tbuckley/cabot-search huggingface dataset:
Temozolomide and capecitabine (CAPTEM) is effective in metastatic well-differentiated gastrointestinal neuroendocrine tumors.
Authors: İzzet Dogan, Didem Tastekin, Senem Karabulut, Burak Sakar
Journal: Journal of Clinical Oncology (2021)

366 Background: The study aimed to evaluate patients' outcomes and prognosis with metastatic gastrointestinal neuroendocrine tumors (mgNET) who treated temozolomide and capecitabine (CAPTEM). Methods: The data of forty-three patients were retrospectively evaluated. Clinicopathological features and treatment approaches were recorded. Kaplan-Meier analysis was used for overall survival (OS) and progression-free survival (PFS). Prognostic factors were assessed with Cox-regression analysis. Results: Median age was 59 (27-85) years. The number of male and female patients was 23 (%53.5) and 20 (%46.5), respectively. Pancreas (%51.2) was the most common site of the tumor. The number of patients with well- and poorly-differentiated mgNET was 38 (%88.4) and 5 (%11.6), respectively. The most common metastatic sites were liver (%62.8), lymph node (%58.1), and bone (%18.6). Eleven (%25.6) of the patients previously had undergone surgery, and some patients received radiotherapy (%9.5), chemotherapy (%19), and nuclear therapy (%9.3). Also, patients received octreotide (%86) or lanreotide (%14) with CAPTEM. In patients with well-differentiated mgNET, median PFS was 17.4 months, and disease control ratio %79.4 (%3-complete response, %38.2-partial response, and %38.2-stable response). No response observed in patients with poorly differianted mgNET, and the median PFS was calculated as 4.5 months. Grade 1-2 toxicity was observed in 34 (%79.1) of the patients, and grade 3-4 toxicity in 8 (%18.6). Four (%9.5) patients discontinued therapy for the toxicity. The most common toxicities were anemia (%37.2), thrombocytopenia (%25.6), and fatigue (%16.3). At a median follow-up of 33.8 (2.9-172.73) months, the ratio of five-years OS was %61. In multivariate analysis; gender (p=0.008), age (p=0.007), and Ki-67 levels (p=0.011) were a statistically significant for OS. However, the site of the tumor (p=0.186), number of metastatic sites (p=0.255), and type of somatostatin receptor ligand (p=0.903) were not. Conclusions: In the study, we showed that CAPTEM + somatostatin receptor ligands (octreotide or lanreotide) were effective and well-tolerated in patients with well-differentiated mgNET. But, it was not effective in patients with poorly-differentiated mgNET. Male gender, aged over 60 years, and tumor with a high level of Ki-67 were negative prognostic factors.
The PSMA-targeting Half-life Extended BiTE Therapy AMG 160 has Potent Antitumor Activity in Preclinical Models of Metastatic Castration-resistant Prostate Cancer
Authors: Petra Deegen, Oliver Thomas, Olivier Nolan-Stevaux, Shyun Li, Joachim Wahl, Pamela Bogner, Famke Aeffner, Matthias Friedrich, Michael Z. Liao, Katja Matthes, Doris Rau, Benno Rattel, Tobias Raum, Peter Kufer, Angela Coxon, Julie M. Bailis
Journal: Clinical Cancer Research (2021)

Abstract Purpose: Metastatic castration-resistant prostate cancer (mCRPC) remains a disease with high unmet medical need, as most patients do not achieve durable response with available treatments. Prostate-specific membrane antigen (PSMA) is a compelling target for mCRPC. It is highly expressed by primary and metastatic prostate cancer cells, with increased expression after progression on androgen deprivation therapy. Experimental Design: We developed AMG 160, a half-life extended, bispecific T-cell engager immuno-oncology therapy that binds PSMA on prostate cancer cells and cluster of differentiation 3 on T cells for treatment of mCRPC. AMG 160 was evaluated in vitro and in mCRPC xenograft models. AMG 160 tolerability was assessed in nonhuman primates (NHP). AMG 160 activity as monotherapy and in combination with a PSMA-imaging agent, novel hormonal therapy, and immune checkpoint blockade was evaluated. Results: AMG 160 induces potent, specific killing