventional study with a 6-month observation period (EP0045; NCT02276053). LCM was added to existing treatment with 1 or 2 AEDs. Patients aged ≥16 years with BTRE secondary to low-grade glioma (WHO Grade I-II) were eligible. Primary endpoints: patients experiencing a ≥50% reduction in seizure frequency from Baseline to Month 6; Patient’s Global Impression of Change (PGIC) rating at Month 6. Secondary endpoints: Kaplan-Meier estimated retention rate and change from Baseline in quality-of-life to Month 6 (EQ-5D-5L and MDASI-BT). Safety variables: occurrence of adverse drug reactions (ADRs) and ADRs leading to discontinuation. The present analysis was performed for the safety set: all patients who took ≥1 dose of lacosamide. RESULTS The study was conducted between November 2014 and December 2017. Patients were enrolled from 24 sites in Italy, the United Kingdom, the Netherlands, Germany, France, and Spain. 93 patients started LCM (mean [SD] age: 44.5 [14.7] years; 50 [53.8%] male); 14 (15.1%) withdrew from the study by 6 months. 85 (91.4%) patients had low-grade glioma, 3 (3.2%) had suspected glioma, 3 (3.2%) had meningioma, 1 (1.1%) had craniopharyngioma, and 1 (1.1%) had a histologically unverified tumor. At 6-months, 66 (71.0%) patients reported a ≥50% reduction in seizure frequency, 30 (32.3%) of whom were seizure-free. Improvements on PGIC were reported by 49 (52.7%) patients. The Kaplan-Meier estimated 6-month retention rate was 86.0%. Quality of life (EQ-5D-5L) and symptoms outcome measures (MDASI-BT) remained stable. ADRs leading to discontinuation occurred in 4 (4.3%) patients, most commonly vertigo (2 [2.2%] patients). CONCLUSION This is the first prospective, multicenter study focusing on epilepsy due to slow-growing tumors (mainly low-grade gliomas), treated with LCM. The results suggest that LCM reduces seizures in patients with resistant BTRE. The majority of patients noticed a clinical improvement with the addition of LCM. Observed ADRs were consistent with the known safety profile of LCM. STUDY SUPPORTED BY: UCB Pharma.
Lactoferrin-induced myeloid-derived suppressor cell therapy attenuates pathologic inflammatory conditions in newborn mice
Authors: Yufeng Liu, Michela Perego, Qiang Xiao, Yumei He, Shuyu Fu, Juan He, Wangkai Liu, Xing Li, Yanlai Tang, Xiaoyu Li, Weiming Yuan, Wei Zhou, Fan Wu, Chunhong Jia, Qiliang Cui, George S. Worthen, Erik A. Jensen, Dmitry I. Gabrilovich, Jie Zhou
Journal: Journal of Clinical Investigation (2019)

Inflammation plays a critical role in the development of severe neonatal morbidities. Myeloid-derived suppressor cells (MDSCs) were recently implicated in the regulation of immune responses in newborns. Here, we report that the presence of MDSCs and their functional activity in infants are closely associated with the maturity of newborns and the presence of lactoferrin (LF) in serum. Low amounts of MDSCs at birth predicted the development of severe pathology in preterm infants — necrotizing enterocolitis (NEC). In vitro treatment of newborn neutrophils and monocytes with LF converted these cells to MDSCs via the LRP2 receptor and activation of the NF-κB transcription factor. Decrease in the expression of LRP2 was responsible for the loss of sensitivity of adult myeloid cells to LF. LF-induced MDSCs (LF-MDSCs) were effective in the treatment of newborn mice with NEC, acting by blocking inflammation, resulting in increased survival. LF-MDSCs were more effective than treatment with LF protein alone. In addition to affecting NEC, LF-MDSCs demonstrated potent ability to control ovalbumin-induced (OVA-induced) lung inflammation, dextran sulfate sodium–induced (DSS-induced) colitis, and concanavalin A–induced (ConA-induced) hepatitis. These results suggest that cell therapy with LF-MDSCs may provide potent therapeutic benefits in infants with various pathological conditions associated with dysregulated inflammation.
P14.86 Bevacizumab-associated intracerebral hemorrhage in patients with CNS malignancy: A single-center retrospective cohort study
Authors: N Clarke, M Ruff
Journal: Neuro-Oncology (2019)

Abstract BACKGROUND Gliomas are a known risk factor for the development of spontaneous intracranial hemorrhage (ICH) independent of therapies directed against them, with studies reporting an incidence of 1.9–3.8%. Bevacizumab (BEV) is a humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF) FDA approved for recurrent glioblastoma. ICH is commonly considered to be a potential adverse effect of BEV use in patients with glioma, with previous retrospective studies describing incidence of intracerebral hemorrhage ranging from 1.9–3.3%. Material and METHODS We performed a single center (Mayo Clinic, Rochester, MN) retrospective chart review of all patients who received BEV therapy at our institution for a diagnosis of primary CNS malignancy. We used ICD-9 and ICD-10 codes to identify adult patients with primary CNS neoplasms that subsequently developed ICH. RESULTS We screened 10,507 adult patients with a diagnosis of primary CNS neoplasm treated at our center from 01/31/2008 to 12/31/2018 and found 644 patients treated with bevacizumab. Of these, 23 (3.6%) suffered an ICH within 12 weeks of a BEV infusion (median 9 days post infusion, 1–24 IQR). The dose of BEV in all hemorrhages was either 10 mg/kg every two weeks (n = 21) or 15 mg/kg every three weeks (n = 2). No patients treated with infusions at 7.5 mg/kg every three weeks (n = 79) or 5 mg/kg every two weeks (n = 17) suffered ICH events, however this did not meet significance (P = 0.06) when compared to patients on 10 mg/kg or above. The median ICH score was 1 (0–2 IQR). There was an increase in ECOG scores documented at clinical follow up following the hemorrhage compared to the pre-hemorrhage functional status (ECOG 3.28 versus 1.2, p = &lt; 0.0001), with 13 patients (56%) having developed severe debility or death (ECOG 4 n = 3, ECOG 5 n = 10). CONCLUSION In our single-center cohort of patients with a primary diagnosis of CNS neoplasms treated with BEV, ICH occurred in 3.6% of patients. Those who experienced an ICH in proximity to BEV infusion had significant morbidity and mortality with a clear decline in functional status. There was a signal of dose response as far as ICH incidence in our cohort with dosages 10 mg/kg per infusion or above.
Brexit: doctors’ duty is to inform patients
Authors: Fiona Godlee
Journal: BMJ (2019)

