tbuckley/cabot-search huggingface dataset:
Prognostic value of dickkopf-1 and ß-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer.
Authors: Seoree Kim, Yoon Ho Ko, Hye Sung Won, Ji Hyun Yang, Der Sheng Sun, Kwangil Yim, Soon Auck Hong, Sang Hoon Chun, Kee-Hwan Michael Kim
Journal: Journal of Clinical Oncology (2021)

e16172 Background: Despite recent advancements in the understanding of the molecular biology of biliary tract cancer (BTC), target therapy and immunotherapy have demonstrated only limited efficacy, with cytotoxic systemic therapy still being the most effective treatment in BTC, except for surgery. Thus, this study aimed to analyze the role of DKK1 or β-catenin as a prognostic factor in BTC and determine the clinical association of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocyte (TIL). Methods: We used data in The Cancer Genome Atlas (TCGA) Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. Immunohistochemistry was performed on formalin-fixed, paraffin-embedded tissue sections, and whole tissue sections of representative tumor samples were used for antigen retrieval. Results: CD8+TIL expression was a significant predictor of favorable overall survival (OS) and recurrence-free survival (RFS) (median OS, 34.9months in TIL-high, 16.7months in TIL-low, P &lt; 0.0001 respectively; median RFS, 27.1months in TIL-high, 10months in TIL-low, P &lt; 0.0001 respectively). Positive ß-catenin expression and high DKK1 expression was also associated with a shorter OS (median OS, 23.95months in positive ß-catenin, 26.1months in negative ß-catenin, P = 0.1009 respectively; median OS, 19.4months in high DKK1, 31.65months in Low DKK1, P = 0.0093 respectively), but not RFS (p = 0.1466, at ß-catenin respectively; p = 0.2924, in DKK1 respectively). In the CD8+TIL-high BTC group, the tumor expression of β-catenin and DKK1 had a significant negative impact on either OS or RFS (p = 0.0146 and p = 0.0112, at ß-catenin respectively; p = 0.0950 and p = 0.3904, in DKK1 respectively). However, in the TIL-low BTC group, there were no differences in OS or RFS according to ß-catenin and DKK1 expression (p = 0.5108 and p = 0.8431, at ß-catenin respectively; p = 0.1127 and p = 0.1095, in DKK1 respectively). Cox regression multivariate analysis demonstrated that CD8+ TIL (hazard ratio [HR], 0.490; 95% confidence interval (CI), 0.303-0.791; p = 0.004) and β-catenin (HR, 1.652; 95% CI, 1.035-2.639; p = 0.036) retained significant association with OS after adjustment for all variables. Conclusions: Among patients with resected BTC, β-catenin and DKK1 protein levels are associated with poor clinical outcomes, whereas high CD8+ TIL levels are associated with good clinical outcomes. This confirms the differential clinical role of Wnt/β-catenin and DKK1 proteins according to TIL expression in BTC.
Differences in clinicopathological characteristics, treatment, and survival outcomes between older and younger breast cancer patients: A regional perspective.
Authors: Hikmat Abdel-Razeq, Sereen Iweir, Rashid Abdel-Razeq, Fadwa Abdel Rahman, Hanan Almasri, Rayan Bater, Ayat Taqash
Journal: Journal of Clinical Oncology (2021)

e18604 Background: In developing countries, breast cancer treatment outcomes may be uniquely affected by the tendency of breast cancer patients to develop the disease at a much younger age than the worldwide average. Contrarily, older patients tend to present with multiple comorbidities that complicate their outcomes and influence their treatment options and decisions. This study will be the first to investigate the dichotomies between older and young breast cancer patients in our region. Methods: The study was based on data collected from the cancer registry of our institution for breast cancer patients 65 years or older (n = 553), and patients 40 years or younger (n = 417) at time of diagnosis. Statistical models were used to investigate the associations between age groups, clinical characteristics and treatment outcomes. Results: A total of 970 patients were included in the final analysis. Compared to younger patients, older ones were more frequently diagnosed with distal metastasis; 20.6% compared to 15.1%, p =0.028. However, among patients with non-metastatic disease, younger ones tended to have more aggressive pathological features, including positive axillary lymph nodes (73.2% vs. 55.6%, p&lt; 0.001), T-3/4 (28.2% vs. 13.8%, p&lt; 0.001) and HER2-positive disease (29.3% vs. 16.3%, p&lt; 0.001). A higher percentage of patients from the young cohort underwent surgery (85.4%) when compared to the older group (74.9%), p&lt; 0.001. More patients in the older group had mastectomy than did younger patients (67.5% versus 40.2%, p&lt; 0.001), while breast conserving surgery (BCS) was performed on almost a third in each cohort, p= 0.245. Skin-sparing, with or without, nipple-sparing mastectomies (SSMs) along with breast reconstruction surgery were more frequently performed on younger patients than they were on the older patients. After a median follow-up of 59 months for the younger patients and 45 months for the older ones, the 5-year OS rate of the older patients was 67.6% compared to 72.1% for the younger patients, p= 0.035. However, the 5-year DFS rates of the two cohorts were not statistically different at 63.9% for the older group and 60.7% for the young patients, p= 0.31. The survival of patients with non-metastatic disease was also compared among both groups; the 5-year OS among the younger patients was significantly higher (83.6% compared to 78.8% among the older patients, p= 0.046). Survival was better among the younger patients across many clinical and pathological characteristics. Conclusions: Younger patients with breast cancer present with worse clinical and pathological features, albeit a better OS rate. The difference in DFS between the two groups was insignificant, suggesting that older women were more likely to die from non-cancer related causes.
