tbuckley/cabot-search huggingface dataset:
Efficacy analysis of a remote symptom management platform.
Authors: Paris A. Kosmidis, Christie Lagogianni, Thanos Kosmidis
Journal: Journal of Clinical Oncology (2021)

1566 Background: Quality of life of cancer patients is a critical part of cancer care. Symptom management is evolving as a multidisciplinary approach, and is increasingly delivered through a combination of physical and remote interactions. CareAcross is an online platform offering personalized, guidelines-based support to cancer patients, that complements physicians’ support and enables remote monitoring. This analysis investigated the improvement in the quality of life of cancer patients delivered through such remote support. Methods: Patients engage with an online interactive platform to receive personalized support based on a variety of parameters, through algorithms incorporating their exact diagnoses, treatments and comorbidities, and more. For symptom management, patients report the presence of specific side-effects via brief questionnaires; for each side-effect reported, they receive tailored support (text and multimedia) to help overcome it. These online questionnaires are repeated periodically to capture the outcome of the supportive process, and provide additional support as necessary. A retrospective analysis evaluated the efficacy of the personalized support: each patient’s reported side-effects were compared before versus after receiving the support, hence calculating the reduced incidence. Results: 2203 patients from 8 countries, with breast, lung, prostate or colorectal cancer (1563, 404, 159 and 77, respectively) reported side-effects, received support, and updated their reports at least once. The median follow-up period was 4.9 months. The patient-reported outcomes on their quality of life revealed substantial improvement, regardless of cancer type (lowest recorded improvement = 25.7%). Commonly reported side-effects included sleep problems, dry mouth, constipation, changes in food taste, and more (see Table). Side-effects reported in specific cancer types also showed substantial improvement, including hot flushes (breast; 32.0% improvement), dyspnea (lung; 38.1%), bowel dysfunction (prostate; 80%) and others. The efficacy of the support to breast, prostate or colorectal cancer patients was similar; support to lung cancer patients exhibited the lowest efficacy (p &lt; 0.05). Fatigue was the most common side-effect. It was also the most resistant to improvement compared to all others (p &lt; 0.05). Conclusions: Digital remote support of cancer patients is a realistic option to improve quality of life. Randomized controlled trials can help quantify its impact on health economics, hospital admissions, resource utilization, and other aspects.[Table: see text]
Frequency of homologous recombination deficiency gene mutations in melanoma and its relevance to the immunotherapeutic response.
Authors: Huanhuan Liu, Yanrui Zhang, Feng Ding, Yun Zhang, Xiayuan Liang, Feng Lou, Shanbo Cao, Huina Wang
Journal: Journal of Clinical Oncology (2021)

e15073 Background: Homologous recombination deficiency (HRD) can regulate the tumor immune microenvironment based on increasing tumor-infiltrating lymphocytes and therefore might serve as a biomarker of immunotherapeutic response. The HRD phenotype has been defined as the presence of a non-silent somatic mutation in homologous recombination-related (HRR) genes. Here, we focused on frequency of HRR genes mutation and the relationship between HRR genes mutation and clinical immunotherapy responses in melanoma. Methods: We prospectively sequenced 130 Chinese melanoma patients using next-generation sequencing techniques with Acornmed panel with 808 cancer-related genes. 