tbuckley/cabot-search huggingface dataset:
Modulation by treatment of tumor infiltrating lymphocytes (TILs) and PDL1 expression in triple-negative breast cancer in the ETNA trial.
Authors: Giampaolo Bianchini, Chanel Smart, Mauro Mansutti, Hans-Joachim Lück, Stefania Zambelli, Clara Olier, Antonio Anton, Giancarlo Bisagni, Laura Merlini, Serafin Morales Murillo, Lourdes Calvo Martínez, Jose Ignacio Chacon, Vladimir Semiglazov, Marc Thill, Arlene Chan, Ignasi Tusquets, Luca Licata, Pinuccia Valagussa, Giuseppe Viale, Luca Gianni
Journal: Journal of Clinical Oncology (2020)

555 Background: We assessed TILs and PDL1 expression before, during and after neoadjuvant treatment in TNBC patients enrolled in the ETNA study, and investigated associations with clinical outcome. Methods: In ETNA patients randomly received paclitaxel or nab-paclitaxel followed by 4 cycles of an anthracycline regimen, including 219 centrally confirmed TNBC. We successfully measured stromal and intratumoral TILs (sTILs, iTILs) and PDL1 status (Ventana SP142, IC≥1%) on biopsies before [n = 186/213 (84.9%)], on d1 cycle 2 (d1c2) of therapy [n = 41/186 (22.0%)], and at surgery [SX, n = 65/129 (34.9%)]. We investigated the expression and modulation over time of TILs and PDL1 and their association with pCR and event-free survival (EFS). Results: Prevalence of PDL1+ was 35.5% (baseline), 20.6% (d1c2) and 30.1% (SX). At each time-point sTILs and iTILs were higher in PDL1+ cases (p≤0.01). An effect of age of the tumor blocks (5-7.5 years) or pre-analytical issues could not be ruled out for the relatively low rate of PDL1 positivity. Paired PDL1 at baseline and d1c2 showed conversion in 25.7% (pos to neg [11.4%] or neg to pos [14.3%]). Comparing PDL1 at baseline and SX, the conversion rate was 30% (pos to neg [8.3%] or neg to pos [21.6%]). sTILs and iTILs significantly increased at cycle 2, more significantly in pCR (p≤0.001) than in RD (p≤0.05) cases, and a not significant trend of decrease was observed at surgery PDL1+ tumors had a higher pCR rate (54.7% vs 32.5%, p = 0.004). PDL1 retained significance (OR 2.00 [1.04-3.88], p = 0.039) after adjustment for sTILs (OR 1.21 [1.03-1.42], p = 0.021). High iTILs and sTILs at d1c2, but not PDL1 status, were predictive of pCR. Notably, adjusting for sTILs, PDL1+ tumors at d1c2 showed a trend for association with lower pCR rate (OR 0.06 [0.01-1.15], p = 0.062). sTILs at cycle 2 was the most informative variable (OR 1.61 [1.28-1.61], p = 0.004) and provided independent information to baseline biomarkers. Baseline PDL1 and biomarkers at cycle 2 were not associated with EFS. In surgical samples with RD, higher sTILs, but not iTILs and PDL1 status, were associated with a trend for a lower risk of recurrence (HR 0.19 [0.02-1.39], p = 0.068). Conclusions: sTILs assessment on core biopsies after one cycle of taxane is a promising early biomarker of pCR. PDL1, as well as sTILs and iTILs, provided independent prediction of pCR and were strongly modulated by treatment. The modulation of PDL1 expression should be considered whenever PDL1 is assessed in view of identifying candidates to atezolizumab in 1 st line advanced setting.
Heterogeneity of PD-L1 expression between primary and metastatic bladder cancer tumors and therapeutic implications between the immune cell score and combined positivity score.
Authors: Gerald Bastian Schulz, Rumyana Todorova, Severin Rodler, Tobias Grimm, Michael D. Staehler, Doris Mayr, Christian G. Stief, Jozefina Casuscelli
Journal: Journal of Clinical Oncology (2020)