Persistence of SARS-CoV-2 RNA in lung tissue after mild COVID-19
Authors: Laurens J Ceulemans, Mona Khan, Seung-Jun Yoo, Bolek Zapiec, Laura Van Gerven, Jan Van Slambrouck, Arno Vanstapel, Dirk Van Raemdonck, Robin Vos, Els Wauters, Joost Wauters, Peter Carmeliet, Peter Mombaerts
Journal: The Lancet Respiratory Medicine (2021)
Biomarkers for the Prediction and Diagnosis of Fibrostenosing Crohn’s Disease: A Systematic Review
Authors: Calen A. Steiner, Jeffrey A. Berinstein, Jeremy Louissaint, Peter D.R. Higgins, Jason R. Spence, Carol Shannon, Cathy Lu, Ryan W. Stidham, Joel G. Fletcher, David H. Bruining, Brian G. Feagan, Vipul Jairath, Mark E. Baker, Dominik Bettenworth, Florian Rieder
Journal: Clinical Gastroenterology and Hepatology (2021)
Physical activity in asthma control and its immune modulatory effect in asthmatic preschoolers
Authors: Debbie J. Maurer, Chengyao Liu, Paraskevi Xepapadaki, Barbara Stanic, Claus Bachert, Susetta Finotto, Ya‐Dong Gao, Anna Graser, Tuomas Jartti, Walter Kistler, Marek Kowalski, Heikki Lukkarinen, Maria Pasioti, Ge Tan, Michael Villiger, Luo Zhang, Nan Zhang, Mübeccel Akdis, Nikolaos G. Papadopoulos, Cezmi A. Akdis
Journal: Allergy (2021)

The impact of physical activity on immune response is a hot topic in exercise immunology, but studies involving asthmatic children are scarce. Our aims were to examine whether there were any differences in the level of physical activity and daily TV attendance, to assess its role on asthma control and immune responses to various immune stimulants.Weekly physical activity and daily television attendance were obtained from questionnaires at inclusion of the PreDicta study. PBMC cultures were stimulated with phytohemagglutinin (PHA), R848, poly I:C, and zymosan. A panel of cytokines was measured and quantified in cell culture supernatants using luminometric multiplex immunofluorescence beads-based assay.Asthmatic preschoolers showed significantly more TV attendance than their healthy peers (58.6% vs. 41.5% 1-3 h daily and only 25.7% vs. 47.2% ≤1 h daily) and poor asthma control was associated with less frequent physical activity (PA) (75% no or occasional activity in uncontrolled vs. 20% in controlled asthma; 25% ≥3 times weekly vs. 62%). Asthmatics with increased PA exhibited elevated cytokine levels in response to polyclonal stimulants, suggesting a readiness of circulating immune cells for type 1, 2, and 17 cytokine release compared to subjects with low PA and high TV attendance. This may also represent a proinflammatory state in high PA asthmatic children. Low physical activity and high TV attendance were associated with a decrease in proinflammatory cytokines. Proinflammatory cytokines were correlating with each other in in vitro immune responses of asthmatic children, but not healthy controls, this correlation was more pronounced in children with sedentary behavior.Asthmatic children show more sedentary behavior than healthy subjects, while poor asthma control is associated with a substantial decrease in physical activity. Our results suggest that asthmatic children may profit from regular exercise, as elevated cytokine levels in stimulated conditions indicate an immune system prepared for responding strongly in case of different types of infections. However, it has to be considered that a hyperinflammatory state in high PA may not be beneficial in asthmatic children.
Phase II study of SM-88 in Ewing's and other sarcomas.