208 patients with WES data from the TCGA project were included. Correlations between HRR gene mutations and clinical outcomes were identified via bioinformatic analysis using TCGA datasets. Results: In the Chinese cohort, 40% (52/130) patients exhibited genomic alterations in HRR genes. The frequently mutated genes were ATM (14%), BRCA2 (13%), CHEK2 (6%), PALB2 (6%), BRIP1 (4.6%), BARD1 (3%), BRCA1 (2%), CDK12 (2%), CHEK1 (1%), FANCL (1%), and RAD54L (1%). In TCGA cohort, 26% (53/208) patients had at least one somatic mutation in an HRR gene. The frequently mutated genes were BRCA2 (9%), BRCA1 (7%), ATM (6%), BRIP1 (4%), PALB2 (4%), BRAD1 (1%), CHEK2 (1%), PPP2R2A (1%), RAD51B (1%), RAD51C (1%), RAD54L (1%), CHEK1 (1%), and RAD51D. Chinese melanoma patients had higher frequently mutated HRR genes compared to that in TCGA patients (40% vs 26%, p=0.005). In addition, compared with TCGA cohort, the Chinese cohort had higher frequency for ATM (14% vs 6%, p=0.019) and CHEK2 (6% vs 2%, p=0.006). The TCGA cohort had a higher frequency of BRCA1 mutations than the Chinese cohort, although the difference was not statistically significant. Unfortunately, we did not find a significant correlation between HRR mutation and immune cells. Interestingly, in the TCGA cohort, patients with HRR-mut had significantly better OS than patients with HRR-wt (log-rank p=0.027). Conclusions: Our data suggest that detection of somatic mutations in HRR genes might contribute to identify patients who might benefit from immune checkpoint blockade therapy. In addition, the molecular features of HRD provide new opportunities to predict the tumor response to multiple treatments.[Table: see text]
Extracting non-small cell lung cancer (NSCLC) diagnosis and diagnosis dates from electronic health record (EHR) text using a deep learning algorithm.
Authors: Alexander S. Rich, Barry Leybovich, Melissa Estevez, Jamie Irvine, Nisha Singh, Aaron B. Cohen, Ben Birnbaum
Journal: Journal of Clinical Oncology (2021)

1556 Background: Identifying patients with a particular cancer and determining the date of that diagnosis from EHR data is important for selecting real world research cohorts and conducting downstream analyses. However, cancer diagnoses and their dates are often not accurately recorded in the EHR in a structured form. We developed a unified deep learning model for identifying patients with NSCLC and their initial and advanced diagnosis date(s). Methods: The study used a cohort of 52,834 patients with lung cancer ICD codes from the nationwide deidentified Flatiron Health EHR-derived database. For all patients in the cohort, abstractors used an in-house technology-enabled platform to identify an NSCLC diagnosis, advanced disease, and relevant diagnosis date(s) via chart review. Advanced NSCLC was defined as stage IIIB or IV disease at diagnosis or early stage disease that recurred or progressed. The deep learning model was trained on 38,517 patients, with a separate 14,317 patient test cohort. The model input was a set of sentences containing keywords related to (a)NSCLC, extracted from a patient’s EHR documents. Each sentence was associated with a date, using the document timestamp or, if present, a date mentioned explicitly in the sentence. The sentences were processed by a GRU network, followed by an attentional network that integrated across sentences, outputting a prediction of whether the patient had been diagnosed with (a)NSCLC and the diagnosis date(s) if so. We measured sensitivity and positive predictive value (PPV) of extracting the presence of initial and advanced diagnoses in the test cohort. Among patients with both model-extracted and abstracted diagnosis dates, we also measured 30-day accuracy, defined as the proportion of patients where the dates match to within 30 days. Real world overall survival (rwOS) for patients abstracted vs. model-extracted as advanced was calculated using Kaplan-Meier methods (index date: abstracted vs. model-extracted advanced diagnosis date). Results: Results in the Table show the sensitivity, PPV, and accuracy of the model extracted diagnoses and dates. RwOS was similar using model extracted aNSCLC diagnosis dates (median = 13.7) versus abstracted diagnosis dates (median = 13.3), with a difference of 0.4 months (95% CI = [0.0, 0.8]). Conclusions: Initial and advanced diagnosis of NSCLC and dates of diagnosis can be accurately extracted from unstructured clinical text using a deep learning algorithm. This can further enable the use of EHR data for research on real-world treatment patterns and outcomes analysis, and other applications such as clinical trials matching. Future work should aim to understand the impact of model errors on downstream analyses.[Table: see text]
Mechanism of inhibitory effect of terpenoid compound from <i>Achillea millefolium</i> on human lung cancer cell proliferation.