e17041 Background: Heterogeneity of PD-L1 expression between primary and metastatic tumors has been reported for different cancer entities. In metastatic bladder cancer (BC), this might have an impact on therapeutic algorithms. For cisplatin-ineligible patients, first-line immune-checkpoint inhibitor therapy is recommended based on the PD-L1 expression assay employed, namely immune cell (IC) or combined positive score (CPS). Here, we compared the CPS and IC scores in bladder tumors (BT) and matched metastatic lymph nodes (LN). Methods: From our institutional database we identified patients with urothelial BC and lymphatic spread on pathologic examination of radical cystectomy specimens. Both CPS and IC were assessed by PD-L1 immunohistochemistry in the BT and matched LN metastases. Positive scores were in accordance to the respective cut-offs (CPS ≥10 and IC ≥2). Key clinicopathological parameters were correlated with CPS and IC scores. Differences between the two scores and between primary BT and LN metastasis were compared. CPS and IC scores both between and within the bladder tumour and LN metastasis were tested for correlation. Finally, the prognostic impact of the CPS and IC score was assessed. Pearson’s chi-squared test, Wilcoxon-test and Log-rank test were employed. Results: We included 108 patients (73.1% males, 26.9% females) with LN-positive urothelial BC. There was no correlation between age, gender, T-stage, number of positive lymph nodes and either CPS or IC scores. CPS was significantly more often positive in BT specimens (43.5%, n = 47/108) compared to LN samples (35.6%, n = 37/104) (p = 0.004). IC score was also significantly more often positive in BT specimens (28.7%, n = 31/108) compared to LN samples (21.2%, n = 22/104) (p = 0.013). There are significantly more CPS positive vs. IC positive cases when assessing PD-L1 expression in BT (p &lt; 0.001). CPS and IC score positively correlated within both BT (r = 0.682, p &lt; 0.001) and LN (r = 0.648, p &lt; 0.001). CPS (r = 0.778, p &lt; 0.001) and IC (r = 0.692, p &lt; 0.001) positively correlated between the bladder tumour and LN. PD-L1 expression had no impact on oncological prognosis. Conclusions: PD-L1 expression measured by CPS correlates with IC scores in BC. There are, however, significant and clinically relevant differences between the BT and LN as well as between the two assays. Besides the implication for checkpoint-inhibitor therapy, PD-L1 expression does not seems to be prognostic in BC.
The preliminary efficacy and safety data of KN046 in patients failed on prior immune checkpoint inhibitors therapy.
Authors: Hongyun Zhao, Yuxiang Ma, Yang Zhang, Shaodong Hong, Yunpeng Yang, Wenfeng Fang, June Xu, Hardy Van, Paul Kong, Fei Yang, Jingying Li, Yao Lu, Li Zhang
Journal: Journal of Clinical Oncology (2020)

