bluuebunny/crossref_metadata_2025 huggingface dataset:
Recommendations from clinical practice guidelines on discussion of costs of care in adult patients with advanced cancer: A systematic review.
Authors: Agarwal Anupriya , Karikios Deme John , Stockler Martin R. , Beale Philip James , Morton Rachael L.
Published: March 2020

e23175

Background: Optimising the care of cancer patients without imposing significant financial burden related to their anticancer treatment is becoming increasingly difficult. The 2009 American Society of Clinical Oncology’s (ASCO) Guidance Statement on the Cost of Cancer Care recommends that ‘patient-physician discussions regarding the cost of care are an important component of high-quality care’.(1) We sought information for oncologists to facilitate patient-clinician communication about the costs of care in published clinical practice guidelines (CPGs). Methods: We searched MEDLINE, EMBASE and multiple databases of CPG from January 2008 to 1st June 2018 for recommendations about discussing the costs of care. We assessed quality with the AGREE II instrument for the assessment of guidelines. Results: We identified 471 publications, of which 25 guidelines met our eligibility criteria. Most guidelines were from ASCO (64%, 16/25) and the Scottish Intercollegiate Guidelines Network (SIGN, 24%, 6/25). Guidelines included recommendations on discussion or consideration of treatment costs when prescribing in 52% (13/25) with information about actual costs in only 20% (5/25). Recognition of the risk of financial burden or financial toxicity was described in 60% (15/25) of guidelines, however, only a minority of these, 28% (7/25) contained information regarding management of patients with financial concerns. Conclusions: Current CPGs have limited information to guide patient-clinician communication about the costs of anticancer treatment and management of financial burden. Future guidelines should contain more information about the optimal timing, frequency, and content of these discussions. Future guidelines should include more guidance about how oncologists should communicate the costs of care accurately and transparently, along with suggestions to reduce financial burden.
Therapy preference scale: A novel questionnaire to understand patients’ preferences of cancer treatment.
Authors: Bhatt Vijaya Raj , Dhakal Prajwal , Wichman Christopher S , Pozehl Bunny J
Published: March 2020

e23179

Background: Engaging patients in shared decision-making can help select an appropriate treatment for an individual and enhance patients’ experience and satisfaction with their care. This requires an in-depth understanding of patients’ values and preferences of various aspects of cancer treatment. A questionnaire to assess patient preferences is currently lacking. The purpose of our study was to develop a questionnaire that would fill this gap. Methods: We reviewed published literature to develop a theoretical framework to explain how cancer patients chose a specific therapy for themselves, and to identify key aspects of treatment that determine patients’ decisions about treatment. Three key domains (efficacy, safety and other characteristics of treatment such as need for hospital stay) were identified (Bhatt VR, J Geriatr Oncol. 2018 Nov 27 [Epub ahead of print]) and a mutli-dimensional self-report questionnaire with 49 items was developed. Each item was rated for relevance by 10 experts (oncologists, oncology nurses, advanced practice providers, social workers and pharmacists) to assess content validity (Lawshe formula) (Meas Eval Couns Dev, 47: 79–86). Ratings of ‘very relevant’ or ‘relevant’ were used to identify an essential question. Experts also suggested refinement of items. Three community members and 9 patients evaluated the instrument for face validity. Results: A content validity index for the questionnaire was 0.82. Face validity was confirmed. Based on input from the various stakeholders, the number of items, content, and format of the questionnaire was revised. The revised questionnaire includes a total of 36 items under four sections: safety (14 items), efficacy (4 items), treatment characteristics (8 items) and global items (10 items). Conclusions: We have developed a novel tool and established content and face validity. This self-report questionnaire can be used to understand patients’ preferences of cancer treatment. Further psychometric studies are planned to evaluate reliability and validity. Our ultimate goal is to use this tool to enhance communication between physicians and patients and facilitate shared decision-making.
Teleoncology: Prospects and challenges for cost effective cancer care.
Authors: Majeed Ammara , Lakhani Midhat , Ashraf Afia , Grewal Udhayvir Singh , Thirunagari Prem , Wahab Ahsan , Hassan Hamza , Faisal Muhammad Salman , Raziq Fazal I , Anwer Faiz
Published: March 2020

e23182

Background: An estimated 20.3 million cancer survivors are expected to be around by 2026. Estimated national expenditure for cancer care in 2017 were $147.3 billion and expected to increase every year. Cancer treatment is complex and requires management decisions, counselling, psychological support to be made by multidisciplinary teams. For rural and remote patients, these teams may be composed of local clinicians, and experts from distant urban centers using telemedicine (TeleMed). Methods: We used 2 databases to study Teleoncology (TelOnc) since 2002. Results: Scope of TelOnc includes cancer Telegenetics, Telepathology, remote supervision, symptom management, survivorship care, palliative care, and increase access to cancer clinical trials. Mobile applications support symptom management, lifestyle modification, and medication adherence. TeleMed can support the oncologist with interactive tele-education. Future TelOnc models would include web-based tools, mobile technologies and remote chemotherapy supervision. TeleMed had a high patient satisfaction rate. In a survey 82.21% participants were satisfied with their TeleMed experience, only 2.14% was not satisfied. Challenges: Despite an area of growing need, few studies have prospectively evaluated its efficacy in cancer. Even fewer data is available in young adults (group with liking for technology) with cancer. Lack of uniform model for reimbursement and hurdles of interstate practice license for providers are unique challenges. Conclusions: TeleMed / TelOnc can improve access to medical care, reduce healthcare costs, (Table) and reduce geographic health disparities. [Table: see text]
Dealing with emotional states during cancer diagnosis and treatment by using cognitive strategies in oncology patients: Comparison to noncancer population.
Authors: Kieszkowska-Grudny Anna , Rucinska Monika , Osowiecka Karolina
Published: March 2020

