tbuckley/cabot-search huggingface dataset:
What is a COPD exacerbation? Current definitions, pitfalls, challenges and opportunities for improvement
Authors: Victor Kim, Shawn D. Aaron
Journal: European Respiratory Journal (2018)

Chronic obstructive pulmonary disease (COPD) is a chronic illness that can be periodically punctuated by exacerbations, characterised by acute worsening of symptoms, including increased dyspnoea, cough, sputum production and sputum purulence. COPD exacerbations are common and have important clinical and economic consequences, including lost work productivity, increased utilisation of healthcare resources, temporary or permanent reductions in lung function and exercise capacity, hospitalisation, and sometimes death. Over the past two decades, clinicians and researchers have broadened their treatment goals for COPD to extend beyond improving lung function and symptoms, and have begun to address the importance of preventing and reducing exacerbations. However, despite the best efforts of clinicians and guideline committees, current definitions of COPD exacerbations are imperfect and fraught with problems. The cardinal symptoms of a COPD exacerbation are nonspecific and can result from acute cardiorespiratory illnesses other than COPD. A proposed definition, which may be more specific than current definitions, suggests that COPD exacerbation be defined as an acute or subacute worsening of dyspnoea (≥5 on a visual analogue scale that ranges from 0 to 10) sometimes but not necessarily accompanied by increased cough, sputum volume and/or sputum purulence. Necessary laboratory criteria for an exacerbation include oxygen desaturation ≤4% below that of stable state, elevated levels of circulating blood neutrophils or eosinophils (≥9000 neutrophils·mm-3 or ≥2% blood eosinophils) and elevated C-reactive protein (≥3 mg·L-1), without evidence of pneumonia or pulmonary oedema on chest radiography and with negative laboratory test results for other aetiologies. Herein, we discuss the current state of the art with respect to how we define COPD exacerbations, associated pitfalls and challenges, and opportunities for improvement.
PRC-2 epigenetic chromatin reprogramming in ALK-positive (ALK+) lung cancer initial emergence of precision drug resistance.
Authors: Patrick C. Ma, Xiaoliang Wu, Satoshi Komo, Zuan-Fu Lim, Haixia Yang, Kacey Rhodes, Brandon C. Jones, Daniel J. Lindner, Francisco Almeida, Veronique Neumeister, Vamsidhar Velcheti, Elena Pugacheva, Ivan Martinez, Lihong Yin, Sijin Wen, Zhenfeng Zhang
Journal: Journal of Clinical Oncology (2018)

12020 Background: Despite remarkable upfront response to ALK tyrosine kinase inhibitors (TKIs) in ALK+ lung cancer, acquired resistance eventually develops. Molecular mechanisms of the initial emergence of drug resistance are poorly understood. Methods: ALK+ H3122, H2228 and a patient-derived Ma-ALK001.S NSCLC cell lines were used in our study. In vitro MTS viability and murine in vivo xenograft assays were performed. siRNA knockdown and CRISPR/cas9 gene knockout were used for mechanistic studies. ChIP-qPCR was conducted to analyze HOXB3 epigenetic marks. RNA-seq was also performed for transcriptome analysis. Tumor microarray (TMA) biomarker study was adopted for outcome analysis of the polycomb repressive complex-2 (PRC-2) in NSCLC. Results: Our study revealed a rapid-onset emergence of adaptive drug-resistant ALK+ lung cancer cells within the first 14 days upon TKI treatment initiation. The expression of stem cell transcription factors, most notably HOXB3, was induced adaptively within the tumor cells undergoing drug escape. Similarly, tumoral TGFβ2 autocrine expression both at mRNA and protein levels were significantly elevated, and it regulated the downstream HOXB3 expression and mitochondrial prosurvival BCL-2/BCL-xL signaling, cancer stemness and EMT markers. RNA-seq revealed a rapid-onset adaptive global transcriptome reprogramming in the drug-escaping persister tumor cells. ChIP-qPCR showed resistance emerged via epigenetic regulation of the untreated bivalent HOXB3 promoter closed chromatin state transforming to stem-like open state during drug-escape, based on H3K4me3/H3K27me3 methylation mark balance. Findings were validated via CRISPR/cas9-EZH2 knockout studies. AQUA-TMA biomarker and survival outcome analysis confirmed the clinical relevance of EZH2/UTX of PRC-2. Finally, direct EZH2 inhibition or knock-out promoted ALK-TKI drug resistance, while UTX inhibition enhanced drug sensitivity. Conclusions: ALK+ lung cancer achieves initial rapid-onset emergence of adaptive drug escape through PRC-2 epigenetic chromatin reprogramming to regulate cancer plasticity-EMT/stemness interplay via the TGFβ2-EZH2/UTX-HOXB3-BCL-2/BCL-xL cascade.