3020 Background: KN046 is a bispecific antibody that blocks PD-L1 and CTLA-4 by interaction with PD1 and CD80/CD86. KN046-CHN-001 (NCT03529526) is a, dose escalation and expansion phase Ia/Ib clinical trial in China. Here we reported safety, tolerability and preliminary efficacy in patients failed on prior immune checkpoint inhibiters (ICIs) treatment. Methods: Patients progressed on ICIs (including but not limited to antibodies targeting PD-1, PD-L1, OX40, et al) with pathologically confirmed solid tumor, ECOG 0-1, measurable lesion per RECIST v1.1, no immune-related adverse events (IRAEs) led to ICIs discontinuation, were enrolled and received intravenous KN046 treatment across four dose levels including 3.0 mg/kg (n = 3) and 5.0 mg/kg (n = 20) Q2W; and 5.0 mg/kg (n = 4), 300.0 mg flat dose (n = 2) Q3W. Safety and tolerability were assessed per NCI-CTCAE v5.0. Treatment-emergent AEs (TEAEs) and IRAEs were decided by investigators. Efficacy was evaluated by investigators per RECIST 1.1 every 6 weeks. Results: Twenty-nine who progressed on prior ICIs therapy were enrolled (25anti-PD-1 antibody; 3 anti-OX40 antibody; and 1 anti-CD137 antibody) and were included in the current analysis. Among 29 patients, 19 were nasopharyngeal cancer (NPC) and 9 were non-small cell lung cancer (NSCLC). The median duration of the exposure of KN046 was 12 weeks (range 2 to 40). Eleven patients remained on the treatment and 18 discontinued due to disease progression (n = 13), AE (n = 1), death (n = 1) and others (n = 3). Twenty-six (89.7%) patients experienced TRAEs of all grades and 2 (6.9%) experienced grade≥3 TRAEs (1 grade 3 anemia and 1 grade 3 infusion-related reaction). The most common (≥10%) TRAEs were pruritus (8, 27.6%), rash (8, 27.6%), asthenia (6, 20.7%), fatigue (6, 20.7%), pyrexia (5, 17.2%), infusion related reaction (4, 13.8%), alanine aminotransferase elevation (3, 10.3%) and white blood cell count elevation (3, 10.3%). Eleven (37.9%) patients experienced irAEs (with no grade≥3). Objective responses were occurred in 3 (12.0%, 25 evaluable) patients, disease control rate was 52.0% (10 stable disease). Median progression free survival was 2.69 (95%CI 1.31,5.52) months. Median overall survival was not reached. PFS rates for 3 and 6 Months were 41.0% (95%CI 18.5, 62.5) and 21.9% (95%CI 4.6, 47.3). OS rates for 6 and 9 months were88% (95%CI 57.2, 97.1) and 58.7% (95%CI 8.3, 89.2), respectively. Conclusions: Overall, KN046 showed a favorable safety profile and promising clinical benefit in advanced solid tumor patients who failed on prior ICIs therapy. Clinical trial information: NCT03529526 .
NGS testing use and results: A survey of U.S. oncologists.
Authors: Mary Lou Smith, Elda Railey, Carol B. White, Julianne S Dieterich, Elizabeth Garrett-Mayer, Suanna S. Bruinooge, Andrew N. Freedman, Janet De Moor, Stacy W. Gray
Journal: Journal of Clinical Oncology (2020)

e19145 Background: Scientific advances in genomics have ushered in new cancer tests and therapies. Many researchers, clinicians and advocates wonder how breakthroughs are implemented in practice. Methods: We examined Next Generation Sequencing (NGS) use, results, actions and outcomes among US oncologists (oncs) in treatment of their patients (pts) with advanced cancer (AC). 178 physician members of ASCO who used NGS for AC pts in past 3 months completed an online survey (response rate=30%). Results: Table shows NGS use, outcomes, and perceptions of treatment response among oncs who treat AC pts. Results from questions that were NOT asked by cancer type: 19% of respondents reported that NGS results guided treatment recommendations to a great extent, and 37% to a moderate extent, 65% reported tests often provided no actionable information; among oncs reporting NGS results provided actionable information, 31% reported they sometimes/often tried but couldn’t obtain the FDA-approved drug; respondents used many approaches to “decide what to do” with results. 83% explored trials, 68% reviewed scientific literature, 64% explored feasibility of FDA-indicated drug, 52% used NGS report recommendations, 47% talked with colleague, and 23% accessed molecular tumor board most (&gt;60%) of the time. Conclusions: Oncologists reported high use of NGS results to guide treatment decisions for pts with select ACs and an associated benefit in some pts. Two-thirds of oncs often experienced lack of actionable information across a broad range of tumor types. Even when NGS yielded actionable information, it was common for oncs to experience problems obtaining FDA-approved drugs. The large number of approaches oncs used to make treatment decisions may suggest an important opportunity to improve decision-making efficiency in healthcare delivery. [Table: see text]
Investigation of pharmacotherapy in patients with hypertension in community of Shanghai and the factors related to blood pressure control
Authors: Qian Chen, Jie Gu, Xiang-jie Zhang, Tian-hao Wang, Yuan Zhang, De-an Liu, Xiao-yan Ou, Ning Zhong, Li-ping Xu
Journal: BMJ (2013)

Objective
To investigate pharmacotherapy in patients with hypertension in community of Shanghai Xuhui District and the related factors related to blood pressure control.


Methods
A cross-sectional sampling survey was undertaken in 47 572 patients incorporated into standardized management of hypertension from 5 communities in Xuhui District of Shanghai during May 2011 to July 2011.