of PSMA-expressing prostate cancer cell lines in vitro, with half-maximal lysis of 6–42 pmol/L. In vivo, AMG 160 administered weekly at 0.2 mg/kg engages T cells administered systemically and promotes regression of established 22Rv-1 mCRPC xenograft tumors. AMG 160 is compatible with the imaging agent gallium 68–labeled PSMA-11, and shows enhanced cytotoxic activity when combined with enzalutamide or an anti-programmed death-1 antibody. AMG 160 exhibits an extended half-life and has an acceptable safety profile in NHPs. Conclusions: The preclinical characterization of AMG 160 highlights its potent antitumor activity in vitro and in vivo, and its potential for use with known diagnostic or therapeutic agents in mCRPC. These data support the ongoing clinical evaluation of AMG 160 in patients with mCRPC. See related commentary by Kamat et al., p. 2675
Suicide terrorism, moral relativism, and the situationist narrative
Authors: David R Mandel
Journal: Behavioral and Brain Sciences (2014)

Abstract Lankford challenges two popular views of suicide terrorists: first, that they are psychologically normal and, second, that they are heroic, not unlike professional soldiers. I augment Lankford's critique by tracing these views to a simplistic situationist narrative and to a careless form of moral relativism to which many scholars adhere. Conceptual weaknesses of these positions are briefly discussed.
High incidence of MYD88 and KMT2D mutations in Chinese with chronic lymphocytic leukemia
Authors: Shuhua Yi, Yuting Yan, Meiling Jin, Wenjie Xiong, Zhen Yu, Ying Yu, Rui Cui, Jun Wang, Yi Wang, Yani Lin, Yujiao Jia, Donglei Zhang, Tingyu Wang, Rui Lv, Wei Liu, Weiwei Sui, Wenyang Huang, Mingwei Fu, Yan Xu, Shuhui Deng, Gang An, Dehui Zou, Zengjun Li, Jun Shi, Zhijian Xiao, Jianxiang Wang, Tao Cheng, Robert Peter Gale, Lili Wang, Lugui Qiu
Journal: Leukemia (2021)
An Empirical Antigen Selection Method Identifies Neoantigens That Either Elicit Broad Antitumor T-cell Responses or Drive Tumor Growth
Authors: Hubert Lam, Lisa K. McNeil, Hanna Starobinets, Victoria L. DeVault, Roger B. Cohen, Przemyslaw Twardowski, Melissa L. Johnson, Maura L. Gillison, Mark N. Stein, Ulka N. Vaishampayan, Arthur P. DeCillis, James J. Foti, Vijetha Vemulapalli, Emily Tjon, Kyle Ferber, Daniel B. DeOliveira, Wendy Broom, Parul Agnihotri, Elizabeth M. Jaffee, Kwok-Kin Wong, Charles G. Drake, Pamela M. Carroll, Thomas A. Davis, Jessica Baker Flechtner
Journal: Cancer Discovery (2021)

Neoantigens are critical targets of antitumor T-cell responses. The ATLAS bioassay was developed to identify neoantigens empirically by expressing each unique patient-specific tumor mutation individually in Escherichia coli, pulsing autologous dendritic cells in an ordered array, and testing the patient's T cells for recognition in an overnight assay. Profiling of T cells from patients with lung cancer revealed both stimulatory and inhibitory responses to individual neoantigens. In the murine B16F10 melanoma model, therapeutic immunization with ATLAS-identified stimulatory neoantigens protected animals, whereas immunization with peptides associated with inhibitory ATLAS responses resulted in accelerated tumor growth and abolished efficacy of an otherwise protective vaccine. A planned interim analysis of a clinical study testing a poly-ICLC adjuvanted personalized vaccine containing ATLAS-identified stimulatory neoantigens showed that it is well tolerated. In an adjuvant setting, immunized patients generated both CD4+ and CD8+ T-cell responses, with immune responses to 99% of the vaccinated peptide antigens. SIGNIFICANCE: Predicting neoantigens in silico has progressed, but empirical testing shows that T-cell responses are more nuanced than straightforward MHC antigen recognition. The ATLAS bioassay screens tumor mutations to uncover preexisting, patient-relevant neoantigen T-cell responses and reveals a new class of putatively deleterious responses that could affect cancer immunotherapy design.This article is highlighted in the In This Issue feature, p. 521.
