tbuckley/cabot-search huggingface dataset:
Patient characteristics, biomarkers and exacerbation risk in severe, uncontrolled asthma
Authors: Monica Kraft, Guy Brusselle, J. Mark FitzGerald, Ian D. Pavord, Matthew Keith, Malin Fagerås, Esther Garcia Gil, Ian Hirsch, Mitchell Goldman, Gene Colice
Journal: European Respiratory Journal (2021)

Background Greater precision in asthma exacerbation risk prediction may improve outcomes. We sought to identify clinical characteristics and biomarkers associated with elevated exacerbation risk in patients with severe, uncontrolled asthma. Methods Data were pooled from seven similarly designed phase II and III randomised controlled clinical trials of biologic therapies for the treatment of severe, uncontrolled asthma that enrolled comparable patient populations. Annualised asthma exacerbation rates (AAERs) for patients randomised to placebo were assessed by baseline clinical characteristics, and by biomarker concentrations at baseline and over the study duration. Results The AAER for the 2016 patients in the combined placebo group was 0.91 (95% CI 0.84‒0.98). Baseline characteristics associated with greater AAER were frequent or severe exacerbations within the prior 12 months, nasal polyposis, maintenance oral corticosteroid use, Asian race and Asian or Western European region. AAER increased with baseline blood eosinophil counts and exhaled nitric oxide fraction ( F ENO ) concentration, with the greatest AAER occurring for patients with eosinophils ≥300 cells·μL −1 and F ENO ≥50 ppb. No relationship was observed between baseline serum IgE concentration and AAER. Combining type 2 inflammation criteria for eosinophils and F ENO had greater prognostic value than either biomarker alone. Persistent eosinophil and F ENO elevations throughout the study period were associated with greater AAER. Conclusions Exacerbation history, maintenance corticosteroid use, nasal polyposis, Asian race, geographic region, and elevations in blood eosinophil counts and F ENO concentrations (particularly when combined and/or persistently achieving type 2 inflammation criteria) were associated with increased exacerbation risk in patients with severe, uncontrolled asthma.
Prediction of the breakthrough cancer pain using deep learning model.
Authors: Yeong Hak Bang, Yoon Ho Choi, Mincheol Park, Geon Hee Lee, Soo-yong Shin, Seok Jin Kim
Journal: Journal of Clinical Oncology (2021)

e24085 Background: Breakthrough cancer pain (BTcP), a transitory flare of pain that occurs on a background of relatively well-controlled baseline pain, is a challenging clinical problem in managing cancer pain. We hypothesized that the BTcP could be predictable according to the patients’ previous observed patterns. In this study, we report on the development of a deep learning model that predicts hourly individual-level breakthrough pain for patients with cancer. Methods: We defined the BTcP as the pain with numerical rating scale (NRS) score 4 or above and developed models predicting the onset time of BTcP with the temporal resolution of 1 hour. The datasets which have more than 20 records of NRS score during hospitalization were included in our study. All the pain records were obtained from patients hospitalized on the wards of hematology-oncology in Samsung Medical Center between July 2016 to February 2020. The model used the time windows of 3 days to predict NRS scores over the next 24 hours. To capture irregular pain patterns, we created the sequence of average pain patterns over 24 hours from the previous 3 days and used it for normalization. We trained a Bi-directional long-short term memory (LSTM) based deep learning model. The model was validated using the holdout method with 20% of the datasets. Its performance was assessed with the area under the receiver operating characteristic curve (AUROC) and the area under the precision-recall curve (AURPC). Results: We included pain log data containing 2,905 admissions from 2,176 patients with solid cancer and 1,755 admissions from 1,082 patients with hematologic cancer in the analysis. The median age was 57 (interquartile range (IQR), 47-64), the most frequent type of cancer was lung cancer (18.0%), and most patients had stage 4 (60.7%). Among the 103,948 hours from patients in whole datasets, 1,091 (4.7%) hours were labeled as the period of BTcP. The patients have the records of NRS score with a median of 3 (IQR, 2.0-4.5) and BTcP with a median of 1.1 (IQR, 0.5-2.0) per day. We allocated approximately 20% of patients (653 patients with 932 admissions) to the holdout test dataset. Our model showed the AUROC 0.719 and AUPRC 0.680 for predicting the BTcP in the test dataset. Conclusions: Our study showed that cancer pain could be predictive by using a deep learning model. Though our exploratory study has a limitation of generalizability, future warranted subgroup analysis and verification research could make our model more applicable in a real-world setting.
Early detection of lung cancer using cfDNA fragmentation.
Authors: Dimitrios Mathios, Jakob Sidenius Johansen, Stephen Cristiano, Jamie Medina, Jillian Phallen, Klaus Richter Larsen, Daniel Bruhm, Noushin Niknafs, Hans J. Nielsen, Gerrit A. Meijer, Claus Lindbjerg Andersen, Stig Egil Bojesen, Robert Scharpf, Victor E. Velculescu
Journal: Journal of Clinical Oncology (2021)

