Citations

Background: After critical illness, new or worsening impairments in physical, cognitive, and/or mental health function are common among patients who have survived. Who should be screened for long-term impairments, what tools to use, and when remain unclear. Objectives: Provide pragmatic recommendations to clinicians caring for adult survivors of critical illness related to screening for postdischarge impairments. Participants: Thirty-one international experts in risk-stratification and assessment of survivors of critical illness, including practitioners involved in the Society of Critical Care Medicine’s Thrive Post-ICU Collaboratives, survivors of critical illness, and clinical researchers. Design: Society of Critical Care Medicine consensus conference on post-intensive care syndrome prediction and assessment, held in Dallas, in May 2019. A systematic search of PubMed and the Cochrane Library was conducted in 2018 and updated in 2019 to complete an original systematic review and to identify pre-existing systematic reviews. Meeting Outcomes: We concluded that existing tools are insufficient to reliably predict post-intensive care syndrome. We identified factors before (e.g., frailty, preexisting functional impairments), during (e.g., duration of delirium, sepsis, acute respiratory distress syndrome), and after (e.g., early symptoms of anxiety, depression, or post-traumatic stress disorder) critical illness that can be used to identify patients at high-risk for cognitive, mental health, and physical impairments after critical illness in whom screening is recommended. We recommend serial assessments, beginning within 2–4 weeks of hospital discharge, using the following screening tools: Montreal Cognitive Assessment test; Hospital Anxiety and Depression Scale; Impact of Event Scale-Revised (post-traumatic stress disorder); 6-minute walk; and/or the EuroQol-5D-5L, a health-related quality of life measure (physical function). Conclusions: Beginning with an assessment of a patient’s pre-ICU functional abilities at ICU admission, clinicians have a care coordination strategy to identify and manage impairments across the continuum. As hospital discharge approaches, clinicians should use brief, standardized assessments and compare these results to patient’s pre-ICU functional abilities (“functional reconciliation”). We recommend serial assessments for post-intensive care syndrome-related problems continue within 2–4 weeks of hospital discharge, be prioritized among high-risk patients, using the identified screening tools to prompt referrals for services and/or more detailed assessments.

AbstractBackgroundEligibility criteria and endpoints for cancer cachexia trials—and whether weight loss should be included—remain controversial. Although most cachexia trials enrol patients after initial cancer diagnosis, few studies have addressed whether weight loss well after a cancer diagnosis is prognostic.MethodsWe pooled data from non‐small cell lung cancer patients from prospectively conducted trials within the Alliance for Clinical Trials in Oncology (1998–2008), a nationally funded infrastructure. We examined (i) weight data availability and weight changes and (ii) survival.ResultsA total of 822 patients were examined. Of these, 659 (80%) were on treatment at the beginning of Cycle 2 of chemotherapy; weight was available for 656 (80%). By Cycles 3 and 4, weight was available for 448 (55%) and 384 (47%), respectively. From baseline to immediately prior to Cycle 2, 208 (32%) gained weight; 225 (34%) lost <2% of baseline weight; and 223 (34% of 656) lost 2% or more. Median survival from the beginning of Cycle 2 was 13.0, 10.9, and 6.9 months for patients with weight gain, weight loss of <2%, and weight loss of 2% or more, respectively. In multivariate analyses, adjusted for age, sex, performance score, type of treatment, and body mass index, weight loss of 2% or more was associated with poor overall survival compared with weight gain [hazard ratio (HR) = 1.66; 95% confidence interval (CI): 1.33–2.07; P < 0.001] and compared with weight loss of <2% (HR = 1.57; 95% CI: 1.27–1.95; P < 0.001). Although weight loss of <2% was not associated with poorer overall survival compared with weight gain, it was associated with poorer progression‐free survival (HR = 1.24; 95% CI: 1.01–1.51; P = 0.036). Similar findings were observed in a separate 255‐patient validation cohort.ConclusionsWeight should be integrated into cancer cachexia trials because of its ease of frequent measurement and sustained prognostic association.

