Improving eligibility criteria for first-line trials for patients with DLBCL using a US-based Delphi-method survey.

Recent first-line randomized controlled trials (RCTs) for patients with diffuse large B-cell lymphoma (DLBCL) have shown negative results, which may be due in part to onerous eligibility criteria limiting enrollment of poor-risk patients who require immediate treatment. We conducted a Delphi-method survey with lymphoma experts in the United States to define recommendations for essential and potentially unnecessary enrollment criteria for modern first-line DLBCL RCTs aimed at increasing clinical diversity of ensuing study groups. We first tabulated enrollment criteria from 19 DLBCL RCTs spanning the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) era to identify common eligibility criteria from prior DLBCL RCTs for inclusion in the Delphi-method survey. We tabulated 451 total eligibility criteria comprising 51 criterion categories across 19 first-line DLBCL RCTs in the R-CHOP era. We then surveyed lymphoma clinical trial experts representing 8 academic medical centers in the United States regarding essential and unnecessary eligibility criteria for modern DLBCL RCTs. Seventeen of 29 invited clinical investigators completed the round-1 questionnaire (response rate, of 58.6%), 15 of 17 round-1 participants (88.2%) completed the round-2 survey, and all round-1 participants reviewed finalized recommendations for eligibility criteria for modern first-line DLBCL RCTs. We defined consensus recommendations for 31 modernized eligibility criteria including threshold values for 10 quantitative eligibility criteria aimed at facilitating enrollment of a clinically diverse study population in first-line DLBCL RCTs designed to improve standard-of-care therapy.

Therapeutic implications of activating noncanonical PIK3CA mutations in head and neck squamous cell carcinoma.

Alpelisib selectively inhibits the p110α catalytic subunit of PI3Kα and is approved for treatment of breast cancers harboring canonical PIK3CA mutations. In head and neck squamous cell carcinoma (HNSCC), 63% of PIK3CA mutations occur at canonical hotspots. The oncogenic role of the remaining 37% of PIK3CA noncanonical mutations is incompletely understood. We report a patient with HNSCC with a noncanonical PIK3CA mutation (Q75E) who exhibited a durable (12 months) response to alpelisib in a phase II clinical trial. Characterization of all 32 noncanonical PIK3CA mutations found in HNSCC using several functional and phenotypic assays revealed that the majority (69%) were activating, including Q75E. The oncogenic impact of these mutations was validated in 4 cellular models, demonstrating that their activity was lineage independent. Further, alpelisib exhibited antitumor effects in a xenograft derived from a patient with HNSCC containing an activating noncanonical PIK3CA mutation. Structural analyses revealed plausible mechanisms for the functional phenotypes of the majority of the noncanonical PIK3CA mutations. Collectively, these findings highlight the importance of characterizing the function of noncanonical PIK3CA mutations and suggest that patients with HNSCC whose tumors harbor activating noncanonical PIK3CA mutations may benefit from treatment with PI3Kα inhibitors.

Media influence on humanitarian interventions: analysis of the Rohingya refugee crisis and international media coverage.

In 2017, the long-festering discriminatory treatment to the Rohingyas in Myanmar, both in law and practice, resulted in the largest cross-border humanitarian crisis in Asia. During the 2016­2017 Rohingya refugee crisis, the aerial shots of burnt villages and images of people trudging toward the horizon in search of refuge in neighboring nations dominated the Western media. However, for humanitarians, the question of whether the media helps with humanitarian crises remains complicated and unclear. This study examines the effects of media coverage on the Rohingya refugee crisis based on articles from two liberal, elite newspaper sources, The New York Times and The Guardian between 2010 and 2020. The study reveals that the attempts of international pressure to stop the crisis have increased through media coverage and political pressures; however, the number of Rohingya refugees fleeing Myanmar intensified due to worsening violence and human rights violations committed by the Myanmar army. Findings are discussed using the lens of cultural and ideological context. The study suggests that in Myanmar, where authoritarian military culture is pervasive, there is a limited influence of the international press on the state-sponsored ethnic cleansing of the Rohingya population and questions whether consistent international pressure could have changed the outcome.

Genome-defined African ancestry is associated with distinct mutations and worse survival in patients with diffuse large B-cell lymphoma.