Authors: Siming Wang, Yu Wang, Yibing Wu, Mei Dong, Zhiyu Ni
Journal: Journal of Clinical Oncology (2021)

e15058 Background: A large number of reports have found that many components in traditional Chinese medicine preparations have obvious anti-tumor activities, and most of these effective components are realized by inducing tumor cell apoptosis. In this part of the experiment, we studied terpenoid compound (3β-acetoxy-1β,4α-dihydroxy-11αH-eudesman-12,6α-olide Achillea millefolium A) from Achillea millefolium anti-cancer mechanism, to determine whether this compound by inducing cell apoptosis plays its antitumor activity of cell proliferation. Methods: (1) The apoptosis of NCI-H292 cells treated with 1 μmol/L and 10 μmol/L Achillea millefolium A was detected by Annexinov-FITC /PI stain. (2) The apoptosis of NCI-H292 cells treated with 10 μmol/L Achillea millefolium A for 12 h and 24 h was detected by in situ end labeling. (3) The changes of p53, Bax, Caspase-3/8/12 and GRP78 in NCI-H292 cells were detected by Western blotting. Results: (1) Effects of Achillea millefolium A on apoptosis of NCI-H292 cells: The apoptosis rate of NCI-H292 cells treated with 1 μmol/L and 10 μmol/ L Achillea millefolium A for 12 h was (15.31)% and (17.84)% respectively. The apoptosis rate of NCI-H292 cells treated with 1 μmol/L and 10 μmol/ L Achillea millefolium A for 12 h was (15.37)% . (2), TUNEL method further verified the cell apoptosis: NCI-H292 cells were treated with 10 μmol/L Achillea millefolium A for 12 h and 24 h, and the positive cells accounted for (13.89)% and (28.37)% respectively, compared with blank control group (4.17)%. (3), Achillea millefolium A up-regulated the expression of p53 protein, Bax protein, Caspase-3/8/12 and GRP78 protein in NCI-H292 cells: After NCI-H292 cells were treated with 1 μmol/L and 10 μmol/ L Achillea millefolium A for 24 h, the expressions of p53, Bax, Caspase-3 and Caspase-8 in NCI-H292 cells were significantly up-regulated. After treatment with 1 μmol/L and 10 μmol/ L Achillea millefolium A for 12 h, the expression of Caspase-12 and GRP78 increased significantly. Conclusions: Achillea millefolium A is a terpenoid compound with obvious apoptosis-inducing activity on human lung cancer cell line NCI-H292. Achillea millefolium A induced apoptosis of NCI-H292 cells was the result of multiple pathways. Achillea millefolium A can up-regulate p53 protein, and then up-regulate Bax, and then activate Caspase-3 protein expression. At the same time, the expression of caspase-3 protein was further increased by activating caspase-8, and apoptosis was induced by both exogenous and endogenous pathways. Notably, the complex of ER stress pathway GRP78 and caspase-12 may also be one of the mechanisms by which Achillea millefolium A induces apoptosis in NCI-H292 cells.