e23184

Background: Diagnosis of cancer is perceived by individuals as a life-threatening event. Patients (pts) experience a great distress, as well as a various emotions and apply diverse cognitive strategies to deal with them during cancer diagnosis and its treatment. State of mind can help in emotions management and could be supportive or destructive during treatment.Employing adaptive strategies may help them to cope better this specific traumatic event and help doctors to get higher compliance with their pts.Therefore, it is important first to recognize these strategies and then arrange personalized psychological support for them in cooperation with oncologist. Methods: 197 individuals were included into the study between 11.2017 and 12.2018: 115 cancer pts ( Me= 62years) and 82 healthy subjects ( Me= 45years). All subjects filled out: Cognitive-Emotional Regulation Questionnaire(with 4 non-adaptive strategies (NAS)–self-blame, blaming others, catastrophizing, rumination and 4 adaptive strategies (AS)–acceptance, refocus on planning, putting into perspective, attention to something positive), and demographic data. Statistical analyses were based on t-Students test and linear correlation (significance level: p < .05). Results: Significant differences were observed between cancer patients and healthy group in all types of cognitive strategies. Cancer pts tend to catastrophize more frequently ( p < .01) and employed planning strategies less often ( p < .001), but generally had more AS( p < .01), especially attention to sth positive and acceptance ( p < .001). In cancer group NAS, especially catastrophizing ( p < .05) and rumination ( p < .001) correlate negatively with education and place of living, which means that less educated pts and living in the countryside had more NAS. In contrast, cancer pts living in cities used more AS( p = .001), mainly attention to sth positive, refocus on planning ( p < .01) and putting into perspective ( p < .001). The older pts less often applied focus-on-planning strategy ( p < .01). Conclusions: Cancer pts rarely used planning strategies and tend to develop an extremely negative future vision, but generally had more AS to deal with traumatic event then healthy population. More attention should be given to pts with cancer who are older, live in in the countryside and are less educated.
Profiling cancer-related distress and problems: A latent class analysis approach.
Authors: Rossi Alessandro , Marconi Maria , Mannarini Stefania , Minelli India , Fusi Chiara , Anderboni Monica , Rossini Chiara , Di Lucca Giuseppe , Verusio Claudio
Published: March 2020

e23191

Background: Psychological distresses, emotional troubles, social difficulties as well as both physical and practical issues are all among oppressive problems that oncological patients have to face almost every day. On one hand, these problems seem to have a strong impact on quality of life; and to the other hand, these issues seem to be related to specific cancer-related variables ( e.g.: type and localization of the tumor). Thus, the aim of the study was to use a Latent Class Analysis (LCA) approach to profile a latent structure accounting for the covariance between psychological distress and everyday problems due to cancer. A one-factor model with three classes was hypothesized, which comprised distress and cancer-related problems as indicators and age, type of medical treatment as well as type and localization of tumor as external variables that moderate the latent structure. Methods: Patients ( N = 264, 62.3% female, mean age = 65.3, SD = 12.4) were enrolled at the Oncology Day Hospital, “Presidio Ospedaliero” of Saronno, ASST Valle Olona, Italy. Using the standardized Distress Thermometer and Problem List (TD&PL; NCCN, 2015) patients were tested for: (A) distress; (B) practical problems (Cronbach’s α = .63); (C) social difficulties (Cronbach’s α = .65); (D) emotional issues (Cronbach’s α = .86) and (E) physical problems (Cronbach’s α = .77). Results: First of all, a CFA was performed to test the original factorial structure of the DT&PL. The original five factor solution was supported by adequate fit indices: RMSEA = .063; CFI = .924. Then, the LCA (10000 bootstrap resampling) shows the goodness-of-model fit [χ2 = 10.01; p = .11; LRχ2 = 9.30; p = .09] and the goodness-of-classification quality [Entropy = .80 ( > .7); Average-Latent-Class-Assignment-Probability: .975, .900, and .902 for Class1, Class2, and Class3, respectively]. The LCA identified a latent variable with three classes (VLMR = 193.38; p < .001; Class1 = .49%; Class2 = .23%, and Class3 = .28%). In addition, interactions with the latent variable were found for age ( β = .12; p = .039), type of medical treatment ( β = .29; p = .009), as well as type and localization of tumor ( β = .20; p = .025). Conclusions: These results provided a better understand of psychological distress and cancer-related issues: each class represents a specific “profile” – moderated by age, type of medical treatment, and type and localization of tumor. These results recommend paying more attention to the specific profile expressed by the patient suggesting new ways to improve their quality of life.
Comparative analysis of molecular aberration in different genders for identification of key pathways in hepatocellular carcinoma.
Authors: Yu Li , Tieshan Feng , Li Lifeng , Chen Shifu , Xiaoliang Liu
Published: March 2020