Results
Total 3800 questionnaires were distributed and 3328 (87.6%) were returned. Among all patients elderly cases accounted for 71.0%(2305/3247); special patients complicated with other diseases, including diabetes mellitus, coronary heart disease and stroke accounted for 72.5%(2158/2978). To make up a prescriptionwas the primary reason of encounter (2929, 90.9%) and 76.8% choose community health service center. Only 454(14.4%) patients knew the major adverse effects of their antihypertensive drugs. The blood pressure control rates in common, elderly and special patients were 62.5%(235/376), 75.9%(487/642) and 17.8%(328/1839), respectively. 65.4%(2176/3328) patients choose monotherapy, only 28.6%(952/3328) used more than 2 drugs and 2.3%(76/3328) patients adjusted drugs by themselves. Additional use Chinese medicine (571/3378,16.9%) was common in community. The blood pressure control rate in patients using monotherapy was higher than that in patients using more than 2 drugs (OR=0.664, OR=0.427, P<0.001, P=0.002). In monotherapy, the control rate of patients using additional Chinese medicine was higher than those used calcium channel blockers (OR=1.717, P<0.001).


Conclusions
The results indicate that the blood pressure control rate in patients complicated with other chronic diseases is very low in communities; which were associated with non-standard medication and inadequate attention on blood pressure control standards in different populations.


Key words: 
Hypertension; Therapy; Community health services; Questionnaires
A phase Ib/II study of eribulin (ERI) plus pembrolizumab (PEMBRO) in metastatic triple-negative breast cancer (mTNBC) (ENHANCE 1).
Authors: Sara M. Tolaney, Kevin Kalinsky, Virginia G. Kaklamani, David R. D'Adamo, Gursel Aktan, Michaela L. Tsai, Ruth O'Regan, Peter A. Kaufman, Sharon Wilks, Eleni Andreopoulou, Debra A. Patt, Yuan Yuan, Grace Wang, Dongyuan Xing, Ella Kleynerman, Vassiliki Karantza, Sami Diab
Journal: Journal of Clinical Oncology (2020)

1015 Background: As monotherapies, both ERI (a chemotherapeutic microtubule inhibitor) and PEMBRO (a programmed death [PD]-1 blocking immunotherapy) have shown promising antitumor activity in mTNBC. Emerging data suggest that the addition of immunotherapy to traditional chemotherapy holds promise for mTNBC. This open-label, single-arm, phase 1b/2 study evaluated the safety and efficacy of ERI + PEMBRO in mTNBC. Methods: Patients (pts) with mTNBC and ≤2 prior systemic anticancer therapies for metastatic disease were enrolled and stratified by prior number of therapy (Stratum 1, 0; Stratum 2, 1–2). Pts received IV ERI 1.4 mg/m 2 on day (d)1 and d8 and IV PEMBRO 200 mg on d1 of a 21-d cycle. The primary objectives were safety and objective response rate (ORR per RECIST 1.1 by independent imaging review). Assessments also included efficacy outcomes by PD ligand-1 (PD-L1) expression status; PD-L1+ was defined as a combined positive score ≥1 using the PD-L1 IHC 22C3 pharmDx. Results: As of data cutoff (July 31, 2019), 167 pts (Stratum 1, n=66; Stratum 2, n=101) were enrolled and treated. No dose-limiting toxicities were observed. The most common treatment-emergent adverse events were fatigue (66%), nausea (57%), peripheral sensory neuropathy (41%), alopecia (40%), and constipation (37%). No deaths were considered treatment related. The overall ORR was 23.4% (95% CI: 17.2–30.5). Efficacy outcomes by PD-L1 status (PD-L1+, n=74; PD-L1-, n=75) and stratum are presented (table). Conclusions: ERI + PEMBRO has activity in pts with mTNBC. There was a trend toward more robust activity for the combination among patients with PD-L1+ tumors compared to PD-L1- tumors in the first-line setting (Stratum 1); whereas, in the later-line setting (Stratum 2) similar survival outcomes were observed among the PD-L1+ and PD-L1- pts. ERI + PEMBRO shows promise for mTNBC with efficacy that appears greater than historical reports of either agent alone. Clinical trial information: NCT02513472 . [Table: see text]
Radiomic response evaluation of recurrent or metastatic head and neck squamous cell cancer (R/M HNSCC) patients receiving pembrolizumab on KEYNOTE-012 study.
Authors: Kirsty Taylor, Michal Kazmierski, Astrid Billfalk-Kelly, Farnoosh Khodakarami, Brandon Driscoll, Lisa Wang, Scott Victor Bratman, Benjamin Haibe-Kains, Lillian L. Siu
Journal: Journal of Clinical Oncology (2020)