Efficacy of an intravenous formulation of NEPA, a fixed combination of fosnetupitant and palonosetron, compared with oral NEPA studies in the prevention of chemotherapy-induced nausea and vomiting (CINV): An analysis of 1026 patient experiences.
Authors: Eric Roeland, Paul Joseph Hesketh, Li Zhang, Richard J. Gralla, Lee Steven Schwartzberg
Journal: Journal of Clinical Oncology (2018)

e22177 Background: The approval of oral NEPA, a novel fixed antiemetic combination comprised of the NK1RA netupitant (300 mg) and 5-HT3RA palonosetron (PALO, 0.50 mg), was based on demonstrating superior prevention of CINV over PALO in patients receiving highly emetogenic chemotherapy (HEC) and anthracycline/cyclophosphamide (AC). An intravenous formulation of NEPA (fosnetupitant 235 mg plus PALO 0.25 mg) was developed to offer additional treatment options. In addition to showing pharmacokinetic bioequivalence, a clinical study showed comparable safety profiles for IV and oral NEPA in patients receiving non-AC HEC (Schwartzberg, Ann Oncol 2017). This post-hoc analysis presents the efficacy of IV and oral NEPA from pivotal studies in non-AC HEC. Methods: Data is compiled from 4 pivotal registration studies in adult chemotherapy-naïve patients with solid tumors undergoing predominantly cisplatin-based HEC. All studies had similar inclusion and exclusion criteria. In Study 1, IV NEPA was administered as a single 30-minute infusion prior to HEC; in Studies 1-4 a single capsule of oral NEPA was given prior to HEC. All patients received dexamethasone on Days 1-4. Complete response (CR: no emesis/no rescue medication) rates are summarized for the overall phase (0-120 h) of the initial cycle of HEC for each study and pooled for oral NEPA. No formal statistical comparisons were done for this post-hoc analysis. Results: The overall CR rate was 76.8% for IV NEPA and 79.8% for oral NEPA for the pooled studies (Table). These results compare favorably to aprepitant and rolapitant pivotal HEC studies where overall CR rates ranged from 62.7% - 72.7%. Conclusions: Both IV and oral formulations of NEPA represent safe, effective, and convenient single-dose prophylactic antiemetics targeting two distinct CINV pathways, offering comparable options for clinicians and patients in different settings. Clinical trial information: NCT02517021.CR (0-120 h) IV NEPA Oral NEPA N % N % Study 1 (Schwartzberg et al) 203 76.8 201 84.1 Study 2 (Hesketh et al) 135 89.6 Study 3 (Gralla et al) 75 84.0 Study 4 (Zhang et al) 412 73.8 Pooled Studies 1-4 823 79.8
SYNFRIZZ: A first-in-human (FIH) study of a radiolabeled monoclonal antibody (Mab) targeting frizzled homolog 10 (FZD10) in patients (pts) with advanced synovial sarcomas (SyS).
