tbuckley/cabot-search huggingface dataset:
Association between major surgical admissions and the cognitive trajectory: 19 year follow-up of Whitehall II cohort study
Authors: Bryan M Krause, Séverine Sabia, Helen J Manning, Archana Singh-Manoux, Robert D Sanders
Journal: BMJ (2019)

Abstract Objective To quantify the association between major surgery and the age related cognitive trajectory. Design Prospective longitudinal cohort study. Setting United Kingdom. Participants 7532 adults with as many as five cognitive assessments between 1997 and 2016 in the Whitehall II study, with linkage to hospital episode statistics. Exposures of interest included any major hospital admission, defined as requiring more than one overnight stay during follow-up. Main outcomes measures The primary outcome was the global cognitive score established from a battery of cognitive tests encompassing reasoning, memory, and phonemic and semantic fluency. Bayesian linear mixed effects models were used to calculate the change in the age related cognitive trajectory after hospital admission. The odds of substantial cognitive decline induced by surgery defined as more than 1.96 standard deviations from a predicted trajectory (based on the first three cognitive waves of data) was also calculated. Results After accounting for the age related cognitive trajectory, major surgery was associated with a small additional cognitive decline, equivalent on average to less than five months of aging (95% credible interval 0.01 to 0.73 years). In comparison, admissions for medical conditions and stroke were associated with 1.4 (1.0 to 1.8) and 13 (9.6 to 16) years of aging, respectively. Substantial cognitive decline occurred in 2.5% of participants with no admissions, 5.5% of surgical admissions, and 12.7% of medical admissions. Compared with participants with no major hospital admissions, those with surgical or medical events were more likely to have substantial decline from their predicted trajectory (surgical admissions odds ratio 2.3, 95% credible interval 1.4 to 3.9; medical admissions 6.2, 3.4 to 11.0). Conclusions Major surgery is associated with a small, long term change in the average cognitive trajectory that is less profound than for major medical admissions. The odds of substantial cognitive decline after surgery was about doubled, though lower than for medical admissions. During informed consent, this information should be weighed against the potential health benefits of surgery.
PHF19 promotes multiple myeloma tumorigenicity through PRC2 activation and broad H3K27me3 domain formation
Authors: Zhihong Ren, Jeong Hyun Ahn, Hequn Liu, Yi-Hsuan Tsai, Natarajan V. Bhanu, Brian Koss, David F. Allison, Anqi Ma, Aaron J. Storey, Ping Wang, Samuel G. Mackintosh, Ricky D. Edmondson, Richard W. J. Groen, Anton C. Martens, Benjamin A. Garcia, Alan J. Tackett, Jian Jin, Ling Cai, Deyou Zheng, Gang Greg Wang
Journal: Blood (2019)
Motexafin gadolinium (MGd) combined with prompt whole brain radiation therapy (RT) prolongs time to neurologic progression in non-small cell lung cancer (NSCLC) patients with brain metastases: Results of a phase III trial
Authors: M. P. Mehta, R. Gervais, P. Chabot, W. R. Shapiro, R. A. Patchell, M. J. Glantz, L. Recht, S. Phan, J. A. Smith, M. F. Renschler
Journal: Journal of Clinical Oncology (2006)