Authors: Victoria S. Chua, Sant P. Chawla, Kitty Zheng, Ted Kim, Giuseppe Del Priore, Semmie Kim
Journal: Journal of Clinical Oncology (2021)

e23505 Background: Sarcomas are rare heterogeneous malignancies. Once recurrent, cure is uncommon. SM-88 (racemetyrosine) is an amino acid analogue with no known cross resistance to typical sarcoma regimens. Based on previous anecdotal experience in Ewing’s (EWS) we initiated a Phase 2 trial (HopES) in EWS and other sarcomas (Ss) after &gt;1 prior systemic therapy. We now report preliminary data after having met prespecified continuation criteria. Methods: Open label prospective trial in 2 separate cohorts (EWS and Ss) of oral SM-88 used with MPS conditioning agents (SM-88 920 mg, methoxsalen 10 mg, phenytoin 50 mg, sirolimus 0.5 mg) all daily until progression. Results: As of Feb 5 2021, 10 pts with incurable sarcomas were enrolled; 4 had high risk but stable EWS. Average age 43.9 yrs (13–77); 70% white; 20% female. Median number of prior regimens 4 (1–9); 70% received prior RT; 50% prior surgery. Median time from initial diagnosis 39.5 months with 50% T2 (40% unknown), 30% M1 (30% unknown). Prespecified futility stopping was exceeded (i.e., &gt;1 of first 5 subjects/cohort) upon achieving clinical benefit in each. Stable disease was achieved in 75.0% (6/8 with available data). Time on treatment (TTx) exceeded last known TTx in 80% (95% CI 44.4–97.5). Median SM-88 TTx was 4.9 vs 2.9 mo for prior TTx (logrank HR 0.53; p=0.12). One EWS subject had unresectable disease that became resectable, was completely resected, and remained disease-free for ≥ 6 months. Prior to SM-88, longest TTx was 12 mo (on IT*) and shortest TTx 1 mo (on IEV*) vs SM-88 TTx of 11.9 mo. An angiosarcoma subject had a 21% reduction in the sum of all target lesions and exceeded all prior TTx (including 8 mo on Ap/N* with 12+ mo duration of treatment of SM-88). There were no serious drug-related AEs. ECOG performance remained stable for all. Conclusions: SM-88 has exceeded pre-specified futility in both cohorts (EWS maintenance and Ss salvage). HopES continues to enroll toward the planned total of 12 subjects to more precisely define its benefit in this ultra-orphan, extremely recalcitrant disease. This trial now confirms the previously reported clinical utility of oral SM-88 in EWS and other high-risk sarcomas. Based on durable response (&gt;6mo), SD and prolonged TTx, SM-88 warrants additional investigation in this setting. Clinical trial information: NCT03778996. [Table: see text]
Comparison of immune microenvironment between primary lung tumors and paired brain metastatic tumors.
Authors: Likun Chen, Lihong Wu, Meichen Li, Huan Chen, Lijia Wu, Pei Hao, Ji He
Journal: Journal of Clinical Oncology (2021)

2020 Background: Lung cancer is one of the most common causes of brain metastases (BMs) and is always associated with poor prognosis. To evaluate the characteristics of the tumor immune microenvironment in brain metastases of non-small-cell lung cancer (NSCLC), we investigated the immunophenotype of primary NSCLC and paired brain metastases. Methods: Forty-three Chinese patients with NSCLC who had BMs at presentation or during the course of their disease were admitted to the Sun Yat-Sen University Cancer Center (Guangzhou, China) from 2000 to 2019. RNA sequencing (RNA-seq) of eighty-six formalin-fixed, paraffin embedded (FFPE) samples from primary lung tumors and paired brain metastases of 43 patients was conducted to comprehensively analyze the tumor immune microenvironment. Results: Our data revealed that brain metastases compared with primary lung tumors exhibited reduced tumor infiltrating lymphocytes (TILs) (all 28 immune cell subtypes P &lt; 0.05), lower fraction of activated CD8 T cell and effector memory CD8 T cell in total TILs (P = 0.028, P &lt; 0.001, respectively); higher fraction of macrophage and neutrophil in total TILs (P &lt; 0.001, P &lt; 0.01, respectively). Comparing with the primary lung tumors, the scores of some immune related signatures, including MHC non-class signature, IFN gamma signature and T-cell-inflamed gene-expression profile (GEP) signature, were significantly lower in brain metastases (P = 0.004, P = 0.009, P = 0.004, respectively), while the score of MHC class-II signature was higher in brain metastases (P = 0.045). We found the distributions of tumor microenvironment immune types (TMIT) in brain metastases and primary lung tumors were different. Brain metastases contained significantly lower proportion of TMIT I (high PD-L1/ high CD8A) (23%) than primary lung tumors (47%) (P &lt; 0.05). Besides, we found three immune inhibitory checkpoint molecules, namely C10orf54 (VISTA), CTLA4 and CD274 (PD-L1) were downregulated in brain metastases than in primary lung tumors (P &lt; 0.001, P &lt; 0.001, P = 0.034, respectively). Moreover, there was poor correlation of PD-L1 expression between paired brain metastases and primary lung tumors (R = 0.28, P = 0.068). Unsupervised hierarchic cluster analysis revealed the primary lung tumors had two distinct patterns of immune gene signatures, namely Cluster A and Cluster B, and the tumors in Cluster B were immune rich, but associated with poor prognosis (log-rank P = 0.021). Conclusions: Our work illustrates the immune landscape of brain metastases from NSCLC, and suggests that the tumor immune microenvironment in brain metastases compared with primary lung tumors is further immunosuppressed, that may help guide immunotherapeutic strategies for NSCLC brain metastases.