Authors: Philippe Alexandre Cassier, Anne Laure Giraudet, Chicaco Iwao-Fukukawa, Gwenaelle Garin, Jean-Noel Badel, David Kryza, Sylvie Chabaud, Claire Cropet, David Sarrut, Laurence Gilles-Afchain, Adrien Halty, Antoine Italiano, Nicolas Penel, Masaharu Mori, Takuya Tsunoda, Toyomasa Katagiri, Yusuke Nakamura, Simon J Baconnier, David Pérol, Jean-Yves Blay
Journal: Journal of Clinical Oncology (2017)

11054 Background: Advanced SyS are rare tumors with limited curative options. FZD10 is highly expressed in SyS but not in normal adult tissue. OTSA101 is a MAb targeting FZD10, labelled with a radioisotope. Methods: We conducted a phase I, FIH study including adult pts with advanced, refractory SyS. In part 1, pts received OTSA101 labelled with In 111 used as radiotracer to assess biodistribution and tumor uptake. In part 2, pts with significant tumor uptake were randomized to receive OTSA101 labelled with 370MBq of Y 90 (Arm A) or 1110MBq Y 90 (Arm B). Primary endpoints were occurrence of unacceptable biodistribution /lack of tumor uptake in part 1 and occurrence of related adverse events (AEs) Grade ≥ 3 during the first 8 weeks following injection of Y 90 OTSA101 in part 2. Responses were assessed per RECIST 1.1. Results: From January 2012 to June 2015, 20 pts (10 females, median age 43, range 21-67) with advanced SyS were enrolled. Ten pts (50%) had sufficient tumor uptake to proceed to part 2 and 8 were randomized (Arm A: 3 and Arm B: 5). Two pts were not randomized due to worsening PS. During part 2, the most common Grade ≥ 3 AEs were haematological, including reversible lymphopenia, thrombocytopenia and neutropenia, and were more common in Arm B. One pt with SD after 12 weeks received a 2 nd injection of 90 Y-OTSA101, but experienced fatal hemoptysis. No objective response was observed. Best response was SD in 5/8 pts lasting up to 21 weeks for 1 pt. Conclusions: This FIH shows that radioimmunotherapy targeting FZD10 is feasible and safe in SyS pts. Tumor uptake was heterogeneous but sufficient to select 50% of pts for 90 Y-OTSA101 treatment. Due to limited sample size, further clinical investigations are needed to assess the therapeutic activity of 90 Y-OTSA101 with a recommended dose of 1110MBq of 90 Y. Clinical trial information: NCT01469975.
Burden of acute myeloid leukemia (AML) in a U.S. commercially insured population.
Authors: May Hagiwara, Arati Sharma, Karen C Chung, Thomas E. Delea
Journal: Journal of Clinical Oncology (2017)

e18330 Background: AML accounts for 25% of acute leukemias in adults worldwide, with an estimated 5-year survival of 26% in the US. Up-to-date information on the clinical and economic burden of AML among US commercially insured patients (pts) is needed to inform reimbursement decisions. Methods: This retrospective study of the burden of AML in a US commercially insured population used the IMS PharMetrics Plus health insurance claims database. Adults with ≥1 claim with a diagnosis (Dx) of AML (ICD-9-CM 205.00, 205.01, or 205.02 or ICD-10-CM C92.00, C92.40, C92.50, C92.01, C92.41, C92.51, C92.02, C92.42, C92.52) during the study period (Jan 2008 through Dec 2015) were identified. To avoid rule-out diagnoses, pts with only 1 outpatient claim (or &gt;1 claim on a single day) with a Dx of AML not in relapse or remission were excluded. Annual incidence and total and AML-related inpatient and outpatient healthcare costs per person year (PY) were calculated by age and gender. For cost analyses, pts with newly diagnosed AML were assessed. To ensure adequate claims history to identify all prevalent cases, prevalence was calculated for the last year of the study period. Results: 26,344 adults with AML were identified during the study period, which covered 228.3 million PY of enrollment. The incidence rate was 4.9 per 100,000 PY. Incidence was greatest in men and pts aged 60+ years. Prevalence was 12.2 per 100,000 persons. Among 11,170 newly diagnosed AML pts, total average costs were $352,138 per PY. 63% of costs were for AML-related care. 70% of AML-related costs were for inpatient care. Costs were greatest for men, pts aged 45-59 years, and during the first 6 months post-diagnosis. Conclusions: Although AML is relatively rare, its economic burden to US commercial insurers is substantial. [Table: see text]
Incidence and risk factors for ibrutinib associated atrial fibrillation.
