bluuebunny/crossref_metadata_2025_split huggingface dataset:
POSEIDON Trial Phase 1b Results: Safety, Efficacy and Circulating Tumor DNA Response of the Beta Isoform-Sparing PI3K Inhibitor Taselisib (GDC-0032) Combined with Tamoxifen in Hormone Receptor Positive Metastatic Breast Cancer Patients
Authors: Baird Richard D. , van Rossum Annelot G.J. , Oliveira Mafalda , Beelen Karin , Gao Meiling , Schrier Mariette , Mandjes Ingrid A.M. , Garcia-Corbacho Javier , Vallier Anne-Laure , Dougall Greig , van Werkhoven Erik , Linossi Constanza , Kumar Sanjeev , van Tinteren Harm , Callari Maurizio , Beddowes Emma , Perez-Garcia José-Manuel , Rosing Hilde , Platte Else , Nederlof Petra , Schot Margaret , de Vries Schultink Aurelia , Bernards René , Saura Cristina , Gallagher William , Cortès Javier , Caldas Carlos , Linn Sabine C. 
Published: August 2019

Abstract

Purpose:
The strategy of combining endocrine therapy with PI3K-mTOR inhibition has shown promise in estrogen receptor (ER)–positive breast cancer, but new agents and combinations with a better therapeutic index are urgently needed. Taselisib is a potent, selective, beta-isoform–sparing PI3 kinase inhibitor.

Patients and Methods:
30 patients with ER-positive, metastatic breast cancer who had failed prior endocrine therapy were treated with escalating doses of taselisib (2 or 4 mg in an intermittent or continuous schedule) combined with tamoxifen 20 mg once daily in this phase 1b study using a “rolling six” design.

Results:
Taselisib combined with tamoxifen was generally well tolerated, with treatment-emergent adverse events as expected for this class of drugs, including diarrhea (13 patients, 43%), mucositis (10 patients, 33%), and hyperglycemia (8 patients, 27%). No dose-limiting toxicities were observed. Objective responses were seen in 6 of 25 patients with RECIST-measurable disease (ORR 24%). Median time to disease progression was 3.7 months. Twelve of 30 patients (40%) had disease control for 6 months or more. Circulating tumor (ct)DNA studies using next-generation tagged amplicon sequencing identified early indications of treatment response and mechanistically relevant correlates of clinical drug resistance (e.g., mutations in KRAS, ERBB2) in some patients.

Conclusions:
Taselisib can be safely combined with tamoxifen at the recommended phase 2 dose of 4 mg given once daily on a continuous schedule. Preliminary evidence of antitumor activity was seen in both PIK3CA mutant and wild-type cancers. The randomized phase 2 part of POSEIDON (testing tamoxifen plus taselisib or placebo) is currently recruiting.
Molecular Characterization of Locally Relapsed Head and Neck Cancer after Concomitant Chemoradiotherapy
Authors: de Roest Reinout H. , Mes Steven W. , Poell Jos B. , Brink Arjen , van de Wiel Mark A. , Bloemena Elisabeth , Thai Elena , Poli Tito , Leemans C. René , Brakenhoff Ruud H. 
Published: August 2019

Abstract

Purpose:
To investigate the pathobiological origin of local relapse after chemoradiotherapy, we studied genetic relationships of primary tumors (PT) and local relapses (LR) of patients treated with chemoradiotherapy.

Experimental Design:
First, low-coverage whole genome sequencing was performed on DNA from 44 biopsies of resected head and neck squamous cell carcinoma (HNSCC) specimens (median 3 biopsies/tumor) to assess suitability of copy number alterations (CNAs) as biomarker for genetic relationships. CNAs were compared within and between tumors and an algorithm was developed to assess genetic relationships with consideration of intratumor heterogeneity. Next, this CNA-based algorithm was combined with target enrichment sequencing of genes frequently mutated in HNSCC to assess the genetic relationships of paired tumors and LRs of patients treated with chemoradiotherapy.