e23192

Background: The incidence rate of hepatocellular carcinoma (HCC) varies significantly between genders, being higher in men than in women. While the molecular mechanisms remain unexplored, we systematically analyzed the gene expression and SNV signature to identify key molecular aberrations and pathways. Methods: Gene expression and simple nucleotide variation data of 407 HCC patients with HCC including 140 females and 267 males were collected. We identified genes with differential mutation frequency in two cohorts using Fisher’s exact test (p-value < 0.05), and Deseq2 to identify differential expression genes (FDR < 0.05 and fold change > 2). Enrichment analysis was applied using the Kyoto Encyclopedia of Genes and Genomes (KEGG) and the Reactome database (p adjust < 0.05). Results: In total, 103 genes with differential mutation frequency in two cohorts were identified. Of these genes, 57 genes were differentially expressed, and the number of up-regulated genes in males and females were 21 and 36, respectively. The genes that show significant up-regulation in males are KDM5D and ANKFN1 which have the log2(fold change) of 7.49 and 4.45. The genes that show significant up-regulation in females are SYT13 and SCD5 which have the log2(fold change) of 2.33 and 2.29. The result of enrichment analysis showed that the up-regulated genes in males and females were involved in different biological pathways. In males, the up-regulated genes mainly participated in the PPAR signaling pathway. In females, the up-regulated genes mainly participated in the Rho GTPase cycle, regulation of insulin secretion and integration of energy metabolism. Conclusions: In this study, 57 genes with differential mutation frequency and differential expression between males and females with HCC were identified based on TCGA dataset. Enrichment analysis result indicated that these genes are mainly involved in signaling pathways relevant to carcinogenesis and metabolism.
A phase II study of ADI-PEG 20 in combination with gemcitabine and docetaxel for the treatment of soft tissue sarcoma.
Authors: Van Tine Brian Andrew , Bui Nam , Prudner Bethany , Bomalaski John S. , Wu Bor-Wen , Chawla Sant P. , Ganjoo Kristen N. , Oppelt Peter John , Hirbe Angela C.
Published: March 2020

TPS11079

Background: The combination of gemcitabine (G) and docetaxel (D) is a standard second line therapy for soft tissue sarcoma (STS) with a modest response rate. Recent studies have looked to add agents to enhance response. We have shown that argininosuccinate synthase 1 (ASS1) expression is silenced in 88% of all sarcomas (n = 708) (Bean et al., 2016, Cell Death and Disease), and that this loss is associated with a reliance on extracellular sources of the amino acid arginine. The arginine depleting enzyme PEGylated arginine deiminase (ADI-PEG 20) depletes extracellular arginine. Preclinical studies have demonstrated that arginine starvation and D administration induce c-Myc-driven hENT1 surface expression overcoming intrinsic cell surface G transporter related resistance. To test this hypothesis, we opened this multi-institutional randomized phase II trial examining the safety and efficacy of ADI-PEG 20 with G + D in STS (NCT03449901) in July of 2018. Methods: Eligible patients are adults with metastatic or unresectable histologically or cytologically confirmed FNCLCC grade 2 or 3 STS that would be standardly treated with G and/or D. Patients are treated with ADI-PEG 20 at a dose of 36 mg/m2 via intramuscular injection on Day -7 of Cycle 1 and then on Days 1, 8, and 15 of each subsequent cycle. G will be given intravenously at a dose of 750 mg/m2 over 90 minutes on Days 1 and 8 and D will be given intravenously at a dose of 75 mg/m2 over 60 minutes on Day 8 of each cycle. The median PFS of metastatic sarcoma patients receiving the standard G + D treatment was estimated to be 6.2 months in a randomized phase II study (Maki et. al., 2007, JCO). With the addition of ADI-PEG 20, we target to improve the median PFS to 9 months, a 45.2% (2.8 months or 12 weeks) improvement in patients treated on G + D + ADI-PEG 20 against the null hypothesis median PFS of 6.2 months to achieve 80% power to detect the improvement in PFS at a 5% alpha level. Tumor specimens (pre- and post-ADI-PEG 20 during week -1) and blood are collected for correlative studies including metabolomics, pharmacodynamics, immunogenicity and ASS1 biomarkers. Quality of life will be measured using FACT-G7. Clinical trial information: NCT03449901.
MIRROS: An ongoing randomized phase 3 trial of idasanutlin + ARA-C in patients with relapsed or refractory acute myeloid leukemia.
Authors: Montesinos Pau , Esteve Jordi , Konopleva Marina , Martinelli Giovanni , Ottmann Oliver , Rodriguez-Veiga Rebeca , Röllig Christoph , Wei Andrew , Vey Norbert , Chiu Idy , Monnet Annabelle , Ott Marion Gabriele , Fenaux Pierre
Published: March 2020

TPS7063

Background: The prognosis for patients (pts) with relapsed or refractory (R/R) acute myeloid leukemia (AML) is poor, with 3-year overall survival rates ~10–30% after intensive chemotherapy-based approaches. Despite the advent of targeted therapies, considerable unmet medical need remains in this population. Idasanutlin (RG7388; RO5503781) is an orally available small molecule that binds to the murine double minute 2 (MDM2) protein and blocks MDM2 interaction with p53. This stabilizes and activates p53 and facilitates cell cycle arrest and apoptosis, preventing tumor growth. A phase 1b study of idasanutlin + ARA-C in pts with R/R AML, irrespective of TP53 mutation status (NCT01773408), has shown a composite complete remission (CR) rate (CR plus CR with incomplete platelet or hematologic recovery) of 29% (Martinelli et al. 2016). Methods: MIRROS (NCT02545283; WO29519) is an international, phase 3, double-blind, randomized study comparing idasanutlin (300 mg bid) + ARA-C (1 g/m2 qd) days 1–5 versus placebo + ARA-C in 440 pts with first or second R/R AML, with or without TP53 mutation. The primary endpoint is overall survival in pts with wild-type (WT) TP53. Secondary endpoints include CR, overall remission rates, event-free survival (EFS) and percentages of pts undergoing hematopoietic stem cell transplantation. MIRROS integrates phase 2 trial methodology into the phase 3 design by incorporating an interim analysis (IA) in 120 pts with WT TP53, using a high bar on the odds ratio for durable CR and EFS to assess for futility. Stop/go gating criteria for safety were also implemented. The IA was performed by an independent data monitoring committee and study continuation criteria were successfully met in mid-2017. This innovative strategy has allowed acceleration of the idasanutlin development program while maintaining a robust trial design. As of December 31 2018, 351 pts had been enrolled. The MIRROS study is ongoing and its results will inform the potential role of idasanutlin and MDM2 inhibition in the treatment of R/R AML. Clinical trial information: NCT02545283; WO29519.
A phase I study of milademetan in combination with quizartinib in patients (pts) with newly diagnosed (ND) or relapsed/refractory (R/R) FLT3-ITD acute myeloid leukemia (AML).
Authors: Daver Naval Guastad , Zhang Weiguo , Graydon Richard , Dawra Vikas , Xie Jingdong , Kumar Prasanna , Andreeff Michael
Published: March 2020