Abstract Purpose: The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors. Patients and Methods: Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics. Results: Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks. Conclusions: MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Abstract Immunotherapy targeting immune checkpoints has become a common approach for many types of cancer but currently there are no reliable biomarkers to predict and monitor treatment response. Immunohistochemical staining of PD-L1, which was initially developed as a companion diagnostic, is problematic due to tumor heterogeneity, variations in specimen preparation and multiple scoring schemes. There is, therefore, a critical need for a better biomarker to guide the use of immunotherapy to improve clinical outcomes. We previously reported that higher levels of Bim and CX3CR1/granzyme B in CD8+ T cells were associated with increased response to PD-1 blockade therapy in patients with melanoma; high levels of Bim were also prognostic of poor survival in melanoma patients. In this study, we investigated the roles of Bim and CX3CR1/granzyme B in patients receiving PD-1 blockade therapy (i.e. pembrolizumab) for small bowel adenocarcinoma as part of planned correlative analysis of the ACCRU clinical trial, NCT02949219. Patients with unresectable or metastatic biopsy-proven small bowel adenocarcinoma (excluding ampulla of Vater and appendix) who had at least one prior line of systemic chemotherapy were eligible for the trial. Pembrolizumab (200 mg) was administered over 30 minutes intravenously every 3 weeks until unacceptable toxicity, disease progression, or patient refusal. All patients underwent peripheral blood collection at baseline prior to initiation of treatment and then after 3 cycles of treatment. Levels of Bim and CX3CR1/granzyme B in circulating T cells were quantified by flow cytometry using patients' peripheral blood mononuclear cells. Data was analyzed via Cox proportional hazards model, Wilcoxon Rank-Sum test, and Kaplan Meier curves using SAS 9.4. A total of 35 eligible patients were included in the analysis. Three patients had confirmed response (all partial responses) and 10 had stable disease as their best overall response. Seven patients had disease progression around the second blood draw. The median time from baseline to the second blood draw was 9 weeks. Lower levels of Bim in CD8+CD11ahi T cells at baseline on the percentage scale were associated with treatment response (median 54.5% vs. 79.5%; p=0.0087) and disease control (partial response plus stable disease; median 71.2% vs. 81.3%; p=0.0104) but higher levels led to worse progression-free survival (hazard ratio=1.05, 95% confidence interval 1.01-1.08; p=0.0051). In addition, positive changes in CX3CR1/granzyme B in CD8+CD11ahi T cells from baseline were associated with better overall survival (median 20.2 months vs. 3.7 months, p=0.0086). The levels of PD-1 and Ki-67 in CD8+CD11ahi T cells were not associated with treatment response or survival. In conclusion, Bim and CX3CR1/granzyme B are biomarkers that associate with response and survival benefits respectively of PD-1 blockade therapy. This preliminary data calls for a larger-scale, prospective study to validate their predictive and prognostic utilities. Citation Format: Mojun Zhu, Henan Zhang, Nathan R. Foster, Haidong Dong, Tanios S. Bekaii-Saab, Brandy L. Jaszewski, Patrick M. Boland, Michael J. Overman, Katrina Pedersen, Robert R. McWilliams, Academic and Community Cancer Research United (AACRU). Bim and CX3CR1/granzyme B in circulating CD8+ T cells are predictive biomarkers for PD-1 blockade therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4467.

Abstract Barrett's esophagus (BE), a complication of gastroesophageal reflux disease (GERD), predisposes patients to esophageal adenocarcinoma (EAC). Reliable biomarkers for early detection and discovery of potential drug targets are urgently needed for improved BE and EAC patient outcomes. In this study, COX2 and TBXAS are highly expressed in BE and EAC patients accompanied by a pronounced elevation of circulating TXA2 levels in patient biopsy samples. Acetylsalicylic acid (ASA) suppressed BE and EAC growth by targeting the TXA2 pathway in a esophagoduodenostomy mouse model of reflux. Additionally, biopsies from patients showed that ASA substantially decreased serum TXA2 levels, resulting in reduced inflammation in a window opportunity clinical trial. Overall, this study establishes the importance of the COX1/2-driven TXA2 pathway in BE and EAC pathophysiology and lays the groundwork for introducing a TXA2-targeting strategy for EAC prevention and early detection. ASA targets the TXA2 pathway and suppresses BE and EAC. Citation Format: Tianshun Zhang, Qiushi Wang, Wei-Ya Ma, Keke Wang, Xiaoyu Chang, Michele L. Johnson, Ruihua Bai, Ann M. Bode, Nathan R. Foster, Gary W. Falk, Prasad G. Iyer, Zigang Dong. Inhibition of COX1/2-driven thromboxane A2 pathway suppresses Barrett's esophagus and esophageal adenocarcinoma development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2593.