7014 Background: In a previous randomized study, RT plus MGd prolonged time to neurologic progression (TNP) in NSCLC patients (pts) with brain metastases (BM) (p=0.048). Methods: This Phase 3 trial randomized pts with BM from NSCLC and KPS ≥70 to RT (30 Gy) or RT+MGd, 5 mg/kg qd x 10. A sample size of 550 was based on α=0.001, β=0.8, hazard ratio (HR)=0.65, with a primary endpoint of TNP determined by a blinded events review committee. Results: 554 pts received RT (N=275) or RT+MGd (N=279), 348 in North America (NA), 206 in Europe and Australia (EA). Treatment arms were balanced for factors of known prognostic importance. Most pts had multiple BM (81%), extracranial metastases (51%) and presented with neurologic deficits (84%). Treatment with MGd was well tolerated, with &gt;92% of intended doses administered. Most common MGd-related grade 3+ adverse events were hypertension (4%), ALT increase (3%), and fatigue (3%). TNP improved from 10 months (mo) for RT to 15.4 mo for RT+MGd, p=0.12, HR=0.78. Time to neurocognitive progression was also improved, p=0.089, HR=0.79. More RT pts required salvage brain surgery or radiosurgery than RT+MGd pts (41 RT, 19 RT+MGd). In NA pts, statistically significant prolongation of both TNP, from 8.8 mo for RT to 24.2 mo for RT+MGd, p=0.004, HR=0.53, and time to neurocognitive progression, p=0.04, HR=0.69, were observed. In NA, RT was started sooner after the diagnosis of BM than in EA (median/mean 1.6/2.2 weeks NA vs. 3.0/6.5 weeks EA). There was a significant interaction between earlier RT and MGd benefit, p=0.017. When RT was initiated within 3 weeks of BM diagnosis, regardless of region, TNP was significantly prolonged by addition of MGd (N=378, p=0.006, HR=0.59). When initiation of RT was delayed beyond 3 weeks after BM diagnosis (N=176, 21% of NA pts, 50% of EA pts), MGd benefit was lost. A major reason for RT delay was use of chemotherapy as initial treatment for BM in 41 pts, 17% NA, 83% EA. Conclusions: MGd significantly prolonged TNP in NSCLC patients with BM receiving prompt RT in this randomized Phase 3 trial. The majority of patients in NA received prompt RT (79%), leading to a statistically and clinically significant benefit when combined with MGd. [Table: see text]
Pattern of local-regional relapse and survival after bimodality therapy for esophageal cancer: Implications for the surveillance strategy.
Authors: Kazuki Sudo, Lianchun Xiao, Roopma Wadhwa, Takashi Taketa, Mariela A. Blum, Heath D. Skinner, Jeffrey H. Lee, Manoop S. Bhutani, Brian Weston, Ritsuko Komaki, David C. Rice, Stephen Swisher, Wayne Lewis Hofstetter, Jaffer A. Ajani
Journal: Journal of Clinical Oncology (2013)

4083 Background: Evidence for definitive chemoradiotherapy (bimodality therapy [BMT]) has been established for patients with esophageal and gastroesophageal junction cancer (EGEJC) who do not qualify for surgery. Surveillance for these patients is often recommended but the literature lacks guidance for an evidence-based surveillance strategy after BMT. Methods: We analyzed 276 patients with EGEJC who underwent BMT and had pre- and postchemoradiation endoscopic biopsies and imaging studies available for review. Patients who underwent planned surgery or salvage surgery (SS) within 6 months from BMT were excluded. We reviewed the pattern of relapse over time. Local-regional disease (LRD) after BMT was classified as regional disease (RD) or luminal-only disease (LD). Overall survival (OS) probabilities were estimated using the Kaplan-Meier method and compared using the log-rank test. Results: For 276 patients, the median follow-up time was 53.0 months (95% confidence interval [CI], 47.3-58.7). A total of 184 (66.7%) patients had a persistent disease or relapse after BMT: 120 distant metastases (43.5% of 276) and 64 LRD (23.2% of 276). Of 64 LRD, 58 (91%) were diagnosed within 2 years of BMT and 63 (98%) were diagnosed within 3 years (see Table). Twenty-three of 64 LRD patients underwent SS. For patients with SS, the median OS time from diagnosis of LRD was 58.0 months (95% CI, not reached), and that for patients without SS was 9.0 months (95% CI, 7.3-10.7); this difference was highly significant (p &lt; 0.001). Conclusions: Our data suggest that 91% of LRD occurred within 2 years after BMT and the OS with SS for LRD was better than that without SS. These data can contribute to the development of an evidence-based surveillance strategy. [Table: see text]
Multiple-Ascending-Dose Study of the Soluble Guanylate Cyclase Stimulator, IW-1701, in Healthy Subjects
Authors: Robert S Mittleman, Phebe Wilson, Kristine Sykes, Marina Mihova, Jennifer G Chickering, Dennis Ruff, Michael Hall, Todd G Milne, Mark G Currie, Yueh-Tyng Chien
Journal: Blood (2017)
Correction: KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2− ILCs biased toward ILC2 or ILC3
Authors: Maho Nagasawa, Balthasar A. Heesters, Chantal M.A. Kradolfer, Lisette Krabbendam, Itziar Martinez-Gonzalez, Marjolein J.W. de Bruijn, Korneliusz Golebski, Rudi W. Hendriks, Ralph Stadhouders, Hergen Spits, Suzanne M. Bal
Journal: The Journal of Experimental Medicine (2019)

JEM regrets that in the original version of this paper, panels E-G were mistakenly omitted from Fig. 4 due to a production error. The corrected and complete Fig. 4 appears on the following page. The online and print versions of this article have been corrected. The error appears only in PDF versions downloaded on or before July 31, 2019.
A phase I, dose escalation trial to assess the safety and biological activity of recombinant human interleukin-18 (SB-485232) in combination with pegylated liposomal doxorubicin in platinum-resistant recurrent ovarian cancer.
Authors: Fiona Simpkins, Aurea M. Flores, Christina Chu, Joseph A. Lucci, Jonathan S. Berek, George Coukos, John W. Bauman, Sharon Cornell Murray, Herbert Struemper, Fiona Germaschewski, Zdenka Jonak, Olivia S. Gardner, John F Toso
Journal: Journal of Clinical Oncology (2012)