Authors: Josephine Ngozi Emole, Federico Viganego, Matthew B. Schabath, Bijal D. Shah, Julio C. Chavez, Christine Marie Walko, Howard L. McLeod, Javier Pinilla-Ibarz, Michael G. Fradley
Journal: Journal of Clinical Oncology (2016)

e19028 Background: Most of the information about ibrutinib-associated atrial fibrillation (AF) has been extrapolated from clinical trials for B cell lymphomas, however there is little information about AF and other supraventricular arrhythmias (SVT) in a “real-world” population of patients (pts) receiving ibrutinib. Our study retrospectively evaluated patient characteristics and risk factors by AF status in a cohort of pts treated with ibrutinib, outside of a clinical trial. Methods: We abstracted information on 73 pts treated at the Moffitt Cancer Center between 11/13/13 and 3/31/15 who completed at least one 28-day cycle of ibrutinib. Fisher's exact test was used to evaluate for any statistically significant differences in patient characteristics by AF status following ibrutinib therapy. Results: Incidence of AF (or other SVT) was 12% (n = 9) among the entire study cohort. Indications for ibrutinib use were primarily chronic lymphocytic leukemia (71%) and mantle cell lymphoma (22%). There were 69 pts without prior history of AF or antiarrhythmic drug use who were further analyzed for arrhythmia risk factors. In all incident cases, arrhythmias were managed by temporary cessation of ibrutinib with resumption after achieving adequate heart rate control. Comparing the pts that developed AF to those that did not, there were no significant differences in age, gender, body mass index, race, prior cardiovascular disease, hypertension, diabetes mellitus, tobacco use, or ibrutinib dose. Median ejection fraction (EF) among pts with AF was 65%, and the median left atrial (LA) size was 3.0cm. In those pts without AF, median EF was 62% and the median LA size was 3.5cm. There was no significant difference between groups (p = 0.96 for EF; p = 0.46 for LA size). Conclusions: The incidence of AF in our study was higher than in the original ibrutinib trials. There was no difference in echocardiographic parameters or traditional risk factors for the development of AF between groups, suggesting that ibrutinib may be intrinsically associated with AF. A case control study is ongoing to evaluate ibrutinib as an independent risk factor for AF.
Management of Complex Arteriovenous Malformations Using a Novel Combination Therapeutic Algorithm
Authors: Malcolm Pyles Chelliah, Huy M. Do, Zachary Zinn, Viraat Patel, Michael Jeng, Rohit K. Khosla, Mai-Thy Truong, Ann Marqueling, Joyce M. C. Teng
Journal: JAMA Dermatology (2018)

Current therapeutic options for patients with extracranial head and neck arteriovenous malformations are limited. Surgical intervention, such as sclerotherapy or resection, often result in rapid recurrence and progression of disease.To assess the efficacy and tolerability of sirolimus as an adjuvant therapy for endovascular embolization in the management of complicated extracranial head and neck arteriovenous malformations.This case series examined 6 patients with extracranial head and neck arteriovenous malformations treated from January 1, 2013, to December 31, 2017, at a multidisciplinary vascular anomalies clinic within Stanford Hospital and Clinics.Initiation of sirolimus at least 1 month prior to endovascular embolization, targeting a trough level of 10 to 15 ng/mL throughout the course of the endovascular embolization series and continued for at least 1 month after the series.Clinical manifestations; disease progression and overall response to treatment were assessed via clinical evaluation and radiographic imaging.All 6 patients (4 male and 2 female patients; mean age, 24.5 years [range, 9-44 years]) responded favorably to the combination of sirolimus therapy followed by endovascular embolization, and 4 patients exhibited a near-complete response. The median duration of follow-up was 19 months (range, 6-40 months). One patient discontinued sirolimus soon after embolization and experienced regrowth of the arteriovenous malformation after 1 year. Sirolimus was resumed, which has stabilized his disease for more than 2 years. Mild adverse effects were noted in 4 patients. The combination therapy was well tolerated in all patients. One patient developed skin ulceration after embolization and required surgical debridement. Another patient developed pulmonary microthrombi after embolization with cyanoacrylate glue that resolved with a brief course of anti-inflammatory therapy.Although further prospective trials are needed, this report suggests the benefit of a mammalian target of rapamycin inhibitor as an adjuvant therapy for surgical embolization of complex, extracranial head and neck arteriovenous malformations. The optimal dosing and therapeutic duration of sirolimus treatment before and after embolization remain to be determined.