Futility and toxicity monitoring without halting for interim analyses.
Authors: Diana L Urbauer, Shannon Neville Westin, Ying Yuan
Journal: Journal of Clinical Oncology (2021)

e13579 Background: Many trial designs with futility or toxicity monitoring require that accrual halt to wait for currently enrolled patients to complete their assessment window. However, logistics often prevent this. In these cases, the performance of those designs might be compromised. This study examines the performance of 2 popular designs when enrollment is not halted at interim. Methods: Simulations were run to examine the effect of continuous enrollment on the operating characteristics (OCs) of a Simon’s 2-stage design for futility monitoring and a design using Bayesian posterior probabilities for toxicity monitoring. Both sets of 10,000 simulations examined the OCs when accrual rate was 0.5, 1.5, 3 and 5 patients/month with an assessment window of 30, 60 and 180 days. Results: The first scenario examined the OCs of a Simon design with 12 patients in the first stage and 21 at the end of the second stage. Regardless of accrual rate, the expected number of patients (EN0) increased and probability of early termination (PET0) decreased under the null hypothesis. Rate of change increased as assessment window increased. EN0 was 16 and PET0 was 54% when halting enrollment between stages. With continuous enrollment, EN0 ranged from 16-19, 17-21, and 18-21 patients for the 30-, 90- and 180-day assessment windows. PET0 ranged from 54%-50% with a 30-day assessment window. It halved to 24% with 3 patients/month enrolled and a 90-day window. PET0 was essentially 0 with a 180-day window and an enrollment of 3 patients/month. OCs for toxicity monitoring were examined for the early stopping rule Pr(toxicity rate &gt; 0.3 | data) &gt; 0.85 with toxicity rate ̃ beta(1, 1) with a maximum sample size of 20 and cohort size of 5. Expected number of patients (EN) increased and probability of early termination (PET) decreased as accrual rate increased, with rate of change increasing as assessment window increased. When the true probability of toxicity was 50% and enrollment halted between cohorts, EN was 10 patients and PET was 78%. EN was 17 and PET 54% with an assessment window of 30 days and 5 patients were enrolled per month. With a 90-day assessment window and 3 patients/month enrolled, EN was 16 and PET 59%. EN was 20 and PET was 12% with a 180-day assessment window and 3 patients were enrolled per month. Similar results were noted for cohorts of size 10 and a maximum number of 40 patients. Conclusions: The performance of designs that require halting enrollment while waiting for results of an interim analysis can be compromised by continuous accrual when assessment windows are lengthy and the accrual is fast. In these circumstances, consideration should be given to designs, such as Bayesian multiple imputation for delayed outcomes (Cai et al Stat Med 2014) and TOP2 (Lin et al JNCI 2019), that do not require accrual halt to make real-time interim analysis in the presence of pending patients, which protects patients from excessive toxicity or a futile intervention.
Impact of RAS status and prior targeted therapy on the activity of aflibercept plus FOLFIRI in patients with metastatic colorectal cancer (mCRC) in daily practice. Final results of the QoLiTrap prospective non-interventional study.