5065 Background: SB-485232, a recombinant human form of interleukin-18 (IL-18), is being studied as a novel cytokine for tumor immunotherapy. IL-18 has been shown to increase the anti-tumor activity of doxorubicin in other cancer mouse models. Methods: This multi-center study enrolled 16 patients (pts), and evaluated four cycles (28 days each) of standard pegylated liposomal doxorubicin (PLD) (40 mg/m 2 day 1) in combination with increasing doses of IL-18 (1, 3, 10, 30, and 100 mg/kg) on days 2 and 9 of each cycle with a 1 yr follow-up to further evaluate safety and efficacy. Results: Of the 16 pts, 10 (63%) completed study treatment and 6 (37%) did not because of disease progression (5 pts) and PLD hypersensitivity (1 pt). Thirteen (82%) were platinum resistant/refractory having received a median of &gt; 3 prior lines of therapy. SB-485232 up to 100 mg/kg in combination with PLD had an acceptable safety profile. All 16 pts experienced at least 1 AE including chills (81%), nausea (75%), anemia (63%), fatigue (56%), hyperglycemia, and pyrexia (50% each). Eight of 16 pts had Grade 3 AEs including anemia (19%), and 6% each for abdominal pain, asthenia, dehydration, PLD hypersensitivity, edema, fatigue, hyperglycemia, hyperkalemia, jaundice, pain, nausea, vomiting, and pyelonephritis. There were no grade 4/5 AEs. Four subjects experienced 10 non-fatal SAEs with 3 related to study drug: anemia, PLD hypersensitivity, and cytokine release syndrome. Maximal SB-485232 biological activity, assessed by peripheral blood NK and T cell markers, was observed at 10mg/kg-100mg/kg. This drug combination resulted in a 6% partial response rate (RR) and a 38% stable disease rate using RECIST 1.0. Median (95% CI) time of progression-free survival (PFS) was 4.50 (3.52,--) months. Conclusions: The SB-485232/PLD combination was tolerable with minimal toxicity. These preliminary efficacy data are comparable to the historical RR and PFS observed with PLD monotherapy in platinum-resistant ovarian cancer. However, given the small sample size, this combination warrants further investigation.
Abstract LB-233: Analysis of personalised circulating tumour DNA to monitor recurrence and metastasis in multiple cancer types
Authors: Guan Wang, Jinwang Wei, Angela Wu, Chun Dai, Wending Sun, Xin Cai, Qiang Xu
Journal: Cancer Research (2019)

Abstract Purpose: The evaluation of circulating tumour DNA (ctDNA) is a promising tool to monitor tumour progression and guide personalised treatments. We evaluated ctDNA in plasma samples from 521 Chinese patients with more than 12 tumour types and explored ctDNA’s ability to predict tumour status, especially recurrence and metastasis. Methods: We established a personalised ctDNA panel sequencing, which targeted trunk clonal somatic mutations of each patient calculated by CSMT-tools (monitors tumour load tools based on paired whole exon and cell-free DNA next generation sequencing data, PCT/CN2016/106284) and drug-resistant mutations. The ctDNA content fraction of all somatic mutations was then evaluated. Furthermore, 209 patients were followed up for ctDNA detection and routine examination. Results: Whole exome sequencing was performed on 1121 patients, and 97% of patients were successfully designed personalised ctDNA assays using CSMT-tools. Currently, 521 Chinese patients mainly with colorectal, liver, lung, gastric cancer, glioma or cholangiocarcinoma received at least one ctDNA detection. 66.79%, 50.86%, 42.99%, and 25.72% of these patients had detectable ctDNA with ctDNA content fractions above 0.25%, 0.5%, 1%, and 5%, respectively. At ctDNA content fraction above 0.25%, the detection rate of ctDNA in major cancer types, excluding liver, pancreatic cancer and glioma, was higher than 70%. In glioma, the rate of ctDNA detection in blood was much lower than in cerebrospinal fluid (24.29% vs 80%). Moreover, dynamic changes of ctDNA were significantly correlated with clinical outcomes for patients, with a consistency rate of 89.51%. The consistency rate of most major cancer types was above 90%, but that of glioma (71.43%) and pancreatic cancer (60%) were lower. ctDNA content fraction increased in all patients with recurrence and metastasis, from 2.72 to 59.8 fold. We also detected a drug-resistance process in a lung cancer patient with EGFR_p.E746_A750del. EGFR_p.T790M was first detected after the patient was administered gefitinib for more than a year, 3 months earlier than radiologic progression. Conclusions: Our personalised ctDNA analysis can effectively detect ctDNA. Hence, it can predict tumour progression and guide precise treatment. Citation Format: Guan Wang, Jinwang Wei, Angela Wu, Chun Dai, Wending Sun, Xin Cai, Qiang Xu. Analysis of personalised circulating tumour DNA to monitor recurrence and metastasis in multiple cancer types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-233.
Validation of Microsatellite Instability Detection Using a Comprehensive Plasma-Based Genotyping Panel
Authors: Jason Willis, Martina I. Lefterova, Alexander Artyomenko, Pashtoon Murtaza Kasi, Yoshiaki Nakamura, Kabir Mody, Daniel V.T. Catenacci, Marwan Fakih, Catalin Barbacioru, Jing Zhao, Marcin Sikora, Stephen R. Fairclough, Hyuk Lee, Kyoung-Mee Kim, Seung Tae Kim, Jinchul Kim, Danielle Gavino, Manuel Benavides, Nir Peled, Timmy Nguyen, Mike Cusnir, Ramez N. Eskander, Georges Azzi, Takayuki Yoshino, Kimberly C. Banks, Victoria M. Raymond, Richard B. Lanman, Darya I. Chudova, AmirAli Talasaz, Scott Kopetz, Jeeyun Lee, Justin I. Odegaard
Journal: Clinical Cancer Research (2019)