Radiation-induced pulmonary cellular senescence and the potential regulatory mechanism of lpa-LPA<sub>1</sub> pathway.
Authors: Mengqian Li, Jianxin Xue, Limei Yin, Xiaowen Sun
Journal: Journal of Clinical Oncology (2018)

e24332 Background: Ionizing Radiation (IR) can inflict irreparable DNA damage on exposed cells that may undergo cellular senescence characterized by the permanent loss of proliferative potential, expression of senescence-associated β-galactosidase (SA-β-gal), and secreting senescence-associated secretory phenotype (SASP) factors. Our group has published that IR powerfully promotes the biosynthesis of lysophosphatidic acid (LPA) in irradiated lungs, which participates in the radiation-induced lung injuries (RILI) via LPA-LPA receptor1 (LPA1) pathway. This study aims to discover whether selectively block the LPA-LPA1 pathway can effectively ameliorate the cellular senescence caused by IR. Methods: SPF C57BL/6J mice were exposed to X-rays at the dose of 16Gy/f on the whole thorax. Irradiated mouse lungs were analysed at different points in time by Western blotting, RT-PCR, immunohistochemical methods, flow cytometry, etc. The irradiated mice were treated with AM966 (15mg/kg, qd), a selective antagonist to LPA1, from the 1st day to the 7th day after irradiation. HBE cells were exposed to the same radiation dose of 16Gy/f in combination with LPA(10μM) and/or AM966(20 μΜ), which was studied 48 hours after irradiation with methods as used in vivo. Results: The irradiated lung tissue was substantially positive of SA-β-gal from the 14th day after irradiation, which culminated in accompanying with extensive pulmonary fibrosis on the 60th day. The levels of SASP factors, such as IL-1α, IL-6, TGF-β, MMP9, boosted from the 7th day after irradiation, which was reduced significantly by AM966 prescription. For HBE cells, the mRNA expression of LPA1 standed out as the highest expressed among the LPA receptor1-6 after irradiation, while the mRNA of Autotaxin, an enzyme for LPA production, was barely detected. More than 90 percent of the HBE cells were arrested in the G2/M phase 48 hours after irradiation and exhibited high activity of SA-β-gal and γH2AX , which was ameliorated significantly by AM966. Conclusions: AM966 treatment ameliorates the cellular senescence at the early stage in the irradiated mouse lungs. The inhibition of formation of DSBs and SASP factors may partly attribute to its attenuating effects.
Phase Ib trial of the RNActive cancer vaccine BI 1361849 (CV9202) and local radiotherapy (RT) in patients (pts) with stage IV NSCLC with disease control after 1st-line chemotherapy or during therapy with an EGFR-TKI: results of an interim analysis.