TPS7067

Background: Fms -like tyrosine kinase 3 internal tandem duplication ( FLT3-ITD) mutations occur in ≈ 25% of pts with AML and are associated with poor prognosis. Quizartinib is a highly potent, selective, next-generation type II FLT3 inhibitor. In the phase 3 QuANTUM-R trial, quizartinib prolonged overall survival vs salvage chemotherapy in pts with R/R FLT3-ITD AML. MDM2 downregulates the p53 tumor suppressor and is upregulated in pts with AML. Targeting MDM2 may restore p53 activity in pts with wild-type p53 AML. Milademetan, a novel and specific MDM2 inhibitor, showed activity in an ongoing phase 1 trial in pts with AML or myelodysplastic syndromes (MDS). Preclinical studies have shown that quizartinib plus milademetan may act synergistically to target FLT3-ITD and restore p53 activity in FLT3-ITD/ TP53 wild-type AML [Andreeff et al. ASH 2018, abstract 2720]. Methods: This open-label phase 1 study (NCT03552029) has 2 parts: dose escalation (part 1) followed by dose expansion (part 2), with 2 planned cohorts. Key inclusion criteria include FLT3-ITD AML (primary or secondary to MDS) and adequate renal, hepatic, and clotting functions. Key exclusion criteria include acute promyelocytic leukemia, prior treatment with a MDM2 inhibitor, QTcF interval > 450 ms, significant cardiovascular disease, and unresolved toxicities from prior therapies. Dose escalation and expansion cohort 1 includes R/R pts. Expansion cohort 2 includes ND pts unfit for intensive chemotherapy. During dose escalation, quizartinib will be administered once daily in 28-day cycles, with 3 proposed levels (30, 40, and 60 mg). Milademetan will be administered on days 1-14 of each 28-day cycle, with 3 proposed levels (90, 120, and 160 mg). The quizartinib dose will be escalated first, followed by the milademetan dose with no simultaneous escalation, guided by modified continual reassessment with overdose control. Primary objectives are safety and tolerability, optimum dosing schedule, maximum tolerated dose, recommended dosing for the expansion cohort, and phase 2 dosing. Secondary objectives are pharmacokinetics and preliminary efficacy. This study is recruiting. Clinical trial information: NCT03552029.
ZUMA-8: A phase 1/2 multicenter study evaluating KTE-X19 in patients (pts) with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL).
Authors: Flinn Ian , Marris Michael , Wierda William G. , Coutre Steven , Pagel John M. , Byrd John C. , Goyal Lovely , Goodman Krista , Zheng Yan , Milletti Francesca , Murugappan Swaminathan , Brown Jennifer R.
Published: March 2020

TPS7566

Background: Despite treatment advances, CLL is largely incurable. First-line targeted therapy with ibrutinib mostly produces durable remissions, but high-risk disease or many prior therapies increases relapse risk (Ghia P, et al. Haematologica. 2014). Relapse after ibrutinib is associated with a poor outcome (Maddocks KJ, et al. JAMA Oncol. 2015). Allogeneic stem cell transplantation potentially offers long-term remissions but has a high risk of morbidity/mortality (Shustik C, et al. Ann Hematol. 2017). Autologous T cells expressing a CD19-specific chimeric antigen receptor (CAR) with a CD28 costimulatory domain may be efficacious against CLL (Kochenderfer JN, et al. Blood. 2012). KTE-X19 is an autologous anti-CD19 CAR T cell therapy under investigation for R/R hematologic malignancies and may offer longer durable remissions with manageable safety in pts with R/R CLL. ZUMA-8 is a Phase 1/2 multicenter study for pts with R/R CLL. Methods: Adult pts must have R/R CLL with ≥ 2 prior treatment regimens, disease progression on ibrutinib, ECOG 0-1, and adequate organ function. Phase 1 will enroll 12-18 pts to assess dose-limiting toxicities (DLTs) with a 6 + 3 dose escalation/de-escalation design; 30 more pts may be enrolled to further assess safety. Phase 2 will enroll ≈60 pts to evaluate efficacy and safety. Pts will undergo leukapheresis followed by optional bridging therapy. Cyclophosphamide (500 mg/m2) and fludarabine (30 mg/m2) conditioning chemotherapy will be given on Days -5, -4 and -3. KTE-X19 will be given on Day 0 at 0.5, 1 or 2 × 106 KTE-X19 cells/kg. The primary endpoint is incidence of DLTs for Phase 1 and independent review committee-assessed objective response rate (ORR) per iwCLL 2018 criteria for Phase 2. Secondary endpoints include complete remission (CR) rate, investigator-assessed ORR, minimal residual disease (MRD) negativity rate, MRD-negative CR rate, duration of response, progression-free survival, overall survival, safety, and patient-reported outcomes (Phase 2). Serum cytokine and blood KTE-X19 cell levels over time and level of anti-KTE-X19 antibodies are exploratory endpoints. Accrual is ongoing. Clinical trial information: NCT03624036.
ENGINE: Phase III randomized study of enzastaurin/R-CHOP versus placebo/R-CHOP in frontline high-risk diffuse large B-cell lymphoma patients with novel genomic biomarker DGM1.
Authors: Smith Stephen , Zhu Jun , O'Connor Owen A. , Luo Wen , Shazer Ronald L. , Zhang Lei , Han Isabel , Jivani Manoj A. , Liu Young , Nowakowski Grzegorz S.
Published: March 2020