To analytically and clinically validate microsatellite instability (MSI) detection using cell-free DNA (cfDNA) sequencing.
Effect of zoledronic acid (Z) on pain in prostate cancer patients with bone metastases based on performance status
Authors: V. Barghout, L. Abetz, R. Arbuckle, V. Bosch, Y. Hei, F. Saad
Journal: Journal of Clinical Oncology (2006)

14544 Background: Z has demonstrated efficacy in reducing, preventing, delaying the occurrence of an SRE (Skeletal Related Event) including pathologic fractures, severe bone pain requiring radiation therapy, spinal cord compression, surgery to bone and hypercalcemia of malignancy which could lead to a loss of independence. Effects of Z on pain were analyzed in a subgroup of patients based on performance status. Methods: Subjects were randomised to Z 4mg (n = 201) or placebo (n = 201). The short form of the Brief Pain Inventory (BPI) was administered at baseline (visit 2), and visits 3 (weeks 3–4), 4 (weeks 6–8), and then every second visit (every 6 weeks) until study end. Changes in BPI individual item scores and the Pain severity and Pain Interference scale scores were compared between Z and placebo groups. Post baseline missing data were replaced by Last Observation carried forward (LOCF). Changes in scores were examined in the subgroup of patients with ECOG performance status scores of ≥ 1. Results: For patients ECOG score of ≥ 1 at baseline (n = 227), Z was superior to placebo in the BPI items ‘pain at its worst’, ‘pain at its least’, ‘pain on average’, and the Pain Severity scale at visit 4 (weeks 6–8) and visit 6 (week 12) (p &lt; 0.05). At visit 8 (weeks 18–20) Z was superior to placebo on the ‘pain on average’ item and Pain Severity scale (p &lt; 0.05). For visit 12 (weeks 30–32) and for LOCF Z was superior to placebo for ‘pain at its worst’, ‘pain on average’ and Pain Severity (p &lt; 0.05 for all). For the ‘pain right now’ item there were statistically significant differences at visits 4, 6, 12 and LOCF (p &lt; 0.05). In addition, at visit 6 (week 12), Z was superior to placebo for changes in items assessing interference with: sleep, general activities, mood, walking and enjoyment of life (p &lt; 0.05). Z was also superior to placebo for ‘interference with general activities’ at visits 12 (weeks 30–32), 16 (weeks 42–44) and LOCF (p &lt; 0.05). Conclusion: Results suggest Z provides significant benefit in pain reduction and Z may have an impact on patients’ daily activities which may lead to a preservation of patients’ functionality. [Table: see text]
CD71<sup>−</sup> Alveolar Macrophages in Idiopathic Pulmonary Fibrosis: A Look beyond the Borders of the Disease
Authors: Ermanno Puxeddu, Daniela Fraboni, Giuseppe Cillis, Francesco Cavalli, Francesco Buccisano, Paola Rogliani
Journal: American Journal of Respiratory and Critical Care Medicine (2019)