Results:
Genetic relationship analysis using CNAs could accurately (96%) predict tumor biopsy pairs as patient-matched or independent. However, subsequent CNA analysis of PTs and LRs after chemoradiotherapy suggested genetic relationships in only 20% of cases, and absence in 80%. Target enrichment sequencing for mutations confirmed absence of any genetic relationship in half of the paired PTs and LRs.

Conclusions:
There are minor variations in CNA profiles within different areas of HNSCC tumors and many between independent tumors, suggesting that CNA profiles could be exploited as a marker of genetic relationship. Using CNA profiling and mutational analysis of cancer driver genes, relapses after chemoradiotherapy appear to be partially genetically related to the corresponding PTs, but seem often genetically unrelated. This remarkable observation warrants further studies and will impact therapeutic innovations and prognostic modeling when using index tumor characteristics.
Phase I Trial of Well-Differentiated Neuroendocrine Tumors (NETs) with Radiolabeled Somatostatin Antagonist 177Lu-Satoreotide Tetraxetan
Authors: Reidy-Lagunes Diane , Pandit-Taskar Neeta , O'Donoghue Joseph A. , Krebs Simone , Staton Kevin D. , Lyashchenko Serge K. , Lewis Jason S. , Raj Nitya , Gönen Mithat , Lohrmann Christian , Bodei Lisa , Weber Wolfgang A. 
Published: August 2019

Abstract

Purpose:
Radiolabeled somatostatin receptor 2 (SSTR2) antagonists have shown higher tumor uptake and tumor-to-organ ratios than somatostatin agonists in preclinical models of neuroendocrine tumors (NETs). We performed a phase I study to evaluate the safety and efficacy of SSTR2 antagonist 177Lu-satoreotide tetraxetan.

Patients and Methods:
Twenty patients with advanced SSTR2-positive NETs were treated with 177Lu-satoreotide tetraxetan. Patients first underwent a dosimetry study with 177Lu-satoreotide tetraxetan to determine the therapeutic activity that could be safely administered. This activity was split into two equal cycles to be delivered 3 months apart. The maximum activity was 7.4 GBq per cycle.

Results:
Of 20 patients with NETs (one lung, seven small bowel, nine pancreatic, one gastric, one rectal, one kidney; mean prior treatments: three), six received one cycle of 177Lu- satoreotide tetraxetan and 14 received two cycles. Hematologic toxicity after cycle 1 was mild-moderate and reversed before cycle 2. However, grade 4 hematologic toxicity occurred in four of seven (57%) patients after cycle 2 of 177Lu-satoreotide tetraxetan. The study was suspended, and the protocol modified to limit the cumulative absorbed bone marrow dose to 1 Gy and to reduce prescribed activity for cycle 2 by 50%. The best overall response rate was 45% [5% complete response (1/20), 40% partial response (8/20)]; with 40% stable disease (8/20) and 15% progression of disease (3/20). Median progression-free survival (PFS) was 21.0 months (95% CI, 13.6–NR).

Conclusions:
In this trial of heavily treated NETs, preliminary data are promising for the use of 177Lu-satoreotide tetraxetan. Additional studies are ongoing to determine optimal therapeutic dose/schedule.
Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating Tumor Cell Sequencing inALK-Rearranged Non–Small-Cell Lung Cancer
Authors: Pailler Emma , Faugeroux Vincent , Oulhen Marianne , Mezquita Laura , Laporte Mélanie , Honoré Aurélie , Lecluse Yann , Queffelec Pauline , NgoCamus Maud , Nicotra Claudio , Remon Jordi , Lacroix Ludovic , Planchard David , Friboulet Luc , Besse Benjamin , Farace Françoise 
Published: August 2019