TPS7569

Background: Progress in genome technology allows analysis of previously completed trials to identify patients subgroups potentially benefiting from therapy. Enzastaurin is a potent inhibitor of protein kinase C beta (PKC- b) and suppresses the phosphoinositide 3-kinase (PI3K)/AKT pathway. The safety and efficacy of Enzastaurin has been tested in more than 60 clinical trials including 2 major studies in DLBCL: (1) PRELUDE (A phase III maintenance trial of Enzastaurin vs Placebo, N=758) ( Crump, 2016), and (2) S028 (A randomized phase II study of Enzastaurin/R-CHOP vs R-CHOP in frontline intermediate/high-risk DLBCL, N=101) ( Hainsworth, 2016). DNA samples extracted from blood of patients from PRELUDE were retrospectively genotyped using whole genome SNP arrays. From the genome wide screening a novel genetic biomarker, DGM1, was identified showing high correlation with response to Enzastaurin treatment ( Luo, ASH 2018). Importantly, these findings were replicated in the phase II S028 study. In the S028 study the hazard ratio (HR) for OS in high-risk (IPI ≥ 3) DGM1 positive (+) patients who received Enzastaurin/R-CHOP was 0.28 (0.1-0.81) when compared to subjects who received R-CHOP, a benefit favoring Enzastaurin (p=0.018). These data suggest that addition of Enzastaurin to R-CHOP may significantly improve outcome in frontline high-risk DGM1 (+) DLBCL. The ENGINE study was initiated to validate this finding in a prospective study. Methods: Adult patients must have untreated CD20+ DLBCL, IPI ≥ 3. Patients are randomized 1:1 to Enzastaurin/R-CHOP or Placebo/R-CHOP for 6 cycles during combination phase. Each subject’s treatment assignment will be unblinded after response assessment at the end of the combination phase. Subjects randomized to the investigational arm who have a complete or partial response will have the option to continue in the single agent phase to receive Enzastaurin for up to 2 additional years. The study intends to enroll approximately 235 patients with primary endpoint of OS in DGM1 (+) patients. The study is ongoing with 51 sites open in the US and China. As of 22 Jan 2019, 70 patients have been randomized. Clinical trial information: NCT03263026.
The DIAL Study (Dual Immunomodulation in Aggressive Lymphoma): A randomized phase 2 study of CDX-1127 (varlilumab) in combination with nivolumab in patients with relapsed or refractory aggressive B-cell lymphomas (NCI 10089/NCT03038672).
Authors: Villasboas Jose Caetano , Reeder Craig B. , Tun Han W. , Bartlett Nancy L. , Sharon Elad , LaPlant Betsy , Adjei Alex A. , Ansell Stephen M.
Published: March 2020

TPS7570

Background: The DIAL study is testing the efficacy of dual immunomodulation in patients with advanced B cell non-Hodgkin lymphoma (B-NHL). Developed by the Cancer Therapy Evaluation Program (CTEP), the trial combines the use of a programmed cell death protein 1 (PD-1) inhibitor (nivolumab) with an agonist of the CD27 receptor (varlilumab) in a randomized phase 2 design. CD27, a co-stimulatory receptor, regulates T cell activation through interaction with CD70. T cell exhaustion plays a major role in immune evasion in B-NHL. Varlilumab is an agonistic IgG1 monoclonal antibody that recognizes CD27 leading to prevention or reversal of exhaustion. Varlilumab also demonstrates direct anti-tumoral activity in xenograft models of human lymphoma cell lines via antibody-dependent cell-mediated cytotoxicity. Phase 1 data supports the safety and tolerability of single-agent varlilumab in advanced hematologic malignancies. We hypothesize that CD27 activation synergizes with PD-1 inhibition resulting in a superior anti-lymphoma effect compared to PD-1 blockade alone. The study will also evaluate the effect of these agents on tumor and immune cells using IHC, mass cytometry (CyTOF), multiplex ELISA, imaging mass cytometry, and whole exome sequencing. Methods: The trial is enrolling patients with advanced aggressive B-NHL. Standard inclusion criteria and prior treatment with at least 2 lines of standard therapy are required. Prior autologous stem cell transplant and/or chimeric antigen receptor (CAR) T cell therapy is allowed. Patients with active CNS disease are excluded. Eligible patients will be randomized to treatment with single-agent nivolumab (group 1) or dual immunotherapy with nivolumab and varlilumab. Group 1 is allowed to cross-over at the time of progression. Nivolumab will be administered intravenously (IV) every 2 weeks (240 mg) for 4 months followed by monthly dosing thereafter (480 mg). Varlilumab will be given IV every 4 weeks (3 mg/kg). Response assessment will be done by PET-CT scan every 12 weeks. Primary outcome is overall response rate (ORR) according to the LYRIC criteria. The trial will enroll 48 patients per arm, allowing 80% power to detect at least 20% increase in ORR in the experimental arm (group 2) assuming a 25% ORR in the control arm (group 1). The trial is registered and open to participation to members of ETCTN and EDDOP. Clinical trial information: NCT03038672.
POLARIX: A phase 3 study of polatuzumab vedotin (pola) plus R-CHP versus R-CHOP in patients (pts) with untreated DLBCL.
Authors: Tilly Herve , Flowers Christopher , Friedberg Jonathan W. , Herbaux Charles , Morschhauser Franck , Sehn Laurie Helen , Sharman Jeff Porter , Trneny Marek , Lee Calvin , Salles Gilles A.
Published: March 2020