Authors: Ralf Dieter Hofheinz, Hendrik Kröning, Mark-Oliver Zahn, Felicitas Scholten, Hans-Günter Derigs, Stefanie Pederiva, Sandro Anchisi, Pierre Oliver Bohanes, Birgit Gruenberger, Christine Windemuth-Kieselbach, Gudrun Piringer, Josef Thaler, Roger von Moos
Journal: Journal of Clinical Oncology (2021)

e15570 Background: The anti-angiogenic fusion protein aflibercept targets VEGF-A, VEGF-B and PIGF. It is approved in combination with FOLFIRI for treatment of mCRC previously treated with an oxaliplatin-containing regimen. We evaluated the influence of RAS status and prior targeted therapy on the efficacy and safety of aflibercept plus FOLFIRI in daily practice. Methods: QoLiTrap is a large international (Germany, Austria, Switzerland), non-interventional study evaluating the quality of life (QoL), efficacy and safety of aflibercept plus FOLFIRI in daily clinical practice. The primary endpoint was QoL assessed by EORTC QLQ-C30 questionnaire. Secondary endpoints included overall survival (OS), progression-free survival (PFS), tumor response and safety. Patients were evaluable for primary and secondary endpoint analysis if they had a QoL questionnaire at baseline and at least 2 post baseline. Safety was analyzed in all patients exposed to at least one dose of study drug. We report here the results by RAS status and prior targeted therapy received. Results: 1277 patients with mCRC were treated (median age 66 years, males 64.8%, right colon tumor 27.6%, liver metastases 53.2% , ECOG 0-1 84.7%) mainly in second-line (50.3%) but also in third-line (23.1%) and fourth-line (11.9%) setting. Median duration of treatment was 12 weeks. Overall, 872 patients were evaluable for the efficacy analysis. At baseline, the global health (mean) score was 58.7 and the mean change from baseline over 12 weeks was -4.6%. A clinically meaningful decline of -10 points was not reached, regardless of RAS status and prior targeted therapy. Secondary endpoints are provided in the Table below. Most common all grade adverse events were diarrhea (34.2%), nausea (17.9%), fatigue (17.2%), stomatitis (17.2%) and hypertension (11.6%). Conclusions: Aflibercept plus FOLFIRI administered in daily practice shows no deleterious effect on QoL and retains its activity irrespective of RAS status and prior targeted therapy. The safety profile was manageable. Clinical trial information: AIO-LQ-0113. [Table: see text]
Risk of Colorectal Cancer in Serrated Polyposis Syndrome: A Systematic Review and Meta-analysis
Authors: Charles Muller, Akihiro Yamada, Sachie Ikegami, Haider Haider, Yuga Komaki, Fukiko Komaki, Dejan Micic, Atsushi Sakuraba
Journal: Clinical Gastroenterology and Hepatology (2021)
The association between myelodysplastic syndromes (MDS) and inflammatory bowel diseases (IBD): Analysis of Nationwide Inpatient Sample (NIS) database.
Authors: Mali Barbi, Sakteesh Gurunathan, Kith Pradhan, Balazs Halmos, Kira Gritsman, Amit K. Verma
Journal: Journal of Clinical Oncology (2021)

e19033 Background: The co-occurrence of MDS and IBD has been gradually recognized in the literature. Yet, large-scale national studies are required to investigate this observed association further. We aimed to delineate the clinical features, outcomes between the concurrent of MDS with IBD and MDS or IBD alone in a nationally representative database. Methods: Data were obtained from the NIS 2010-2014, using appropriate ICD-9 codes to identify patients who were admitted with a principal diagnosis of MDS with IBD as secondary (MDS-1/IBD) and MDS without IBD and patients who were admitted with a principal diagnosis of IBD with MDS (IBD-1/MDS) and without MDS. We assessed the mortality rate as the primary outcome, mean length of stay (LOS), and rate of blood transfusion as secondary outcomes by Pearson χ2 -test and univariate regression (logistic regression). Results: We identified 190 hospitalizations for MDS-1/IBD and 4895 hospitalizations for IBD-1/MDS. The mean LOS was higher for MDS-1/IBD group than for IBD or MDS only (11.7 vs. 6.1 and 7 days). However, the mortality rate in the MDS-1/IBD group was lower than in patients with IBD or MDS only (2.6% vs. 3.8% and 4.4%). While the rate of blood transfusion was higher among males in the MDS group, it was significantly higher among females when there is a concurrent MDS-1/IBD. However, the differences were not significant when MDS is not the primary diagnosis i.e IBD-1/MDS. In univariate analysis, age and Charlson comorbidity index were significantly associated with an increased mortality rate when there are IBD and MDS than MDS or IBD alone. Conclusions: While unable to assess appropriateness, NIS data indicate that there are significant differences in outcomes such as mean LOS, rate of blood transfusion and mortality rate when there is a concurrence of MDS and IBD than MDS or IBD alone. The underlying pathogenicity remains unclear and warrants additional study.[Table: see text]