BACKGROUND: Significant racial differences have been observed in the incidence and clinical outcomes of diffuse large B-cell lymphoma (DLBCL) in the United States, but to the authors' knowledge it remains unclear whether genomic differences contribute to these disparities. METHODS: To understand the influences of genetic ancestry on tumor genomic alterations, the authors estimated the genetic ancestry of 1001 previously described patients with DLBCL using unsupervised model-based Admixture global ancestry analysis applied to exome sequencing data and examined the mutational profile of 150 DLBCL driver genes in tumors obtained from this cohort. RESULTS: Global ancestry prediction identified 619 patients with >90% European ancestry, 81 patients with >90% African ancestry, and 50 patients with >90% Asian ancestry. Compared with patients with DLBCL with European ancestry, patients with African ancestry were aged >10 years younger at the time of diagnosis and were more likely to present with B symptoms, elevated serum lactate dehydrogenase, extranodal disease, and advanced stage disease. Patients with African ancestry demonstrated worse overall survival compared with patients with European ancestry (median, 4.9 years vs 8.8 years; P = .04). Recurrent mutations of MLL2 (KMT2D), HIST1H1E, MYD88, BCL2, and PIM1 were found across all ancestry groups, suggesting shared mechanisms underlying tumor biology. The authors also identified 6 DLBCL driver genes that were more commonly mutated in patients with African ancestry compared with patients with European ancestry: ATM (21.0% vs 7.75%; P < .001), MGA (19.7% vs 5.33%; P < .001), SETD2 (17.3% vs 5.17%; P < .001), TET2 (12.3% vs 5.82%; P = .029), MLL3 (KMT2C) (11.1% vs 4.36%; P = .013), and DNMT3A (11.1% vs 4.52%; P = .016). CONCLUSIONS: Distinct prevalence and patterns of mutation highlight an important difference in the mutational landscapes of DLBCL arising in different ancestry groups. To the authors' knowledge, the results of the current study provide the first-ever characterization of genetic alterations among patients with African descent who are diagnosed with DLBCL.

Using Informatics Tools to Identify Opportunities for Precision Medicine in Diffuse Large B-cell Lymphoma.

INTRODUCTION: Diffuse large B-cell lymphoma (DLBCL) is genetically and clinically heterogeneous. Despite advances in genomic subtyping, standard frontline chemoimmunotherapy has remained unchanged for years. As high-throughput analysis becomes more accessible, characterizing drug-gene interactions in DLBCL could support patient-specific treatment strategies. MATERIALS AND METHODS: From our systematic literature review, we compiled a comprehensive list of somatic mutations implicated in DLBCL. We extracted reported and primary sequencing data for these mutations and assessed their association with signaling pathways, cell-of-origin subtypes, and clinical outcomes. RESULTS: Twenty-two targetable mutations present in ≥ 5% of patients with DLBCL were associated with unfavorable outcomes, yielding a predicted population of 31.7% of DLBCL cases with poor-risk disease and candidacy for targeted therapy. A second review identified 256 studies that had characterized the drug-gene interactions for these mutations via in vitro studies, mouse models, and/or clinical trials. CONCLUSIONS: Our novel approach linking the data from our systematic reviews with informatics tools identified high-risk DLBCL subgroups, DLBCL-specific drug-gene interactions, and potential populations for precision medicine trials.

Alterations and molecular targeting of the GSK-3 regulator, PI3K, in head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is a highly morbid, genetically unstable disease derived from the mucoepithelium of the upper aerodigestive tract. Recent characterization of this disease has implicated the PI3K-Akt-mTOR pathway as one of the most frequently dysregulated pathways. As such, there are several classes of PI3K inhibitors currently undergoing clinical trials. In this article, we review the PI3K pathway, mutations of this pathway in HNSCC, drugs that target PI3K, the impact of these agents on the PI3K and GSK-3 signaling axes, ongoing clinical trials evaluating PI3K inhibitors, and the challenges of using these drugs in the clinic. This article is part of a Special Issue entitled: GSK-3 and related kinases in cancer, neurological and other disorders edited by James McCubrey, Agnieszka Gizak and Dariusz Rakus.

Remaining challenges in predicting patient outcomes for diffuse large B-cell lymphoma.

Introduction: Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma and is an aggressive malignancy with heterogeneous outcomes. Diverse methods for DLBCL outcomes assessment ranging from clinical to genomic have been developed with variable predictive and prognostic success.Areas covered: The authors provide an overview of the various methods currently used to estimate prognosis in DLBCL patients. Models incorporating cell of origin, genomic features, sociodemographic factors, treatment effectiveness measures, and machine learning are described.Expert opinion: The clinical and genetic heterogeneity of DLBCL presents distinct challenges in predicting response to therapy and overall prognosis. Successful integration of predictive and prognostic tools in clinical trials and in a standard clinical workflow for DLBCL will likely require a combination of methods incorporating clinical, sociodemographic, and molecular factors with the aid of machine learning and high-dimensional data analysis.