8519 Background: Lung cancer incidence and mortality are increasing worldwide despite more effective treatments. This is primarily due to the late stage of diagnosis when treatments are less effective. Although large randomized trials have demonstrated a significant decrease in lung cancer mortality through screening of high-risk individuals with chest low dose computed tomography (LDCT), LDCT has made little impact in the community, mainly due to lack of accessibility. There is therefore an unmet clinical need for development of cost-effective and easily implemented tests for early lung cancer detection. Methods: We have previously shown that altered genome-wide fragmentation of cell free DNA (cfDNA) is a common characteristic of many cancers. In this study, we leverage this knowledge to increase the sensitivity of lung cancer detection by interrogating characteristics of the size distribution of cfDNA fragments across the genome using machine learning methods. The approach we present, called DELFI (DNA evaluation of fragments for early interception) generates a score that reflects the presence of tumor-derived DNA in plasma based on a multi-feature genomic analysis that assesses millions of cfDNA fragments for tumor-derived genomic and epigenomic changes in a small amount of blood (2-4 mls) via inexpensive low coverage (1-2x) whole genome sequencing. We applied this methodology in a prospectively collected cohort of 365 individuals under investigation for lung cancer and we prospectively validated it in a separate case-control cohort of patients with newly diagnosed early stage lung cancer as well as individuals without cancer (n=427). Results: These analyses revealed high performance for detection of early and late stage disease (Table). When DELFI was used as a prescreen for LDCT it increased specificity from 58% with CT imaging alone to 80% using the combined approach. The DELFI score was significantly associated with T and N stage in lung cancer cases (p&lt;0.0001) as well as with overall survival (p=0.003). In a multivariable analysis including age, histology and stage, DELFI score was an independent prognostic factor of overall survival (HR=2.53; p=0.0003). Finally, we determined that genome-wide fragmentation profiles can be used to distinguish small cell lung cancer from non-small cell lung cancer with high accuracy (AUC 0.98). Conclusions: These findings provide key insights into cfDNA fragmentation in patients with cancer and a new and easily accessible avenue for non-invasive diagnosis and molecular profiling of lung cancer.[Table: see text]
Dysregulation of mannose-6-phosphate–dependent cholesterol homeostasis in acinar cells mediates pancreatitis
Authors: Olga A. Mareninova, Eszter T. Vegh, Natalia Shalbueva, Carli J.M. Wightman, Dustin L. Dillon, Sudarshan Malla, Yan Xie, Toshimasa Takahashi, Zoltan Rakonczay, Samuel W. French, Herbert Y. Gaisano, Fred S. Gorelick, Stephen J. Pandol, Steven J. Bensinger, Nicholas O. Davidson, David W. Dawson, Ilya Gukovsky, Anna S. Gukovskaya
Journal: Journal of Clinical Investigation (2021)

Disordered lysosomal/autophagy pathways initiate and drive pancreatitis, but the underlying mechanisms and links to disease pathology are poorly understood. Here, we show that the mannose-6-phosphate (M6P) pathway of hydrolase delivery to lysosomes critically regulates pancreatic acinar cell cholesterol metabolism. Ablation of the Gnptab gene encoding a key enzyme in the M6P pathway disrupted acinar cell cholesterol turnover, causing accumulation of nonesterified cholesterol in lysosomes/autolysosomes, its depletion in the plasma membrane, and upregulation of cholesterol synthesis and uptake. We found similar dysregulation of acinar cell cholesterol, and a decrease in GNPTAB levels, in both WT experimental pancreatitis and human disease. The mechanisms mediating pancreatic cholesterol dyshomeostasis in Gnptab-/- and experimental models involve a disordered endolysosomal system, resulting in impaired cholesterol transport through lysosomes and blockage of autophagic flux. By contrast, in Gnptab-/- liver the endolysosomal system and cholesterol homeostasis were largely unaffected. Gnptab-/- mice developed spontaneous pancreatitis. Normalization of cholesterol metabolism by pharmacologic means alleviated responses of experimental pancreatitis, particularly trypsinogen activation, the disease hallmark. The results reveal the essential role of the M6P pathway in maintaining exocrine pancreas homeostasis and function, and implicate cholesterol disordering in the pathogenesis of pancreatitis.
Clinical outcomes in patients relapsed/refractory after ≥ 2 prior lines of therapy for follicular lymphoma: A systematic literature review and meta-analysis.
Authors: Steve Kanters, Brad S. Kahl, Adriana Wiesinger, Binu Gurung, Eve Limbrick-Oldfield, Akshay Sudhindra, Julia Snider, Anik R. Patel
Journal: Journal of Clinical Oncology (2021)