The US news has this week been issuing a constant stream of reports on the path of Hurricane Dorian, its ferocity, timing, and likely effects of landfall.Regular government updates give advice to stock up on food, water, and drugs and instructions on when and where to evacuate.Emergency services and healthcare teams are on the scene to advise and provide what help they can.
Anti-programmed cell death protein 1 (anti-PD1) immunotherapy induced autoimmune polyendocrine syndrome type II (APS-2): a case report and review of the literature
Authors: Ashray Gunjur, Oliver Klein, Damien Kee, Jonathan Cebon
Journal: Journal for ImmunoTherapy of Cancer (2019)

<h3>Background</h3> Autoimmune polyendocrine syndrome type II (APS-2) is a rare constellation of autoimmune hypoadrenalism, thyroid dysfunction and/or type 1 diabetes (T1DM), usually occurring in the 3rd or 4th decades and associated with a human leukocyte antigen (HLA) DR3 or DR4 serotype. We detail the first report of an elderly woman developing the full triad of APS-2 shortly after commencing anti-programmed cell death protein 1 (anti-PD1) immune checkpoint inhibition for unresectable melanoma and review the literature for similar presentations secondary to anti-PD1 axis therapy. <h3>Case</h3> A 78-year-old female with advanced unresectable BRAF wild-type melanoma was treated with pembrolizumab (2 mg/kg 3-weekly). Three weeks following the first dose she developed fulminant autoimmune diabetes, with an initially low C-peptide denoting rapid destruction of ß-islet cells. Following stabilisation of her diabetes, two further doses of pembrolizumab was administered. She then represented with symptomatic hypoadrenalism and hypothyroidism, consistent with APS-2. Her&nbsp;HLA class II genotype was HLA-DRB1*04.16 (DR4 serotype), a recognised association with this syndrome. Her melanoma responded rapidly to anti-PD1 therapy, and a complete response (CR) was attained after four doses of pembrolizumab. Treatment was discontinued and her CR is ongoing. <h3>Conclusion</h3> This is the first report of the full triad of APS-2 developing in a genetically susceptible individual at the age of 78 after treatment with an anti-PD1 agent. Although scarcely reported, a literature review of similar reports seems to indicate a predilection for this syndrome in patients with HLA-DR4 serotypes. HLA Class II typing is not routinely recommended, but may provide useful predictive information for patients at risk of poly-endocrinopathy even in patients without a relevant personal or family history. Additional studies are required to determine if such testing would be useful and/or cost effective.
Predictive Signatures Inform the Effective Repurposing of Decitabine to Treat KRAS–Dependent Pancreatic Ductal Adenocarcinoma
Authors: Carla Mottini, Hideo Tomihara, Diego Carrella, Alessia Lamolinara, Manuela Iezzi, Justin K. Huang, Carla A. Amoreo, Simonetta Buglioni, Isabella Manni, Frederick S. Robinson, Rosalba Minelli, Ya'an Kang, Jason B. Fleming, Michael P. Kim, Christopher A. Bristow, Daniela Trisciuoglio, Antonella Iuliano, Donatella Del Bufalo, Diego Di Bernardo, Davide Melisi, Giulio F. Draetta, Gennaro Ciliberto, Alessandro Carugo, Luca Cardone
Journal: Cancer Research (2019)

Mutated KRAS protein is a pivotal tumor driver in pancreatic cancer. However, despite comprehensive efforts, effective therapeutics that can target oncogenic KRAS are still under investigation or awaiting clinical approval. Using a specific KRAS-dependent gene signature, we implemented a computer-assisted inspection of a drug-gene network to in silico repurpose drugs that work like inhibitors of oncogenic KRAS. We identified and validated decitabine, an FDA-approved drug, as a potent inhibitor of growth in pancreatic cancer cells and patient-derived xenograft models that showed KRAS dependency. Mechanistically, decitabine efficacy was linked to KRAS-driven dependency on nucleotide metabolism and its ability to specifically impair pyrimidine biosynthesis in KRAS-dependent tumors cells. These findings also showed that gene signatures related to KRAS dependency might be prospectively used to inform on decitabine sensitivity in a selected subset of patients with KRAS-mutated pancreatic cancer. Overall, the repurposing of decitabine emerged as an intriguing option for treating pancreatic tumors that are addicted to mutant KRAS, thus offering opportunities for improving the arsenal of therapeutics for this extremely deadly disease. SIGNIFICANCE: Decitabine is a promising drug for cancer cells dependent on RAS signaling.
Nucleome Dynamics during Retinal Development
Authors: Jackie L. Norrie, Marybeth S. Lupo, Beisi Xu, Issam Al Diri, Marc Valentine, Daniel Putnam, Lyra Griffiths, Jiakun Zhang, Dianna Johnson, John Easton, Ying Shao, Victoria Honnell, Sharon Frase, Shondra Miller, Valerie Stewart, Xin Zhou, Xiang Chen, Michael A. Dyer
Journal: Neuron (2019)