participate in the telehealth intervention, as our traditional PR participation rate after discharge has been approximately 5% (4), a number reflected in the data for control subjects in this study.The videoconferencing sessions were performed using a Health Insurance Portability and Accountability Act-compliant app, and no video data were recorded.Although there are privacy concerns with conducting live monitoring at a patient's home, we believe these are no greater than those possible in supervised home PR sessions and perhaps group activities in traditional PR.Dr. Moy suggests that the observed benefits of our video intervention were possibly due to individual counseling and monitoring that could have led to earlier detection of exacerbations and outpatient therapy.Although this is possible, we believe this is unlikely to explain the benefits, as patients who were not exposed to the telehealth intervention also received daily phone calls for 2 weeks and then weekly phone calls for 3 months (4).Dr. Moy also calls for a randomized controlled trial with three arms comparing video PR, traditional PR, and no PR before video PR attains PR status.An important distinction to make in comparing our video telehealth PR program with other centerbased and home-based programs is the indication for receipt of telehealth PR in our study (5).Our patients were enrolled during hospitalization and had extremely poor functional capacity at discharge.Their ability to participate in an optimal-intensity PR program was thus limited.We also believe we should not be too dogmatic about the notion that PR interventions can be called PR only if they involve attending sessions at a center with access to expensive equipment and a team of experts.Although this is ideal, this approach has clearly failed in the real world (6), and efforts should be made to test and invest in new and alternative methods for delivering PR (7).These approaches include alternative exercise strategies such as tai chi and yoga (8), interactive web-based PR (9), home-based supervised PR, and video telehealth PR (5).
Profiling of targetable aberrations in advanced sarcoma.
Authors: Muhammad Saad Hamid, Nada Al Masalmeh, Kelsey Anne Poorman, Amy M. Weise
Journal: Journal of Clinical Oncology (2019)

e22559 Background: Soft tissue and bone sarcoma (STS/BS) are heterogeneous and difficult to treat malignancies. Recent advances in molecular testing improved our understanding of the disease biology. Methods: Retrospective data on non-GIST sarcoma cases were analyzed using next genomic sequencing (NGS) (MiSeq on 47 genes, NextSeq on 592 genes), immunohistochemistry (IHC), fusion transcript detection and copy number alterations (CNA) by Caris Life Sciences between July 2010 and November 2018 at Karmanos Cancer Institute. Targetable aberrations (TA) were identified by searching available literature on therapeutics tested in clinical trials. Results: Demographic data on 64 patients were analyzed; median age 56 (21-87y) and a 1:1 gender ratio. Most frequent histologies include Leimyosarcoma (LMS) 15.3% (n = 10) and Undifferentiated Pleomorphic Sarcoma (UPS) 12.5% (n = 8). Genetic aberrations occurred in 78% of cases, with a cumulative 302 aberrations and a mean 4.7 TA (1-11)/case. Frequent aberrations by methodologies include a) IHC: TOP2A 64.3% (n = 36), MGMT 53.9% (n = 28), TUBB3 49% (n = 24); b) NGS: TP53 37.8% (n = 17); c) CNA: CDK4 and MDM2 at 9.3% (n = 4) respectively; d) fusion transcript: NOTCH2 fusion (n = 1), p &lt; 0.05. All cases were MSI stable. TA constituted 37.1% (n = 112) of the identified aberrations in the cohort and existed in 89.1% (n = 57) cases with a mean of 3.08 TA/case, p &lt; 0.05. Frequent TA other than TOP2A, TP53, MGMT by histologies included a) LMS: RRM1 28.6% (n = 4), PI3KCA and ER/PR at 14.3% (n = 1) each respectively; b) UPS: TUBB3 50% (n = 4), PD-1 25% (n = 2); c) Sarcoma NOS: CDK4 28.6% (n = 2), TS 28.6% (n = 2), C-MET and EGFR at 14.3% (n = 1) each respectively; d) Well Differentiated/Dedifferentiated Liposarcoma: CDK4, MDM2 and PD-1 at 20% (n = 1) each respectively. Conclusions: Incorporating genomic profiling has helped personalize treatment to include clinical trial enrollment. Further drug development and prospective studies are required in this population.
Nurse-like Cells Express High-Levels of Wnt5a, Which Induces ROR1-Dependent Signaling That Promotes Migration and Survival of Neoplastic Cells in Chronic Lymphocytic Leukemia
Authors: Yun Chen, Liguang Chen, Jian Yu, Ling Zhang, Laura Z. Rassenti, Thomas J. Kipps
Journal: Blood (2017)