e19548 Background: Patients with follicular lymphoma (FL) can have high response rates to early lines of treatment. However, among FL patients relapsed/refractory (r/r) after ≥2 prior lines of therapies (LOT), remission tends to be shorter and there is limited treatment guidance. This study sought to evaluate the clinical outcomes for r/r FL after ≥2 prior LOT using currently available treatment options. Methods: Electronic databases were searched on June 2, 2020. Eligible studies were comparative or non-comparative interventional or observational studies of systemic therapies among adults with FL r/r after ≥2 prior LOT. Prior LOT must have included anti-CD20 monoclonal antibodies and alkylating agents, in combination or separately. Overall response rate (ORR) and complete response (CR) were analyzed using inverse-variance weighting with Freeman-Tukey double-arcsine transformations. Kaplan-Meier (KM) analysis for progression-free survival (PFS) and overall survival (OS) were conducted using digitized curves and the Guyot algorithm. Survival analyses were stratified by ≥2 prior LOT and ≥3 prior LOT groups and were restricted to the observational cohorts as a sensitivity analysis. Results: The meta-analysis included 12 studies published from 2014-2020. Sample size for response outcomes was 340, for survival outcomes with ≥2 prior LOT was 1024 and for ≥3 prior LOT was 502. The estimated ORR in the ≥2 prior LOT group was 56.0% (95% confidence interval [CI]: 47.2 – 64.5) and proportion of patients with CR was 12.2% (95% CI: 8.0 – 17.3). The median OS was 54.4 months (95% CI: 45.8 – 76.0) and median PFS was 10.3 months (95% CI: 9.3 – 11.1). The 24-month OS decreased from 66% in the ≥2 prior LOT group to 60% in the ≥3 prior LOT group (Table 1), with a similar trend in PFS at 24-month (28% vs 24%). Conclusions: This study found that few r/r FL patients with ≥2 prior LOT achieve CR, and despite some benefit, approximately 1/3 of patients die within 24 months. The shorter median PFS with increasing prior LOT suggest treatment durability is suboptimal in later LOT. These findings indicate that patients are underserved by current treatments, demonstrating a need for new treatments that can achieve high rates of response that are durable in this disease.[Table: see text]
Simultaneous stimulation of growth of malignant tumors with epithelioid and sarcomatous nature in experiment.
Authors: Irina V. Kaplieva, Elena M. Frantsiyants, Lidia K. Trepitaki, Ekaterina I. Surikova, Valeria A. Bandovkina, Irina V. Neskubina, Inga Movlievna Kotieva, Konstantin A. Shumarin, Galina V. Zhukova
Journal: Journal of Clinical Oncology (2021)