TPS7571

Background: Rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) remains the standard of care in pts with previously untreated diffuse large B-cell lymphoma (DLBCL) but outcomes remain poor in pts with high-risk disease. Pola is an antibody–drug conjugate targeting CD79b; it delivers the antimitotic agent monomethyl auristatin E. Addition of pola to bendamustine and R in pts with transplant-ineligible DLBCL resulted in improved OS (Sehn et al, 2018). In front-line treatment of DLBCL, pola is being evaluated as a replacement for vincristine within the R-CHOP regimen. In a phase Ib/II study in pts with higher risk DLBCL, pola + R-CHP demonstrated promising efficacy and a safety profile similar to that observed in the R-CHOP arm of the GOYA study (Tilly et al, 2017; Vitolo et al, 2017). The phase 3 POLARIX study investigates pola + R-CHP in untreated DLBCL. Methods: POLARIX is an ongoing, international, randomized, double-blind, active-placebo-controlled, phase 3 study in pts with previously untreated DLBCL. Pts aged 18–80 years with CD20-positive DLBCL (including DLBCL not otherwise specified, GCB, and ABC subtypes), ECOG performance status 0–2, and IPI score 2–5, are stratified by IPI score (2 vs 3–5), bulky disease and geographical region and randomized (1:1). Pts receive 6 cycles of either: pola 1.8 mg/kg on Day 1 plus R-CHP (standard dosing schedule) plus vincristine placebo; or pola placebo plus R-CHOP (standard dosing schedule). R monotherapy is administered in cycles 7 and 8 (both arms). PET-CT and CT scans are obtained at screening, after 4 cycles (planned interim assessment), and 6–8 weeks after end of study treatment. Follow-up will continue for 5 years after treatment. Primary endpoint: investigator-assessed progression-free survival (PFS; Lugano classification). Secondary endpoints: independent review committee-assessed PET-CT complete response rate at end of treatment, event-free survival, 2-year PFS rate, and OS. Enrolment began Nov 2017. This trial is currently recruiting, and plans to enrol 875 patients in 24 countries. Clinical trial information: NCT03274492.
Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with newly diagnosed multiple myeloma (NDMM) for whom transplant is not planned as initial therapy: A multicenter, randomized, phase III study (CEPHEUS).
Authors: Zweegman Sonja , Usmani Saad Zafar , Chastain Katherine , Carey Jodi , Ren Karen , Smith Elena , Krevvata Maria , Wang Jianping , Vermeulen Jessica , Facon Thierry
Published: March 2020

TPS8056

Background: DARA is a human, anti-CD38 IgGκ monoclonal antibody that significantly reduced the risk of progression/death with a manageable safety profile across several phase 3 studies in relapsed/refractory MM and NDMM. DARA + VRd (D-VRd) demonstrated efficacy and tolerability in the safety run-in cohort of the ongoing phase 2 GRIFFIN study that included transplant-eligible NDMM pts. To determine whether D-VRd demonstrates efficacy and tolerability in NDMM pts for whom transplant is not intended as initial therapy, the phase 3 CEPHEUS study will evaluate the efficacy and safety of D-VRd vs VRd alone in this pt population. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd vs VRd alone in pts with NDMM for whom transplant is not intended as initial therapy. Approximately 360 pts will be stratified by ISS stage and age/transplant eligibility (age < 70 years and transplant-ineligible, or age < 70 years and refusal to transplant, or age ≥70 years) and will be randomized in a 1:1 ratio. All pts will receive eight 21-day cycles of VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-14; d: 20 mg PO/IV Days 1, 2, 4, 5, 8, 9, 11, 12), followed by 28-day cycles of Rd (R: 25 mg PO Days 1-21; d: 40 mg PO/IV Days 1, 8, 15, 22) until progressive disease (PD). Patients in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) weekly in Cycles 1-2, every 3 weeks in Cycles 3-8, and every 4 weeks in Cycles 9+ until PD. All pts will receive preinfusion medications. Minimal residual disease (MRD)-negative rate at 10–5 sensitivity threshold by NGS is the primary endpoint. MRD will be evaluated at suspected complete response or better. Secondary endpoints include progression-free survival (PFS), MRD-negative rate at 1-year, durable MRD negativity, overall response rate, time to and duration of response, PFS on next line of therapy, overall survival, clinical efficacy in high-risk molecular subgroups, health-related quality of life, pharmacokinetics, immunogenicity, and safety. Clinical trial information: NCT03652064.
Phase 2 trial of first-line pembrolizumab with platinum doublet chemotherapy and radiotherapy in patients (pts) with unresectable, locally advanced stage III non–small-cell lung cancer (NSCLC): KEYNOTE-799.
Authors: Jabbour Salma K. , Park Keunchil , Cohn Dosinda , Liu Hong , Keller Steven M. , Kowalski Dariusz M.
Published: March 2020