AbstractPurpose:Patients with anaplastic lymphoma kinase (ALK)–rearranged non–small-cell lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New diagnostic strategies are needed to assess resistance mechanisms and provide patients with the most effective therapy. We asked whether single circulating tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors and underlying tumor heterogeneity in ALK-rearranged NSCLC.Experimental Design:Resistance mutations were investigated in CTCs isolated at the single-cell level from patients at disease progression on crizotinib (n = 14) or lorlatinib (n = 3). Three strategies including filter laser-capture microdissection, fluorescence activated cell sorting, and the DEPArray were used. One hundred twenty-six CTC pools and 56 single CTCs were isolated and sequenced. Hotspot regions over 48 cancer-related genes and 14 ALK mutations were examined to identify ALK-independent and ALK-dependent resistance mechanisms.Results:Multiple mutations in various genes in ALK-independent pathways were predominantly identified in CTCs of crizotinib-resistant patients. The RTK-KRAS (EGFR, KRAS, BRAF genes) and TP53 pathways were recurrently mutated. In one lorlatinib-resistant patient, two single CTCs out of 12 harbored ALK compound mutations. CTC-1 harbored the ALKG1202R/F1174C compound mutation virtually similar to ALKG1202R/F1174L present in the corresponding tumor biopsy. CTC-10 harbored a second ALKG1202R/T1151M compound mutation not detected in the tumor biopsy. By copy-number analysis, CTC-1 and the tumor biopsy had similar profiles, whereas CTC-10 harbored multiple copy-number alterations and whole-genome duplication.Conclusions:Our results highlight the genetic heterogeneity and clinical utility of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients. Single CTC sequencing may be a unique tool to assess heterogeneous resistance mechanisms and help clinicians for treatment personalization and resistance options to ALK-targeted therapies.
Perioperative Dynamic Changes in Circulating Tumor DNA in Patients with Lung Cancer (DYNAMIC)
Authors: Chen Kezhong , Zhao Heng , Shi Yanbin , Yang Fan , Wang Lien Tu , Kang Guannan , Nie Yuntao , Wang Jun 
Published: August 2019

Abstract

Purpose:
No study has investigated the precise perioperative dynamic changes in circulating tumor DNA (ctDNA) in any patients with early-stage cancer. This study (DYNAMIC) investigated perioperative dynamic changes in ctDNA and determined the appropriate detection time of ctDNA-based surveillance for surgical patients with lung cancer.
Experimental Design: Consecutive patients who underwent curative-intent lung resections were enrolled prospectively (NCT02965391). Plasma samples were obtained at multiple prespecified time points including before surgery (time A), during surgery after tumor resection (time B–time D), and after surgery (time P1–time P3). Next-generation sequencing–based detection platform was performed to calculate the plasma mutation allele frequency. The primary endpoint was ctDNA half-life after radical tumor resection.

Results:
Thirty-six patients showed detectable mutations in time A. The plasma ctDNA concentration showed a rapid decreasing trend after radical tumor resection, with the average mutant allele fraction at times A, B, C, and D being 2.72%, 2.11%, 1.14%, and 0.17%, respectively. The median ctDNA half-life was 35.0 minutes. Patients with minimal residual disease (MRD) detection had a significant slower ctDNA half-life than those with negative MRD (103.2 minutes vs. 29.7 minutes, P = 0.001). The recurrence-free survival of patients with detectable and undetectable ctDNA concentrations at time P1 was 528 days and 543 days, respectively (P = 0.657), whereas at time P2 was 278 days and 637 days, respectively (P = 0.002).