e23517 Background: The relevance of studying multiple primary malignant tumors (MPMTs) is determined by poor understanding of their pathogenesis. Our purpose was to create an experimental model of synchronous MPMTs with the stimulation of malignant growth of tumors with different histostructure. Methods: The study included 20 male BALB/c Nude mice. The main group included mice with simultaneous subcutaneous inoculation of tumors: murine B16/F10 melanoma (0.5 ml of suspension diluted 1:20 in saline solution) below the left scapula and rat sarcoma 45 (0.5 million tumor cells in 0.5 ml of saline solution) below the right scapula. Control groups included males with melanoma or sarcoma inoculated at the same dosage and volume as in the main group. Results: In the model of synchronous MPMTs, tumors appeared faster than in controls: melanoma–by 3 times, sarcoma–by 2 times; their volume was larger: melanoma–by 2.2 times, sarcoma–by 3.2 times. Melanoma metastasized, in addition to typical sites (the lungs, spleen, liver), into sarcoma 45 to the side adjacent to the chest, under the tumor node. The survival of mice with MPMTs was lower. The morphological structure of melanoma metastasis into sarcoma 45 was represented by large lamellar-rounded epithelium-like cells of melanosarcoma type with transparent cytoplasm and nuclei with a high frequency of pathological mitosis figures. Bundles of elongated spindle-shaped melanocytes with processes of the cytoplasm were determined in some melanoma areas, as well as alveolar and concentric structures. Conclusions: Synchronous subcutaneous inoculation of murine B16/F10 melanoma and rat sarcoma 45 to male BALB/c Nude mice increases their malignant potential due to an exchange of “structural information"; as a result, sarcoma acquires impulses of proliferative activity of melanoma, which, in turn, adapts and “mimics” a tumor into which it is going to metastasize.
Efficacy of enobosarm, a selective androgen receptor (AR) targeting agent, correlates with the degree of AR positivity in advanced AR+/estrogen receptor (ER)+ breast cancer in an international phase 2 clinical study.
Authors: Carlo Palmieri, Hannah M. Linden, Stephen Birrell, Elgene Lim, Lee S. Schwartzberg, Hope S. Rugo, Patrick Wayne Cobb, Kirti Jain, Charles L. Vogel, Joyce O'Shaughnessy, Stephen R. D. Johnston, Robert H. Getzenberg, K. Gary Barnette, Mitchell S. Steiner, Adam Brufsky, Beth Overmoyer
Journal: Journal of Clinical Oncology (2021)

1020 Background: The AR is expressed in up to 90% of ER+ breast cancer where it acts as a tumor suppressor. Historically, therapy with synthetic androgens had efficacy, but virilizing side effects and toxicity limited their use. Enobosarm is a selective AR activating agent that does not cause masculinization and has positive attributes such as promotion of bone and improvement of physical function. In a phase 2 study, correlation between the degree of AR staining and antitumor activity in AR+/ER+ patients with metastatic breast cancer (MBC) was examined. Methods: A phase 2, open label, parallel design randomized study was conducted in 136 patients to evaluate the efficacy and safety of enobosarm in heavily pretreated women with AR+/ER+ MBC. Patients were randomized to 9 mg (n=72) or 18 mg (n=64) of oral daily enobosarm. AR expression (%AR nuclei staining) in breast cancer samples was determined centrally by immunohistochemistry. The correlation between %AR staining and clinical outcomes was examined with a focus on the 9mg dose, selected for the phase 3 study and the optimal %AR staining established. Results: Tumor objective outcomes correlated with percent AR staining (Table). Further, using a 40% AR staining cutoff in patients with measurable disease, the clinical benefit rate (CBR) for ≥40% AR is 80% and &lt;40% is 18% (p&lt;0.0001). Best objective tumor response (BOR) in patients with ≥40% AR is 48% and &lt;40% is 0% (p&lt;0.0001). At ≥40% AR, median radiographic progression free survival (rPFS) is 5.47 and mean is 7.15 months vs &lt;40% AR where the median rPFS is 2.72 and mean is 2.7 months. Similar %AR staining correlation was observed in the 18mg cohort. Enobosarm treatment was well tolerated with significant positive effects on quality of life measurements. Conclusions: Enobosarm is a novel oral selective AR activating agent in which a higher % AR staining correlates with a greater antitumor activity. By targeting and activating AR, enobosarm may represent a new hormone treatment approach for AR+/ER+ MBC. The phase 3, ARTEST trial will commence in early 2021 and randomize patients with AR+/ER+/HER2- heavily treated MBC that have progressed on a non-steroidal aromatase inhibitor, fulvestrant and CDK 4/6 inhibitor to receive enobosarm or standard endocrine therapy. Clinical trial information: NCT02463032 .[Table: see text]
Single institution toxicity of definitive chemoradiation and maintenance durvalumab in locally advanced non-small cell lung cancer.
Authors: Pranitha Prodduturvar, Konstantinos Leventakos, Ashley Potter, Robert W. Gao, Anastasios Dimou, Randolph Marks, Yolanda I. Garces, Kenneth R. Olivier, Julian R. Molina, Kenneth Merrell, Aaron Scott Mansfield, Alex A. Adjei, Anna Schwecke, Craig Hocum, Jenesse Nicole Moffett, Sean Sunghun Park, Dawn Owen
Journal: Journal of Clinical Oncology (2021)