TPS8575

Background: Standard therapy for pts with unresectable stage III NSCLC is concurrent platinum doublet chemotherapy with radiotherapy (CCRT); however, this therapy does not reduce the risk of distant relapse, and the 5-y survival rate is low. The anti–PD-1 checkpoint inhibitor pembrolizumab has durable clinical activity as first-line therapy for advanced/metastatic NSCLC: as monotherapy for PD-L1–positive tumors and in combination with chemotherapy irrespective of PD-L1 status. KEYNOTE-799 evaluates the safety/efficacy of first-line pembrolizumab plus CCRT for unresectable, locally advanced stage III NSCLC. Methods: This nonrandomized, open-label phase 2 study enrolls pts ≥18 y with previously untreated, unresectable, pathologically confirmed stage IIIA–C NSCLC with measurable disease per RECIST 1.1. Pts receive 17 cycles of pembrolizumab 200 mg Q3W plus standard thoracic radiotherapy in cycles 2 and 3 (60 Gy in 30 daily 2 Gy fractions). In cycles 1–3, treatment also includes investigator’s choice of either paclitaxel 200 mg/m2 and carboplatin area under the curve (AUC) 6 Q3W for 1 cycle, followed by paclitaxel 45 mg/m2 and carboplatin AUC 2 weekly for 6 weeks, or cisplatin 75 mg/m2 and pemetrexed 500 mg/m2 Q3W (nonsquamous only). Tumor imaging occurs at baseline and Q9W until week 54, verified PD, initiation of new cancer therapy, study withdrawal, or death. AEs are graded by NCI CTCAE v4.0. Primary endpoints are the rate of grade ≥3 pneumonitis and ORR (RECIST 1.1 by blinded independent central review [BICR]); confidence intervals for both will be estimated by the Clopper-Pearson method. Secondary endpoints are PFS (RECIST 1.1 modified to follow ≤10 target lesions; ≤5 per organ by BICR), OS, and safety. PFS and OS will be analyzed by Kaplan-Meier method. Approximately 216 pts (108 per cohort) will be enrolled in 59 sites in 10 countries beginning on Nov 5, 2018. As of Feb 12, 2019, 30 pts have enrolled. Continuous interim analyses using binomial sequential testing will be performed after ≥36 pts have ≥15 weeks of follow up in each cohort, to allow earlier treatment discontinuation, if required. Clinical trial information: NCT03631784.
Acute Hyperketonemia Does Not Affect Glucose or Palmitate Uptake in Abdominal Organs or Skeletal Muscle
Authors: Lauritsen Katrine M , Søndergaard Esben , Luong Thien V , Møller Niels , Gormsen Lars C
Published: March 2020

Context

It has recently been hypothesized that ketone bodies may have independent cardioprotective effects due to increased myocardial efficiency and that this may explain the improved survival of individuals with type 2 diabetes treated with mildly ketogenic sodium–glucose cotransporter-2 inhibitors.

Objective

To determine whether ketone bodies are selectively utilized in tissues critical for preservation of conscience and circulation. We investigated the effect of acute hyperketonemia on substrate metabolism in less prioritized tissues such as abdominal organs, adipose tissue, and skeletal muscle.

Design

Acute, randomized, single-blinded, crossover design.

Setting

Ambulatory care.

Participants

Eight healthy participants completed the study. Two additional participants withdrew because of claustrophobia during the scans.

Intervention

Infusions of saline and ketone bodies during a hyperinsulinemic-euglycemic clamp.

Main Outcome Measures

Organ-specific glucose and palmitate uptake was determined by dynamic positron emission tomography/computed tomography (PET/CT) scans with 18F-fluorodeoxyglucose (18F-FDG) and 11C-palmitate. Blood flow to abdominal organs was measured with O-15-labeled water (15O-H2O) perfusion PET. The study was performed as a post hoc analysis.

Results

We found that ketone body infusion did not affect glucose uptake, palmitate uptake, or blood flow to abdominal organs and skeletal muscles.

Conclusion

Acute hyperketonemia does not affect glucose or palmitate uptake in skeletal muscle or abdominal tissues, supporting the notion that ketone bodies are selectively used by critical organs such as the heart and brain.
Variation in outer blubber lipid concentrations does not reflect morphological body condition in humpback whales
Authors: Christiansen Fredrik , Sprogis Kate R. , Gross Jasmin , Castrillon Juliana , Warick Hunter A. , Leunissen Eva , Bengtson Nash Susan
Published: March 2020

An animal's body condition provides valuable information for ecophysiological studies, and is an important measure of fitness in population monitoring and conservation. While both the external body shape of an animal, as well as its internal tissues (i.e. fat content) can be used as measures of body condition, the relationship between the two is not always linear. We compared the morphological body condition (external metric obtained through aerial photogrammetry) of migrating humpback whales (Megaptera novaeangliae) with their outer blubber lipid concentration (internal metric obtained through blubber biopsy sampling) off south-west Australia early and late in the breeding season (spanning ∼4.5 months). The external body condition index of juvenile and adult humpback whales decreased with 26.9 (from 18.8 to −8.1%) and 12.0 percentage points (from 8.6 to −3.4%) between the early and late phase, respectively. In contrast, we found no intra-seasonal change in blubber lipid concentration, and no difference between reproductive classes (juveniles, adults and lactating females), however the small sample size prevented us from effectively testing these effects. Importantly however, in the 33 animals for which paired metrics were obtained, we found no correlation between the morphometric body condition index and the blubber lipid concentration of individual whales. The lack of a linear relationship suggest that changes in outer blubber lipid concentration do not reflect external changes in body shape, thus limiting the utility of outer blubber lipid reserves for individual body condition evaluation. The wider spectrum of change in body morphometry captured with aerial photogrammetry, supports the use of body morphometry as a reliable and well tested method.
Skeletal muscle thermogenesis induction by exposure to predator odor
Authors: Gorrell Erin , Shemery Ashley , Kowalski Jesse , Bodziony Miranda , Mavundza Nhlalala , Titus Amber R. , Yoder Mark , Mull Sarah , Heemstra Lydia A. , Wagner Jacob G. , Gibson Megan , Carey Olivia , Daniel Diamond , Harvey Nicholas , Zendlo Meredith , Rich Megan , Everett Scott , Gavini Chaitanya K. , Almundarij Tariq I. , Lorton Diane , Novak Colleen M.
Published: March 2020