Conclusions:
ctDNA decays rapidly after radical tumor resection. The ctDNA detection on the third day after R0 resection can be used as the baseline value for postoperative lung cancer surveillance.
Transforming the Early Drug Development Paradigm at the National Cancer Institute: The Formation of NCI's Experimental Therapeutics Clinical Trials Network (ETCTN)
Authors: Massett Holly A. , Mishkin Grace , Moscow Jeffrey A. , Gravell Amy , Steketee Michael , Kruhm Martha , Han Sae H. , Barry Barbara , Montello Michael , Zwiebel James , Abrams Jeffrey S. , Doroshow James H. , Ivy S. Percy 
Published: August 2019

Abstract
Early drug development for cancer requires broad collaboration and skilled clinical investigators to enable enrollment of patients whose tumors have defined molecular profiles. To respond to these challenges, the National Cancer Institute (NCI) transformed its 60-year-old early-phase drug development program in 2014 into the Experimental Therapeutics Clinical Trials Network (ETCTN). The ETCTN is a consolidated, national network of 40+ academic institutions responsible for conducting more than 100 early-phase clinical trials. It promotes team science coordinated among basic, translational, and clinical investigators, emphasizing the inclusion of early career trialists. This perspective provides a brief overview of the ETCTN, summarizes its successes and challenges over its first grant funding cycle, and discusses the program's future directions. Measures indicated strong connectivity across the institutions, significant increases in investigator approval of the ETCTN scientific portfolio from years 1 to 4, and substantial research activity over 5 years, with 334 letters of intent submitted, 102 trials activated, and 3,570 patients accrued. The ETCTN's successful adoption relied heavily on the inclusion of senior investigators who have long-standing interactions with the NCI and a willingness to participate in a team science approach and to mentor early career investigators. In addition, NCI invested substantial resources in a centralized infrastructure to conduct trials and to support the inclusion of biomarkers in its studies. The ETCTN provides evidence that a collaborative national clinical trial network for early drug development is feasible and can address the demands of precision medicine approaches to oncologic clinical trials.
Targeting PI3K/Akt/mTOR Pathway Identifies Differential Expression and Functional Role of IL8 in Liver Cancer Stem Cell Enrichment
Authors: Kahraman Deniz Cansen , Kahraman Tamer , Cetin-Atalay Rengul 
Published: August 2019

Abstract
Activation of the PI3K/Akt/mTOR pathway is an important signaling mechanism involved in the development and the progression of liver cancer stem cell (LCSC) population during acquired Sorafenib resistance in advanced hepatocellular carcinoma (HCC). Therefore, identification of novel therapeutic targets involving this pathway and acting on LCSCs is highly essential. Here, we analyzed the bioactivities and the molecular pathways involved in the action of small-molecule PI3K/Akt/mTOR pathway inhibitors in comparison with Sorafenib, DNA intercalators, and DAPT (CSC inhibitor) on CD133/EpCAM-positive LCSCs. Sorafenib and DNA intercalators lead to the enrichment of LCSCs, whereas Rapamycin and DAPT significantly reduced CD133/EpCAM positivity. Sequential treatment with Rapamycin followed by Sorafenib decreased the ratio of LCSCs as well as their sphere formation capacity, as opposed to Sorafenib alone. Under the stress of the inhibitors, differential expression analysis of 770 cancer pathway genes using network-based systems biology approach singled out IL8 expression association with LCSCs. Furthermore, IL8 secretion and LCSC enrichment ratio was also positively correlated. Following IL8 inhibition with its receptor inhibitor Reparixin or siRNA knockdown, LCSC features of HCC cells were repressed, and sensitivity of cells to Sorafenib increased significantly. Furthermore, inflammatory cytokines (IL8, IL1β, and IL11) were also upregulated upon treatment with HCC-approved kinase inhibitors Sorafenib and Regorafenib. Hence, chemotherapeutic stress alters inflammatory cytokine gene expression in favor of hepatic CSC population survival. Autocrine IL8 signaling is identified as a critical event, and its inhibition provides a promising complimentary therapeutic approach for the prevention of LCSC population enrichment.
Endothelial-to-Mesenchymal Transition in Human Adipose Tissue Vasculature Alters the Particulate Secretome and Induces Endothelial Dysfunction
Authors: Haynes Bronson A. , Yang Li Fang , Huyck Ryan W. , Lehrer Eric J. , Turner Joshua M. , Barabutis Nektarios , Correll Vanessa L. , Mathiesen Allison , McPheat William , Semmes O. John , Dobrian Anca D. 
Published: August 2019

Objective:
Endothelial cells (EC) in obese adipose tissue (AT) are exposed to a chronic proinflammatory environment that may induce a mesenchymal-like phenotype and altered function. The objective of this study was to establish whether endothelial-to-mesenchymal transition (EndoMT) is present in human AT in obesity and to investigate the effect of such transition on endothelial function and the endothelial particulate secretome represented by extracellular vesicles (EV).