Authors: Martin Sebastian, Ute Klinkhardt
Journal: Journal of Clinical Oncology (2016)

e20627 Background: Preclinical studies demonstrated that local RT acts synergistically with RNActive immunotherapy to enhance anti-tumor effects and increase tumor-infiltrating lymphocytes. BI 1361849 is a therapeutic vaccine comprising optimized mRNA constituents encoding six NSCLC-associated antigens. Here we report interim results of a phase Ib study, employing local RT to increase the immune mediated tumor control by BI 1361849. Methods: Pts with stage IV NSCLC were enrolled in three cohorts based on histological and molecular NSCLC subtypes (squamous [SQ] and non-squamous [non-SQ] cell with/without activating EGFR mutations). Pts received two vaccinations with BI 1361849 before local RT to a single tumor lesion (thoracic, bone, lymph node, skin/subcutaneous) was administered in four consecutive daily fractions of 5 GY. Vaccination was continued until start of subsequent anti-cancer therapy. mP and EGFR-TKIs were given in parallel according to the label. The primary endpoint was safety, secondary endpoints included objective response, PFS and OS. Results: 26 pts were enrolled (non-SQ/SQ/EGFR-activating mutations = 16/8/2 pts). Median number of vaccinations was 7 (range = 2-18). 15 pts received mP, two received EGFR TKIs. Most frequent AEs were mild to moderate injection-site reactions and flu-like symptoms. No BI 1361849-related SAEs were reported. One confirmed PR was observed in a pt on mP, 13 pts (52%) experienced SD (8 pts on mP, 3 pts with SQ NSCLC, 2 pts on EGFR-TKI). Tumor shrinkage of ≥ 15% at sites outside of the irradiated field occurred in 7 of 25 (28%) assessable pts: 6 pts on mP, one pt with SQ NSCLC. Durable disease stabilization of ≥ 24 weeks was observed in 5 pts on mP and one pt on EGFR-TKI, with remarkable long-lasting disease control up to 72 and 54 weeks at cut off, respectively, in two pts. Conclusions: BI 1361849 can be safely combined with local RT and mP treatment. Shrinkage of non-irradiated lesions and prolonged disease stablization was observed in a subset of pts, mainly in combination with mP. Follow up observation for survival of pts is ongoing. Clinical trial information: NCT01915524.
The utility of a modified frailty index in predicting chemotherapy toxicity, response and survival for older patients (pts) with advanced pancreatic cancer receiving first-line palliative chemotherapy: A single institution experience.
Authors: Hanbo Zhang, David Dawe, Robert Kudlovich, Christina Kim
Journal: Journal of Clinical Oncology (2018)

e22030 Background: Advanced pancreatic cancer (APC) primarily occurs in pts ≥ 65 years old. Chemotherapy decisions are challenging in this group. The Modified Frailty Index (mFI) is an 11-component measure of frailty which has been validated in surgical fields, but yet to be tested in older pts with APC receiving first-line palliative chemotherapy, with 5-fluorouracil, irinotecan and oxaliplatin (FOLFIRINOX), nab-paclitaxel and gemcitabine (NG), or gemcitabine alone (GEM). We sought to assess the correlation between mFI scores for older chemotherapy-treated APC pts with toxicity, response and survival. Methods: Pts ≥65 diagnosed with APC from 2011-2016 and treated with palliative chemotherapy at CancerCare Manitoba were identified from the Manitoba Cancer Registry. A retrospective analysis was performed to determine mFI scores for all pts based on 11 components (Nonindependent functional status, diabetes, chronic obstructive pulmonary disease, myocardial infarction, coronary artery disease, hypertension, congestive heart failure, peripheral vascular disease, transient ischemic attack, stroke, and impaired sensorium). Demographics, toxicity, response and survival were compared by mFI score. Results: 87 pts received chemotherapy, of which 20, 28, 25 and 14 had mFI scores of 0, 1, 2, and ≥ 3 respectively. Median age by mFI score was 69 (65-88), 73(65-80), 71(65-84) and 71(66-78), respectively. 52 pts received FOLFIRINOX (14 mFI 0, 19 mFI 1, 12 mFI 2, 7 mFI ≥ 3); 24 pts received NG and 14 pts received GEM. Neutropenia was similar (55%, 67.9%, 60%, 57.1% respectively), and there was no difference in other toxicities across mFI scores. Response rates were similar across mFI scores (p = 0.695), as were 6 and 12-month survival (p = 0.981 and p = 0.430, respectively). Conclusions: In elderly treated with chemotherapy for APC, retrospective mFI did not correlate with chemotherapy toxicity, response or survival. This may be due to small sample and the rigorous selection of older pts receiving chemotherapy for APC.