Non-shivering thermogenesis can promote negative energy balance and weight loss. In this study, we identify a contextual stimulus that induces rapid and robust thermogenesis in skeletal muscle. Rats exposed to the odor of a natural predator (ferret odor) show elevated skeletal muscle temperatures detectable as quickly as 2 min after exposure, reaching maximum thermogenesis of >1.5 °C at 10-15 min. Mice exhibit a similar thermogenic response to the same odor. Ferret odor induces a significantly larger and qualitatively different response than do novel or aversive odors, fox odor, or moderate restraint stress. Exposure to predator odor increases energy expenditure, and both the thermogenic and energetic effects persist when physical activity levels are controlled. Predator odor-induced muscle thermogenesis is subject to associative learning as exposure to a conditioned stimulus provokes a rise in muscle temperature in the absence of the odor. The ability of predator odor to induce thermogenesis is predominately controlled by sympathetic nervous system activation of β-adrenergic receptors, as unilateral sympathetic lumbar denervation and a peripherally acting β-adrenergic antagonist significantly inhibit predator odor-induced muscle thermogenesis. The potential survival value of predator odor-induced changes in muscle physiology is reflected in an enhanced resistance to running fatigue. Lastly, predator odor-induced muscle thermogenesis imparts a meaningful impact on energy expenditure as daily predator odor exposure significantly enhances weight loss with mild calorie restriction. This evidence signifies contextually provoked, centrally mediated muscle thermogenesis that meaningfully impacts energy balance.
Quantum Chemical Reaction Prediction Method Based on Machine Learning
Authors: Fujinami Mikito , Seino Junji , Nakai Hiromi
Published: March 2020

A quantum chemical reaction prediction (QC-RP) method based on machine learning was developed to predict chemical products from given reactants. The descriptors contain atomic information in reactants such as charge, molecular structure, and atomic/molecular orbitals obtained by the quantum chemical calculations. The QC-RP method involves two procedures, namely, learning and prediction. The learning procedure constructs screening and ranking classifiers using 1625 polar and 95 radical reactions in a textbook of organic chemistry. In the prediction procedure, the screening classifier distinguishes reactive and unreactive atoms and the ranking one provides reactive atom pairs in ranking order. Numerical assessments confirmed the high accuracies both of the screening and ranking classifiers in the prediction procedures. Furthermore, an analysis on the classifiers unveiled important descriptors for the prediction.
Value of Information Analysis for Complex Simulator Models: Application to Wind Farm Maintenance
Authors: Myklebust Hans Olav Vogt , Eidsvik Jo , Sperstad Iver Bakken , Bhattacharjya Debarun
Published: March 2020

Many domains require the use of sophisticated simulators to adequately model the effect of chosen alternatives on the decision maker’s value. Decision support in such complex systems brings unique challenges around efficiency, because simulating each combination of inputs can be time-consuming. In this paper, we conduct a value of information (VOI) analysis to study whether one should purchase information about critical input uncertainties in such complex systems. We propose a novel computational approach, where Gaussian processes are used to model the decision maker’s profit as a function of different alternatives and uncertainties. Under this modeling assumption, the expected improvement of the profit is analytically available, which we use to approximate the VOI effectively over batches of simulations, thus avoiding too many computer-intensive evaluations of the system. We illustrate the proposed computational approach with an offshore wind farm maintenance application, where the decision maker relies on outputs from large-scale simulations to determine the optimal vessel fleet mix and number of personnel for operation and maintenance. Such computer-intensive simulations mimic long-term energy production under different input conditions. It is often not possible to explore all the alternatives exhaustively, and one must therefore guide the simulations to run on promising alternatives. We conduct a VOI analysis to study whether one should purchase information about failure rates of wind turbines for this application. The proposed methodologies are general and apply to other domains involving expensive simulators.
COVID-19 and emergency planning
Authors: Winter George
Published: March 2020

As COVID-19 continues to spread worldwide, George Winter discusses emergency strategies, lessons from past epidemics and the vital role that healthcare managers can play in shaping responses to infectious diseases in today's global society.
Research roundup: December 2019
Authors: Dawn Odd , Poole Patricia , Willis Angela
Published: March 2020

In this section, a range of brief synopses of recently published articles that may be of interest to health visitors is presented. The aim of this roundup is to provide an overview, rather than a detailed summary, of the research papers selected. Should you wish to look at any of the papers in more detail, a full reference is provided.
Newly qualified health visitor: Child health clinics – A missed opportunity?
Authors: Boddy Bethany
Published: March 2020

Bethany Boddy considers the evidence around child health clinics, and how teams and can use this client interaction to discuss health promotion messages
The impact on parents of gastroesophageal reflux
Authors: Noakes Amy
Published: March 2020

Health visitors are encouraged to provide supportive and information for parents of children with diagnosed or suspected gastroesophageal reflux, says Amy Noakes