Approach and Results:
We identified EndoMT in obese human AT depots by immunohistochemical co-localization of CD31 or vWF and α-SMA (alpha-smooth muscle actin). We showed that AT EC exposed in vitro to TGF-β (tumor growth factor-β), TNF-α (tumor necrosis factor-α), and IFN-γ (interferon-γ) undergo EndoMT with progressive loss of endothelial markers. The phenotypic change results in failure to maintain a tight barrier in culture, increased migration, and reduced angiogenesis. EndoMT also reduced mitochondrial oxidative phosphorylation and glycolytic capacity of EC. EVs produced by EC that underwent EndoMT dramatically reduced angiogenic capacity of the recipient naïve ECs without affecting their migration or proliferation. Proteomic analysis of EV produced by EC in the proinflammatory conditions showed presence of several pro-inflammatory and immune proteins along with an enrichment in angiogenic receptors.

Conclusions:
We demonstrated the presence of EndoMT in human AT in obesity. EndoMT in vitro resulted in production of EV that transferred some of the functional and metabolic features to recipient naïve EC. This result suggests that functional and molecular features of EC that underwent EndoMT in vivo can be disseminated in a paracrine or endocrine fashion and may induce endothelial dysfunction in distant vascular beds.
Effect of Empagliflozin on Left Ventricular Mass in Patients With Type 2 Diabetes Mellitus and Coronary Artery Disease
Authors: Verma Subodh , Mazer C. David , Yan Andrew T. , Mason Tamique , Garg Vinay , Teoh Hwee , Zuo Fei , Quan Adrian , Farkouh Michael E. , Fitchett David H. , Goodman Shaun G. , Goldenberg Ronald M. , Al-Omran Mohammed , Gilbert Richard E. , Bhatt Deepak L. , Leiter Lawrence A. , Jüni Peter , Zinman Bernard , Connelly Kim A. ,   For the EMPA-HEART CardioLink-6 Investigators
Published: August 2019

Background:
SGLT2 (sodium-glucose cotransporter 2) inhibitors lower cardiovascular events in type 2 diabetes mellitus but whether they promote direct cardiac effects remains unknown. We sought to determine if empagliflozin causes a decrease in left ventricular (LV) mass in people with type 2 diabetes mellitus and coronary artery disease.

Methods:

Between November 2016 and April 2018, we recruited 97 individuals ≥40 and ≤80 years old with glycated hemoglobin 6.5% to 10.0%, known coronary artery disease, and estimated glomerular filtration rate ≥60mL/min/1.73m
2
. The participants were randomized to empagliflozin (10 mg/day, n=49) or placebo (n=48) for 6 months, in addition to standard of care. The primary outcome was the 6-month change in LV mass indexed to body surface area from baseline as measured by cardiac magnetic resonance imaging. Other measures included 6-month changes in LV end-diastolic and -systolic volumes indexed to body surface area, ejection fraction, 24-hour ambulatory blood pressure, hematocrit, and NT-proBNP (N-terminal pro b-type natriuretic peptide).