Treatment patterns and survival outcomes of older patients with advanced pancreatic cancer (APC): A Canadian real-world evidence study.
Authors: Atul Batra, Ravi Ramjeesingh, Brandon M. Meyers, Michael M. Vickers, Rachel Anne Goodwin, Dawn Elizabeth Armstrong, Winson Y. Cheung, Christina Kim
Journal: Journal of Clinical Oncology (2021)

385 Background: We aimed to compare chemotherapy regimens used and overall survival (OS) among geriatric patients (≥ 75 years) with APC as compared to old (65-74 years) and young (&lt; 65 years) patients with APC. Methods: In this retrospective population-based analysis, we identified patients with APC (defined as inoperable/metastatic disease) from 5 large provinces in Canada who were diagnosed from 2011 to 2016. Kaplan-Meier curves were plotted to derive OS and multivariable Cox regression models were constructed to determine the associations of different age groups on OS. Results: We included 636 patients diagnosed with APC of whom 258 (40.6%), 247 (38.8%) and 131 (20.6%) were young, old and geriatric. Approximately half (45.7%) of all patients were women. Eastern Cooperative Oncology Group performance status (ECOG PS) was known in 508 patients at diagnosis among whom 62.2% were 0-1 and 37.8% were 2+. ECOG PS was more likely to be 2+ in the geriatric group (46.8% vs 41.1% vs 31.3%; P = 0.017). Most patients (95.8%) had metastatic disease while the remaining patients had inoperable locally advanced disease. Within the study cohort, 38.7% received chemotherapy. Treatment rates differed based on age: 41.9% in young patients, 40.9% in old patients and 28.2% in geriatric patients (P = 0.02). Choice of first-line chemotherapy varied and included FOLFIRINOX (F) in 99 (40.2%), gemcitabine and nab-paclitaxel (GN) in 91 (37.0%) and gemcitabine (G) in 56 (22.8%). F, GN and G were administered in 27.0%, 32.4% and 40.5% of geriatric patients, 40.6%, 32.7% and 26.7% of old patients, and 44.4%, 42.6% and 13.0% of young patients, respectively (P = 0.007). After adjusting for baseline factors, both geriatric (odds ratio [OR], 0.70; 95% confidence interval [CI], 0.42-1.17; P = 0.175) and old patients were as likely to receive chemotherapy (OR, 1.04; 95% CI, 0.70-1.56; P = 0.815) as their young counterparts. The median OS was 7.1 (6.3-8.4), 6.7 (5.5-8.9) and 5.3 (4.3-6.8) months in young, old and geriatric patients, respectively. After adjusting for baseline variables, both geriatric (hazard ratio [HR], 1.25; 95% CI, 0.96-1.62; P = 0.101) and old patients (HR, 1.16; 95% CI, 0.94-1.42; P = 0.171) experienced similar OS as young patients. ECOG PS 2+ at presentation was associated with worse OS as was treatment with G. Conclusions: Overall treatment rates for APC are low in the real world. The poor OS in geriatric patients with APC is driven by poor PS and use of less intensive chemotherapy. Age alone should not be considered a contraindication for more intensive chemotherapy since treatment benefit is observed across all age groups. [Table: see text]
Noble Metal Nanomaterials for NIR‐Triggered Photothermal Therapy in Cancer
Authors: Zhuoqian Lv, Sijia He, Youfu Wang, Xinyuan Zhu
Journal: Advanced Healthcare Materials (2021)