RARE-04. IMPACT OF LIVE, VIRTUAL EDUCATIONAL SYMPOSIA ON PEDIATRIC NEURO-ONCOLOGIST, NEURO-ONCOLOGIST, AND NEUROSURGEON CONFIDENCE, KNOWLEDGE, AND INTENTION TO EMPLOY TARGETED MEDICAL THERAPIES FOR THEIR PATIENTS WITH NEUROFIBROMATOSIS TYPE 1
Authors: Bryan Taylor, Rebecca Weaver, Andrea Gross, Bruce Korf, Jaishri Blakeley
Journal: Neuro-Oncology (2021)

Abstract Historical treatment options and management strategies for neurofibromatosis type 1 (NF1) have been limited, with a relative paucity of clinical studies and the traditional paradigm focused on an ineffectual, and possibly even harmful, trimodal combination of radiation, surgery, and surveillance. Fortunately, an emerging preponderance of trial data supporting the use of targeted medical therapies, including MEK inhibitors and multi-kinase TKIs, is expanding the stale treatment paradigm and broadening horizons for patients. Given the profound novelty of this paradigmatic shift in NF1 management, it is imperative that timely, adaptive, and evidence-based educational initiatives be developed and delivered to the interdisciplinary neuro-oncology treatment team in an effort to bridge both learning and practice gaps. With an appreciation of the intrinsically multi-system nature of NF1, which necessitates a longitudinal treatment approach encompassing the totality of the multidisciplinary team, CEC Oncology designed and tailored targeted NF1 educational activities to improve confidence, advance knowledge, and promote enhanced utilization of targeted medical therapies among pediatric neuro-oncologists, neuro-oncologists, and neurosurgeons who manage patients with NF1. We conducted two independent satellite symposia, one at the 2020 Society for Neuro-Oncology (SNO) Annual Meeting and another at the 2020 AANS/CNS Section on Pediatric Neurological Surgery (PNSS), and achieved robust educational outcomes across Moore’s Levels 1–5. There were notable statistical advancements in clinician confidence, knowledge, and intention to employ targeted medical therapies for NF1-related symptomatic, inoperable plexiform neurofibromas from pre-activity to post-activity assessment, and many of these improvements were retained at 6-week follow-up analysis. In conclusion, our outcomes data evidence the critical need for responsive educational activities in the NF1 treatment space, especially as trial data continue to galvanize evolution of this novel pharmacologic armamentarium. Such activities possess the capacity to improve clinician confidence, advance knowledge, and promote utilization of targeted medical therapies in NF1, thereby optimizing patient outcomes.
Circulating progenitor cells are associated with plaque progression and long-term outcomes in heart transplant patients
Authors: Ilke Ozcan, Takumi Toya, Michel T Corban, Ali Ahmad, Darrell Loeffler, David Morse, Lilach O Lerman, Sudhir S Kushwaha, Amir Lerman
Journal: Cardiovascular Research (2021)

Circulating progenitor cells (CPCs) play a role in vascular repair and plaque stability, while osteocalcin (OC) expressing CPCs have been linked to unstable plaque and adverse cardiovascular outcomes. However, their role in cardiac allograft vasculopathy (CAV) has not been elucidated. This cohort study aimed to investigate the contribution of CPCs on CAV progression and cardiovascular events after heart transplantation.A total of 80 heart transplant patients (mean age 55 ± 14 years, 72% male) undergoing annual intravascular ultrasound (IVUS) had fresh CPCs marked by CD34, CD133, and OC counted in peripheral blood using flow cytometry, on the same day as baseline IVUS. CAV progression was assessed by IVUS as the change (Δ) in plaque volume divided by segment length (PV/SL), adjusted for the time between IVUS measurements [median 3.0, interquartile range (2.8-3.1) years] and was defined as ΔPV/SL that is above the median ΔPV/SL of study population. Major adverse cardiac events (MACEs) were defined as any incident of revascularization, myocardial infarction, heart failure admission, re-transplantation, stroke, and death. Patients with higher CD34+CD133+ CPCs had a decreased risk of CAV progression [odds ratio 0.58, 95% confidence interval (CI) (0.37-0.92), P = 0.01] and MACE [hazard ratio (HR) 0.79, 95% CI (0.66-0.99), P = 0.05] during a median (interquartile range) follow-up of 8.0 years (7.2-8.3). Contrarily, higher OC+ cell counts were associated with an increased risk of MACE [HR 1.26, 95% CI (1.03-1.57), P = 0.02].Lower levels of CD34+CD133+ CPCs are associated with plaque progression and adverse long-term outcomes in patients who underwent allograft heart transplantation. In contrast, higher circulating OC+ levels are associated with adverse long-term outcomes. Thus, CPCs might play a role in amelioration of transplant vasculopathy, while OC expression by these cells might play a role in progression.