Results:

Among the 97 participants (90 men [93%], mean [standard deviation] age 62.8 [9.0] years, type 2 diabetes mellitus duration 11.0 [8.2] years, estimated glomerular filtration rate 88.4 [16.9] mL/min/1.73m
2
, LV mass indexed to body surface area 60.7 [11.9] g/m
2
), 90 had evaluable imaging at follow-up. Mean LV mass indexed to body surface area regression over 6 months was 2.6 g/m
2
and 0.01 g/m
2
for those assigned empagliflozin and placebo, respectively (adjusted difference −3.35 g/m
2
; 95% CI, −5.9 to −0.81g/m
2
,
P
=0.01). In the empagliflozin-allocated group, there was significant lowering of overall ambulatory systolic blood pressure (adjusted difference −6.8mmHg, 95% CI −11.2 to −2.3mmHg,
P
=0.003), diastolic blood pressure (adjusted difference −3.2mmHg; 95% CI, −5.8 to −0.6mmHg,
P
=0.02) and elevation of hematocrit (
P
=0.0003).

Conclusions:
Among people with type 2 diabetes mellitus and coronary artery disease, SGLT2 inhibition with empagliflozin was associated with significant reduction in LV mass indexed to body surface area after 6 months, which may account in part for the beneficial cardiovascular outcomes observed in the EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients) trial.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02998970.
The kitābī Wife’s Conversion to Islam: An Unusual Interpretation by Ibn Qayyim al-Jawziyya
Authors: Bosanquet Antonia 
Published: August 2019

Abstract
This essay analyzes Ibn Qayyim al-Jawziyya’s (d. 751/1350) teaching about the legal options open to a woman who converts to Islam while married to a Jewish or Christian husband. I argue that Ibn al-Qayyim’s preferred position is unusual for the eighth/fourteenth century in which he wrote, although it may derive from Ibn Taymiyya’s (d. 728/ 1328) teaching on the subject. In order to contextualize Ibn al-Qayyim’s view, I summarize the variety of approaches to single-spouse conversion that dominated in the first century AH, and the broad consensus on the topic that developed after this. Although female conversion to Islam has received some attention in historical studies, there has been less focus on the legal discourse surrounding this question. The essay seeks to contribute to this discussion.
Islamic Law on the Provincial Margins: Christian Patrons and Muslim Notaries in Upper Egypt, 2nd-5th/8th-11th Centuries
Authors: Weitz Lev 
Published: August 2019

Abstract
This article examines the interaction of Coptic Christians with Islamic legal institutions in provincial Egypt on the basis of a corpus of 193 Arabic legal documents, as well as relevant Coptic ones, dating to the 2nd-5th/8th-11th centuries. I argue that around the 3rd/9th century Islamic Egypt’s Christian subjects began to make routine use of Islamic legal institutions to organize their economic affairs, including especially inheritance and related matters internal to Christian families. They did so in preference to the Christian authorities and Coptic deeds that had been their standard resource in the first two centuries of Muslim rule. The changing character of the Egyptian judiciary encouraged this shift in practice, as qāḍīs who adhered to fiqh procedural rules increasingly filled judicial roles formerly held by administrative officials. By eschewing and nudging into disuse a previously vital Coptic legal tradition, Christian provincials participated in the Islamization of ʿAbbāsid and Fāṭimid Egypt.
Life as a Reflexive Project: The Logics of Ethical Veganism and Meat-Eating
Authors: Presser Lois , Schally Jennifer L. , Vossler Christine 
Published: August 2019

Abstract
This paper is concerned with the ways that vegans and meat-eaters talk about themselves and their dietary practices. Data from a total of 81 semi-structured interviews with ethical vegans (n = 21) and meat-eaters (n = 60) were analyzed for themes and discursive strategies, and results were compared. Vegans insisted that nonhuman animals had interests of their own and spoke of making consumption choices. Meat-eaters tended to reduce animals to human purposes and claimed powerlessness to avoid doing harm to animals while also referencing some license to eating meat. Vegans shared stories of eating meat, whereas few of the meat-eaters did so. Turning points in those (vegan) stories pertained to realizations of harming animals, and thought knowledge were prominent themes in their accounts generally. Vegans were prone to critique past selves and the movement they had aligned themselves with. This research can help promote discourses of compassion and counter discourses of harm.