e20554 Background: The paradigm for locally advanced non-small cell lung cancer has been markedly altered to include maintenance durvalumab (D) post completion of definitive chemoradiation (CRT) following the publication of the Pacific trial in 2018. The toxicity of this treatment has not been well evaluated in the real-world setting. Methods: We identified 42 patients (pts) with Stage IIB-IIIC NSCLC treated at Mayo Clinic Rochester between 6/1/2018 and 10/1/2020 who received definitive CRT followed by maintenance D. Data were abstracted by retrospective chart review under an IRB approved protocol. Results: Median age was 66 yrs (range 47-90) and 62% were women. Primary lung cancer histology included 19 adenocarcinoma, 20 squamous cell, and 3 adenosquamous. The distribution of stages was: IIB (4/42), IIIA (15/42), IIIB (19/42), IIIC (4/42). Approximately half of patients had PDL1 expression &gt; 25% (20/42). With a median follow up of 12.2 months (calculated from first cycle of D; range 4.2-30.5 months), 14 had completed one year of maintenance D, 16 were receiving ongoing D, and 10 stopped D early with 6/12 discontinuing due to disease progression (4/6 local progression, 2/6 distant progression). Other reasons for discontinuation (5/10) included grade 3 colitis, grade 2 hepatitis, aspergillus lung infection, and flare of autoimmune disorders. One quarter of patients experienced grade 2 radiation pneumonitis (RP; 10/42) with median time to development of RP 78 days from end of CRT and 45 days from start of D. RP was determined by multidisciplinary review of imaging and treatment fields. 17/42 patients developed immune related adverse events (see Table for details). There was minimal overlap between the patients who experienced pneumonitis and immune related toxicity; 2/17 had both pneumonitis and immune related toxicity (hepatitis, thyroiditis). Conclusions: In our early experience with the Pacific regimen, 29% of patients did not complete D due to either toxicity or progression during D administration. Pneumonitis was common (10/42 patients) although there were no grade 3 events. Nearly half of the patients developed an immune-related adverse event. Further analysis is needed to evaluate the real-world toxicity of this treatment as well as oncologic outcomes.[Table: see text]
MELK is a downstream target of Del-1 and promotes breast cancer progression.
Authors: Soo Jung Lee, Yee Soo Chae, Jeeyeon Lee, Jieun Kang, Eun Ae Kim, Jin Hyang Jung, Ho Yong Park, In Hee Lee
Journal: Journal of Clinical Oncology (2021)

e12578 Background: Del-1 is a promising prognostic marker for breast cancer in our previous study. However, the downstream targets and biological effectors of Del-1 remain unclear and still untargetable in breast cancer. We performed transcriptome analysis using RNA-seq and explored the mechanism of Del-1 in regulating the progression of breast cancer to find druggable target. Methods: Total RNA was isolated using RNAiso Plus (TaKaRa, Otsu, Shiga, Japan), Libraries were prepared from total RNA using the NEBNext Ultra II Directional RNA-Seq Kit. High-throughput sequencing was performed as paired-end 100 sequencing using NovaSeq 6000 (Illumina, Inc., USA). OTSSP167(OTS167) were treated for inhibition of MELK. The effects of MELK on cell proliferation, invasion were determined using MTT, Matrigel Transwell assays. The tumoral expression of Del-1 and MELK were determined based on tissue microarrays and immunohistochemistry results from 440 early breast cancer patients. Results: To investigate Del-1 downregulation effect on breast cancer, we performed RNA-seq of Del-1 knock downed MDA-MB-231 and MCF 7-Tamoxifen resistant (TamR) cell line. Compared with si-control, MELK gene were downregulated in both knock downed cell lines. While a high Del-1 and MELK mRNA expressions were found in all the breast cancer cell lines, both expressions were significantly higher in MDA MB-231. MELK inhibitor (OTS167) treatment to breast cancer cell line MDA-MB-231 and MCF 7-TamR showed similar results as Del-1 down regulation by si-RNA. Inhibition of MELK suppressed proliferation and invasion of breast cancer cell line. Tumoral MELK expression correlate with increased aggressiveness and poor clinical outcomes in 440 breast cancer patients. Conclusions: Our results indicate that Del-1 may regulate MELK expression which has a role in breast cancer progression. In conclusion, modulation of Del-1 status by targeting MELK may be a new therapeutic strategy for breast cancer patients.