Use of Janus kinase inhibitors in COVID-19: a prospective observational series in 522 individuals
Authors: Oleg Melikhov, Tatiana Kruglova, Karine Lytkina, Georgy Melkonyan, Elena Prokhorovich, Gleb Putsman, Grigory Rodoman, Arkady Vertkin, Alena Zagrebneva, Justin Stebbing
Journal: Annals of the Rheumatic Diseases (2021)

Table 1 Clinical outcomes in patients with COVID-19 treated with tofacitinib All cases <65 years old >65 years old Population Number of patents, n (%) 320 (100) 210 (66) 110 (34) Female, % 50 46 57 Mean age (range), years 59 (22-96) 52 (22-64) 74 (65-96) Mean treatment duration (range), days 7 (1-18) 6 (1-17) 7 (1-18) Dexamethasone, % 30.0 30.0 30.0 Disease (on admission) Clinical severity, % Mild 4.7 3.8 6.4
HINT1 (Histidine Triad Nucleotide-Binding Protein 1) Attenuates Cardiac Hypertrophy Via Suppressing HOXA5 (Homeobox A5) Expression
Authors: Yan Zhang, Qiang Da, Siyi Cao, Ke Yan, Zhiguang Shi, Qing Miao, Chen Li, Lulu Hu, Shixiu Sun, Wei Wu, Lingxiang Wu, Feng Chen, Liansheng Wang, Yuanqing Gao, Zhengrong Huang, Yongfeng Shao, Hongshan Chen, Yongyue Wei, Feng Chen, Yi Han, Liping Xie, Yong Ji
Journal: Circulation (2021)

Background: Cardiac hypertrophy is an important prepathology of, and will ultimately lead to, heart failure. However, the mechanisms underlying pathological cardiac hypertrophy remain largely unknown. This study aims to elucidate the effects and mechanisms of HINT1 (histidine triad nucleotide–binding protein 1) in cardiac hypertrophy and heart failure. Methods: HINT1 was downregulated in human hypertrophic heart samples compared with nonhypertrophic samples by mass spectrometry analysis. Hint1 knockout mice were challenged with transverse aortic constriction surgery. Cardiac-specific overexpression of HINT1 mice by intravenous injection of adeno-associated virus 9 (AAV9)–encoding Hint1 under the cTnT (cardiac troponin T) promoter were subjected to transverse aortic construction. Unbiased transcriptional analyses were used to identify the downstream targets of HINT1. AAV9 bearing shRNA against Hoxa5 (homeobox A5) was administrated to investigate whether the effects of HINT1 on cardiac hypertrophy were HOXA5-dependent. RNA sequencing analysis was performed to recapitulate possible changes in transcriptome profile.Coimmunoprecipitation assays and cellular fractionation analyses were conducted to examine the mechanism by which HINT1 regulates the expression of HOXA5. Results: The reduction of HINT1 expression was observed in the hearts of hypertrophic patients and pressure overloaded–induced hypertrophic mice, respectively. In Hint1 -deficient mice, cardiac hypertrophy deteriorated after transverse aortic construction. Conversely, cardiac-specific overexpression of HINT1 alleviated cardiac hypertrophy and dysfunction. Unbiased profiler polymerase chain reaction array showed HOXA5 is 1 target for HINT1, and the cardioprotective role of HINT1 was abolished by HOXA5 knockdown in vivo. Hoxa5 was identified to affect hypertrophy through the TGF-β (transforming growth factor β) signal pathway. Mechanically, HINT1 inhibited PKCβ1 (protein kinase C β type 1) membrane translocation and phosphorylation via direct interaction, attenuating the MEK/ERK/YY1 (mitogen-activated protein kinase/extracellular signal-regulated kinase kinase/yin yang 1) signal pathway, downregulating HOXA5 expression, and eventually attenuating cardiac hypertrophy. Conclusions: HINT1 protects against cardiac hypertrophy through suppressing HOXA5 expression. These findings indicate that HINT1 may be a potential target for therapeutic interventions in cardiac hypertrophy and heart failure.