6545 Background: Immunotherapy has become a standard of care in the treatment of R/M HNSCC, however only a subset of patients respond, highlighting the need for predictive and prognostic biomarkers. Radiomics is a non-invasive method to quantitatively analyze tumors through conventional imaging. Methods: The pre-treatment and first-on-treatment (after 8 weeks) computed tomography (CT) scans from 132 R/M HNSCC patients treated with single-agent Pembrolizumab (10mg/kg Q2W or 200mg Q3W IV) on the KEYNOTE-012 study were analyzed. Identified target lesions, per RECIST 1.1, were manually contoured, and radiomic features from the tumor and peritumoral region (3 mm expansion of the tumor) were extracted using PyRadiomics. All combinations of image filters and feature classes, not including shape descriptors of peritumoral region, were extracted. Feature space dimensionality was reduced by clustering features (hierarchical clustering using Pearson-based distance and complete linkage) and selecting the medoid of each cluster. Correlation with lesion-level response (LLR) at first-on-treatment CT and overall response (OR) was evaluated using concordance index (CI) with Benjamini-Hochberg multiple testing correction. Results: A total of 406 lesions were included (45 head &amp; neck (HN), 207 lung, 57 liver, 86 lymph nodes (LN), 11 other). 3562 features were extracted from pre-treatment scans (2246 tumor, 1316 peritumor). Considering all lesion sites collectively, 27 of 110 feature clusters were significantly correlated with LLR (false discovery rate (FDR) &lt; 0.05) but not with best overall RECIST response per patient on study. However, when grouped by organ, a number of feature cluster medoids were significantly associated (FDR &lt; 0.05) with LLR (HN: 1, lung: 28, liver: 8, LN: 1) and OR (liver: 18). Feature clusters predictive of LLR and OR included descriptors of both tumor-specific and tumor/peritumoral gray-level intensity and texture (e.g. 74% tumor and 26% peritumoral features in clusters significantly associated with OR in liver). Conclusions: Tumor and peritumoral radiomic features at baseline correlate with LLR and OR to immunotherapy in R/M HNSCC. Despite significant heterogeneity in lesion site, both global and site-specific significant feature clusters could be identified.
Effect of integrating machine learning mortality estimates with behavioral nudges to increase serious illness conversions among patients with cancer: A stepped-wedge cluster randomized trial.
Authors: Chris Manz, Ravi Bharat Parikh, Chalanda N. Evans, Corey Chivers, Susan B Regli, Sujatha Changolkar, Justin E. Bekelman, Dylan Small, Charles A.L. Rareshide, Nina O'Connor, Lynn Mara Schuchter, Lawrence N. Shulman, Mitesh S. Patel
Journal: Journal of Clinical Oncology (2020)