Abstract It is of great significance to develop anticancer therapeutic agents or technologies with high degree of specificity and patient compliance, while low toxicity. The emerging photothermal therapy (PTT) has become a new and powerful therapeutic technology due to its noninvasiveness, high specificity, low side effects to normal tissues and strong anticancer efficacy. Noble metal nanomaterials possess strong surface plasmon resonance (SPR) effect and synthetic tunability, which make them facile and effective PTT agents with superior optical and photothermal characteristics, such as high absorption cross‐section, incomparable optical‐thermal conversion efficiency in the near infrared (NIR) region, as well as the potential of bioimaging. By incorporating with various functional reagents such as antibodies, peptides, biocompatible polymers, chemo‐drug and immune factors, noble metal nanomaterials have presented strong potential in multifunctional cancer therapy. Herein, the recent development regarding the application of noble metal nanomaterials for NIR‐triggered PTT in cancer treatment is summarized. A variety of studies with good therapeutic effects against cancer from impressive photothermal efficacy of noble metal nanomaterials are concluded. Intelligent nanoplatforms through ingenious fabrication showing potential of multifunctional PTT, combined with chemo‐therapy, immunotherapy, photodynamic therapy (PDT), as well as simultaneous imaging modality are also demonstrated.
Impaired antibacterial response of liver sinusoidal Vγ9<sup>+</sup>Vδ2<sup>+</sup> T cells in patients with chronic liver disease
Authors: Min-Seok Rha, Ji Won Han, June-Young Koh, Ha Seok Lee, Jong Hoon Kim, Kyungjoo Cho, Soon Il Kim, Myoung Soo Kim, Jae Geun Lee, Su-Hyung Park, Dong Jin Joo, Jun Yong Park, Eui-Cheol Shin
Journal: Gut (2021)

Objective The liver acts as a frontline barrier against diverse gut-derived pathogens, and the sinusoid is the primary site of liver immune surveillance. However, little is known about liver sinusoidal immune cells in the context of chronic liver disease (CLD). Here, we investigated the antibacterial capacity of liver sinusoidal γδ T cells in patients with various CLDs. Design We analysed the frequency, phenotype and functions of human liver sinusoidal γδ T cells from healthy donors and recipients with CLD, including HBV-related CLD (liver cirrhosis (LC) and/or hepatocellular carcinoma (HCC)), alcoholic LC and LC or HCC of other aetiologies, by flow cytometry and RNA-sequencing using liver perfusates obtained during living donor liver transplantation. We also measured the plasma levels of D-lactate and bacterial endotoxin to evaluate bacterial translocation. Results The frequency of liver sinusoidal Vγ9 + Vδ2 + T cells was reduced in patients with CLD. Immunophenotypic and transcriptomic analyses revealed that liver sinusoidal Vγ9 + Vδ2 + T cells from patients with CLD were persistently activated and pro-apoptotic. In addition, liver sinusoidal Vγ9 + Vδ2 + T cells from patients with CLD showed significantly decreased interferon (IFN)-γ production following stimulation with bacterial metabolites and Escherichia coli . The antibacterial IFN-γ response of liver sinusoidal Vγ9 + Vδ2 + T cells significantly correlated with liver function, and inversely correlated with the plasma level of D-lactate in patients with CLD. Repetitive in vitro stimulation with E. coli induced activation, apoptosis and functional impairment of liver sinusoidal Vγ9 + Vδ2 + T cells. Conclusion Liver sinusoidal Vγ9 + Vδ2 + T cells are functionally impaired in patients with CLD. Bacterial translocation and decreasing liver functions are associated with functional impairment of liver sinusoidal Vγ9 + Vδ2 + T cells.