Abstract Introduction: The effector protein of the Hippo pathway, Yes-associated protein (YAP), functions as a transcriptional coactivator and has been implicated in the biology of cholangiocarcinoma (CCA). Although the Hippo cascade consists of serine kinases, which act to sequester YAP in the cytosol, we have recently demonstrated the importance of tyrosine phosphorylation in regulating YAP localization and function in CCA. Furthermore, previous evaluation of clinical samples of CCA demonstrated a high frequency of mutations in tyrosine phosphatases. Evaluation of YAP-interacting proteins identified several tyrosine phosphatases, including SHP2. Herein, we describe the ability to modulate YAPY357 phosphorylation status, localization, and activity through manipulation of SHP2 levels and activity. Methods: The cholangiocarcinoma cell lines HuCCT-1 and KMCH were utilized. SHP2 activity was modulated utilizing the inhibitors NSC87877 and SHP099 (Selleckchem). SHP2 levels were modulated utilizing knockout via a doxycycline-inducible CRISPR/Cas9 system. Enforced expression of SHP2 was explored utilizing catalytically active and dead constructs. Tyrosine phosphorylation was assessed via immunoblot. Transcriptional activity was assessed by qRT-PCR for YAP target genes. YAP sub-cellular localization was assessed by immunofluorescence. Proliferation was evaluated by MTS assay utilizing SHP2 inhibitors and the Src-family kinase inhibitor dasatinib (Selleckchem). Results: The HuCCT-1 and KMCH cell lines were noted to have unique p-YAPY357 profiles (HuCCT-1 [p-YAPY357 high] KMCH [p-YAPY357 low]), and these profiles correlated with SHP2 levels and YAP subcellular localization with HuCCT1 cells demonstrating low levels of SHP2 and prominent nuclear YAP localization, while KMCH cells demonstrated high levels of SHP2 and predominately cytoplasmic YAP. In both cell lines, pharmacologic inhibition of SHP2 was accompanied by an increase in p-YAPY357 levels and YAP cotranscriptional activity (as noted by increased expression of cognate YAP target genes). In KMCH cells SHP2 inhibition shifted YAP from the cytoplasm to the nucleus, and these findings were confirmed by CRISPR/Cas9-mediated deletion of SHP2. In contrast, enforced expression of catalytically active SHP2 in HuCCT1 cells was associated with a decrease in p-YAPY357 levels and a shift of YAP from the nucleus to the cytoplasm. As predicted, based on an increase in YAP activity and nuclear localization, SHP2 inhibition was associated with an increase in cellular proliferation in both cell lines. Incubation of the cell lines with dasatinib was associated with decreased proliferation, which was partially rescued by pretreatment with an SHP2 inhibitor. Conclusions: The tyrosine phosphatase SHP2 can regulate YAPY357 phosphorylation, transcriptional coactivity, and subcellular localization in CCA. Inhibition of SHP2 activity protects cells from the effects of Src kinase inhibition on cellular proliferation and caspase activation. Citation Format: EeeLN Buckarma, Nathan Werneburg, Ayano Kabashima, Gregory Gores, Rory Smoot. The tyrosine phosphatase SHP2 regulates YAPY357 phosphorylation, subcellular localization, and transcriptional coactivity in cholangiocarcinoma [abstract]. In: Proceedings of the AACR Special Conference on the Hippo Pathway: Signaling, Cancer, and Beyond; 2019 May 8-11; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(8_Suppl):Abstract nr A17.