A phase 2 study of pamiparib in the treatment of patients with locally advanced or metastatic HER2-negative breast cancer with germline <i>BRCA</i> mutation.
Authors: Tao Sun, Yanxia Shi, Jiuwei Cui, Yongmei Yin, Quchang Ouyang, Qiang Liu, Qingyuan Zhang, Yiding Chen, Shao Zhimin, Shouman Wang, Xiaojia Wang, Zhongsheng Tong, Yahua Zhong, Min Yan, Xi Yan, Chuan Wang, Haiyuan Yang, Miao Li, Xiao Xiang, Binghe Xu
Journal: Journal of Clinical Oncology (2021)

1087 Background: Breast cancer is the most common cancer among women, with up to 37% of patients (pts) harboring germline BRCA1/2 mutations (g BRCA1/2m) that appear to be sensitive to poly (ADP-ribose) polymerase proteins 1 and 2 (PARP1/2) inhibition. Pamiparib is an orally administered selective PARP1/2 inhibitor that has the potential to cross the blood-brain barrier. This study evaluated the efficacy and safety of pamiparib in pts with locally advanced/metastatic human epidermal growth factor receptor 2-negative (HER2-) breast cancer, with deleterious or suspected deleterious g BRCA1/2m, who received ≤ 2 prior lines of chemotherapy. Methods: In this open-label, phase 2, multi-center study in China (NCT03575065), pts with locally advanced/metastatic HER2- breast cancer with deleterious or suspected deleterious g BRCA1/2m triple negative breast cancer (TNBC cohort) or hormone receptor-positive (HR+)/HER2- breast cancer (HR+ cohort) were enrolled. Pts received pamiparib 60 mg orally twice daily in 28-day cycles. The primary endpoint was objective response rate (ORR; RECIST v1.1) by independent review committee (IRC). Secondary endpoints included duration of response (DOR) and progression free survival (PFS) by IRC, overall survival (OS), safety and tolerability. Results: 88 pts were enrolled (median age 45.5 years), 76 pts (TNBC cohort n = 55; HR+ cohort n = 21) had measurable disease at baseline per IRC. 60 pts (68.2%) received 1 or 2 prior lines of chemotherapy; 42 pts (47.7%) were treated with platinum previously. Median follow-up was 13.77 months (TNBC cohort, 10.87 months; HR+ cohort, 18.45 months). In the TNBC cohort: confirmed ORR was 38.2% (95% CI: 25.4–52.3); median DOR (mDOR) was 6.97 months (95% CI: 3.94–not estimable[NE]); median PFS (mPFS) was 5.49 months (95% CI: 3.65–7.33); median OS (mOS) was 17.08 months (95% CI:13.70–NE). In the HR+ cohort: confirmed ORR was 61.9% (95% CI: 38.4–81.9); mDOR was 7.49 months (95% CI: 5.55–14.75); mPFS was 9.20 months (95% CI: 7.39–11.93); mOS was not reached (NR; 95% CI 18.10–NE). ≥ Grade 3 treatment emergent adverse events (TEAEs) occurred in 54 pts (61.4%); anemia was the most common TEAE, occurring in 77 pts (87.5%). Dose reduction due to TEAEs occurred for 57 pts (64.8%); discontinuations due to TEAEs occurred for 2 pts (2.3%). Conclusions: Pamiparib showed a promising response in pts with locally advanced/metastatic HER2- breast cancer with a g BRCA1/2m. The safety profile of pamiparib was considered acceptable and was generally consistent with therapies in the same class. Clinical trial information: NCT03575065 .[Table: see text]