AB0105 Dynamics of humoral immunity indices in systemic sclerosis patients depending on the therapy carried out
Authors: AB Zborovsky, IP Gontar, AV Alexandrov, LA Maslakova, GF Sychova, OI Emelyanova
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> <h3>Objectives</h3> The aim of our study was to improve immunological control of specific antibodies (Ab) dynamics in blood of systemic sclerosis (SSc) patients during the therapy carried out using immunofluorescent (IFA) and immunoenzyme (IEA) analyses taking advantages of immobilised magnosorbents (MS). <h3>Methods</h3> The Ab towards denatured deoxyribonucleic acid (dDNA), ribonucleic acid (RNA), cardiolipin (CL) were determined by IEA method, Ab towards catalase (Cat) ? by IFA method in sera of 28 SSc patients using immobilised MS before and after hospital treatment. Immobilisation was carried out by method of emulsion polymerisation by Gontar <i>et al</i>. (1990) in nitrogen gas flow with magnetic material incorporation in polyacrilamid gel structure. All observed patients were divided into 3 subgroups: first group (32 patients) was treated with basic medicines (D-penicillamine, vasomotor medicaments, physiotherapy, exercises, massage, symptomatic therapy), second group (22 patients) – + glucocorticosteroids; and third group (14 patients) – + plasmapheresis (Pph). <h3>Results</h3> There were not reliable decrease of studied Ab (p &gt; 0,05) in first group by IEA method, except Ab towards RNA (p &lt; 0,05). However, we noted reliable decrease of Ab towards Cat (p &lt; 0,05 after the course of therapy by IFA. In second group we revealed the decrease of Ab towards dDNA and RNA (p &lt; 0,05), while the dynamics of Ab towards Cat and CL were less evident (p &gt; 0,05). The positive effect of Pph was noted in third group, where we revealed marked tendency to decrease of Ab towards dDNA (p &lt; 0,02), CL (p &lt; 0,001), Cat and RNA (p &lt; 0,05). <h3>Conclusion</h3> The decrease of Ab towards dDNA, RNA, CL and Cat were noted in SSc patients during hospital treatment that allow the use of these indices as criteria for therapy efficiency and its duration. The use of extracorporal treatment method ? Pph in complex therapy of SSc patients allow to achieve clinical improvement in patients side by side with significant decrease o f Ab towards dDNA, RNA, CL and Cat.
Exploring the clinical value of tumor microenvironment in platinum-resistant ovarian cancer
Authors: Alia Ghoneum, Sameh Almousa, Bailey Warren, Ammar Yasser Abdulfattah, Junjun Shu, Hebatullah Abouelfadl, Daniela Gonzalez, Christopher Livingston, Neveen Said
Journal: Seminars in Cancer Biology (2021)
Landmark analysis of overall survival (OS) by objective response (OR) in previously treated patients (pts) with advanced hepatocellular carcinoma (aHCC): Post-hoc analysis of the randomized, phase III KEYNOTE-240 study.