12002 Background: Most patients with cancer die without a documented serious illness conversation (SIC) about prognosis and goals. Interventions that increase SICs between oncology clinicians and patients may improve goal-concordant care and end-of-life outcomes. Methods: In this stepped-wedge cluster randomized trial (NCT03984773), we tested the effect of an intervention delivering machine learning-based mortality estimates with behavioral nudges to oncologists to increase SICs among patients with cancer. The clinician-focused intervention consisted of 1) weekly emails providing individual SIC performance feedback (number of SICs in the past month) and peer comparisons; 2) a list of patients scheduled for the next week with a ≥10% predicted risk of 6 month mortality by a validated machine learning prognostic algorithm, and 3) automated opt-out text prompts on the patient’s appointment day to consider an SIC. Eight medical oncology clinics were randomized to receive the intervention in a stepped-wedge fashion every four weeks for a total of 16 weeks. Medical oncology clinicians were included if they were trained to use the SIC Guide (Ariadne Labs, Boston MA). Patients were included if they had an outpatient encounter with an eligible clinician between June 17 and November 1, 2019. The primary outcome was the percent of patient encounters with a documented SIC. Intention to treat analyses adjusted for clinic and wedge fixed effects and clustered at the oncologist level. Results: The sample consisted of 78 clinicians and 14,607 patients. The mean age of patients was 61.7 years, 55.7% were female, 70.4% were white, and 19.6% were black. The percent of patient encounters with an SIC was 1.2% (106/8536) during the pre-intervention period and 4.0% (401/10,152) during the intervention period. In intention to treat adjusted analyses, the intervention led to a significant increase in SICs (adjusted odds ratio, 3.7; 95% CI, 2.5 to 5.4, P value &lt; 0.0001). Conclusions: An intervention consisting of machine learning mortality estimates and behavioral nudges to oncology clinicians increased SICs by three-fold over 16 weeks, a significant difference.This is one of the first studies evaluating a machine learning-based behavioral intervention to improve serious illness communication in oncology. Secondary analyses (completed April 2020) will clarify whether this intervention leads to a sustained increase in SIC rates and improves goal-concordant care and end-of-life outcomes. Clinical trial information: NCT03984773 .
Methylenetetrahydrofolate reductase C677T polymorphism for primary hyperuricemia and gouty arthritis
Authors: Qiao-hui Zhang, Jie Liu
Journal: BMJ (2008)

The relation of methylenetetrahydrofolate(MTHFR)reductase C677T polymorphism with primary hyperuricemia and gouty arthritis was observed in People's Hospital of Shanxi Province.MTHFR reductase C677T pdymorphism in 195 subjects was examined by PCR-restriction fragment length polymorphism.The results showed that MTHFR gene mutation might be a risk factor for primary hyperuricemia.However,C677T polymorphism of the MTHFR gene was not related to the development of gouty arthritis.

Key words: 
Hyperuricemia;  Methylenetetrahydrofolate reductase
The association between initial chemotherapy treatment timing, intensity, and end-of-life (EOL) care trajectory among older adults with advanced stage lung cancer (aLC).
Authors: Carolyn J Presley, Haseeba Shahzad, Maureen Canavan, Elizabeth Horn Prsic, Maureen Saphire, Shi-Yi Wang, Amy J. Davidoff
Journal: Journal of Clinical Oncology (2020)

e24009 Background: The use of chemotherapy regimens with varying intensities at specific time points may have an effect on EOL care trajectories among older adults with aLC (IIIB &amp; IV). Methods: Using the Surveillance, Epidemiology, and End Results (SEER)–Medicare registry and claims data, we selected decedents diagnosed with aLC (small cell: SCLC and non-small cell: NSCLC) between 2008 and 2013 who survived ≥6 months (death between 2008 and 2014). Main outcome measures were EOL care trajectories in the 6 months prior to death among patients receiving chemotherapy characterized by intensity levels. A multinomial logit model was used to determine the association between intensity of initial chemotherapy regimen and EOL care trajectory. Results: Our sample (N = 10,594) was mostly NSCLC (77%) of whom only 63% received chemotherapy. Patients receiving chemotherapy were predominantly males (70.4%), age 66-69 years (80%), non-Hispanic white (68.1%) and 78.4% were married. 41 % received treatment prior to EOL-6 and 10.4 % first initiated treatment during EOL-6. The majority of patients received a platinum-based doublet as a first line therapy. Compared to non-cisplatin platinum doublet chemotherapy, patients receiving cisplatin were least likely to be in the decreasing intensity EOL group and most likely to be in increasing intensity EOL group (see table). Conclusions: Among aLC decedents, patients who received cisplatin chemotherapy as compared to non-cisplatin doublet chemotherapy were least likely to be in the decreasing EOL intensity group and most likely to be in the increasing EOL intensity group. EOL care preferences may need to be considered when choosing initial chemotherapy treatment regimens. [Table: see text]