Authors: Julien Edeline, Stéphane Cattan, Philippe Merle, Bruno Daniele, Stephen Lam Chan, Thomas Yau, Mohamed Bouattour, Ho Yeong Lim, Yee Chao, Jennifer J. Knox, Sadahisa Ogasawara, Marcelo Garrido, Ann-Lii Cheng, Andrew X. Zhu, Richard S. Finn, Abby B. Siegel, Ahmadur Rahman, Chih-Chin Liu, Masatoshi Kudo
Journal: Journal of Clinical Oncology (2021)

318 Background: Studies have shown that OR is prognostic of OS in pts with HCC. KEYNOTE (KN)-224 (NCT02702414) evaluated pembrolizumab (pembro; anti-PD-1) in sorafenib (sora)-treated pts with aHCC and demonstrated an OR rate of 17% that was durable in responders receiving pembro, ultimately leading to its FDA approval. In KN-224, a landmark analysis showed that OR in pembro-treated pts was prognostic of longer OS. The KN-240 (NCT02702401) study evaluated pembro + best supportive care (BSC) vs placebo (pbo) + BSC in sora-treated pts with aHCC. Although clinical benefit was observed in KN-240 with pembro vs pbo, prespecified statistical significance criteria for OS and PFS were not met. This post hoc analysis of KN-240 was performed to determine whether OR at landmark is prognostic of longer survival after landmark time. Methods: Eligible pts were aged ≥18 y, had confirmed aHCC, and experienced progression during or after sora treatment or intolerance to sora. Landmark analyses of OS according to OR at 6, 12, and 18 wk after randomization were performed on the pembro arm to examine the association between survival after the landmark with response achieved prior to the landmark. OR was assessed by blinded independent central review per RECIST v1.1. Responders at each landmark were defined as pts with any response assessment of CR or PR before the landmark date; all other pts were defined as nonresponders. HRs and 95% CIs for survival after the landmark were calculated from the Cox proportional model with Efron’s method of tie handling with responder status as a single covariate. Analyses were performed in the ITT population. Results: As of Jan 2, 2019, the median time from randomization to data cutoff was 21.2 months (range 13.4-30.4) for pembro. There were 51 pts (18.3%) with a BOR of CR or PR in the pembro arm and 6 pts (4.4%) with a BOR of PR (no CR) in the pbo arm (excluded from landmark analyses). OS after landmark time was longer for responders compared with nonresponders at the wk 6, 12, and 18 time points (Table). The HR for OS after landmark time for responders versus nonresponders were 0.37 (95% CI 0.18-0.75), 0.39 (95% CI 0.23-0.66), and 0.37 (95% CI 0.21-0.63) at wk 6, 12, and 18, respectively. Conclusions: This post hoc analysis demonstrates that pts with sora-treated aHCC who achieve OR by landmark time with pembro have longer OS after the landmark time, confirming the prognostic association between OR with pembro and OS observed in KN-224. Clinical trial information: NCT02702401. [Table: see text]
A versatile platform for generating engineered extracellular vesicles with defined therapeutic properties
Authors: Kevin Dooley, Russell E. McConnell, Ke Xu, Nuruddeen D. Lewis, Sonya Haupt, Madeleine R. Youniss, Shelly Martin, Chang Ling Sia, Christine McCoy, Raymond J. Moniz, Olga Burenkova, Jorge Sanchez-Salazar, Su Chul Jang, Bryan Choi, Rane A. Harrison, Damian Houde, Dalia Burzyn, Charan Leng, Katherine Kirwin, Nikki L. Ross, Jonathan D. Finn, Leonid Gaidukov, Kyriakos D. Economides, Scott Estes, James E. Thornton, John D. Kulman, Sriram Sathyanarayanan, Douglas E. Williams
Journal: Molecular Therapy (2021)

Extracellular vesicles (EVs) are an important intercellular communication system facilitating the transfer of macromolecules between cells. Delivery of exogenous cargo tethered to the EV surface or packaged inside the lumen are key strategies for generating therapeutic EVs. We identified two "scaffold" proteins, PTGFRN and BASP1, that are preferentially sorted into EVs and enable high-density surface display and luminal loading of a wide range of molecules, including cytokines, antibody fragments, RNA binding proteins, vaccine antigens, Cas9, and members of the TNF superfamily. Molecules were loaded into EVs at high density and exhibited potent in vitro activity when fused to full-length or truncated forms of PTGFRN or BASP1. Furthermore, these engineered EVs retained pharmacodynamic activity in a variety of animal models. This engineering platform provides a simple approach to functionalize EVs with topologically diverse macromolecules and represents a significant advance toward unlocking the therapeutic potential of EVs.