Application of a sorbent trap system to gas-phase elemental and oxidized mercury analysis.

A sorbent trap that utilizes activated carbon (AC) as the solid trapping medium is a new technology for measuring total mercury (Hg) emissions from combustion facilities. In this study, sorbent trap technology was further developed, improved and evaluated at the laboratory scale. AC was impregnated with 5% aqua regia to enhance its Hg adsorption capacity. Sorbent traps spiked with an Hg standard solution were found to be reproducibly prepared and highly stable. The effect of the Hg concentration on the spiking efficiency was further investigated. The adsorption of elemental and oxidized Hg by the sorbent trap was studied under various experimental conditions (temperature, flow rate and inlet Hg concentration). The Hg concentration of the flue gas effluent from the sorbent trap was measured. In addition, the concentration of Hg adsorbed on the AC was determined by digesting the used AC with an acid according to US EPA method 3052 and then analyzing it with cold vapor atomic absorption spectrometry. Furthermore, the gas-phase Hg emissions from a combustion source were measured using the sorbent trap according to US EPA method 30B. The results showed that the sorbent trap could be used for Hg concentrations between 10.0 and 40.0 µg m(-3) and flow rates between 0.5 and 1.0 lpm with adsorption efficiencies greater than 90%.

Type 1 Diabetes Duration Decreases Pulmonary Diffusing Capacity during Exercise.

BACKGROUND: Diabetes damages peripheral tissues; however, its effects on the lung are less known. Lung diffusing capacity (DLCO) is influenced by alveolar-capillary membrane conductance (DM) and pulmonary capillary blood volume (VC), both of which are reduced in adults with type 1 diabetes (T1D). OBJECTIVE: We sought to determine if diabetes duration affects DLCO, DM, VC, and cardiac output (Q). METHODS: 24 T1D patients (10.7-52.8 years) and 24 non-diabetic controls were recruited and had DLCO, DM, VC, and Q measured at rest and during exercise (40, 70 and 90% VO2max). RESULTS: When stratified into two groups based on age (young, <20.6 years old), there were no significant differences in DLCO, DM, VC, or Q (all of which were normalized to body surface area [BSA]) in the young group or in the old group. When stratified by diabetes duration (short duration, 0.33-8.9 years vs. long duration, 9.6-28 years), the T1D patients in the long duration group had lower DLCO/BSA and DM/BSA compared to the controls (p < 0.05). There were no differences in any of the variables in the short duration group. CONCLUSIONS: This study has shown that duration of diabetes is associated with decrements in diffusing capacity and its components.

Is lung diffusing capacity lower in expiratory flow limited women compared to non-flow limited women during exercise?

PURPOSE: Women tend to have smaller lungs than men of the same size as well as narrower airways compared to men when matched for the same lung size. Additionally, women with smaller airways relative to lung size are more likely to experience expiratory flow limitation (EFL) as well as exercise-induced arterial hypoxemia (EIAH). One of the possible causes of EIAH includes excessive widening in the alveolar-to-arterial oxygen pressure difference (A-aDO2) due to diffusion limitation. This study investigated if lung diffusing capacity (D LCO) is lower in women with EFL compared to non-flow limited (NEFL) women during exercise. METHODS: D LCO was measured using the rebreathing technique at rest and at 40, 60, and 80 % of [Formula: see text] on a treadmill in healthy women with EFL (n = 7; 21.6 ± 2.3) and without EFL (NEFL, n = 9; 21.2 ± 2.3). Arterial oxygen saturation was measured using pulse oximetry (SpO2). RESULTS: There was no difference (p > 0.05) in D LCO between groups at rest or during exercise; however, SpO2 was significantly lower in the EFL females compared to NEFL females during exercise. CONCLUSION: Due to the lack of differences in D LCO between women with EFL and without EFL, our results suggest that this is not a possible cause for the significant differences in SpO2 between the two groups.

A Qualitative Investigation of Therapists' Attitudes towards Research: Horses for Courses?

BACKGROUND: A large body of research has identified that many therapists do not use research to inform their practice, but few studies investigate the reasons behind this. AIMS: The current study seeks to understand what sources therapists use to inform their practice and why they are chosen. METHOD: Thirty-three interviews with psychological therapists in the UK were undertaken. These were transcribed and analysed using Interpretative Phenomenological Analysis. RESULTS: Two superordinate themes emerged. The former focused on the nature of evidence and the latter described why certain sources were used to make clinical decisions. When discussing evidence, participants felt that research studies, specifically Randomized Controlled Trials (RCTs), used unrepresentative samples. Therapists felt that research other than RCTs, particularly qualitative research, was important. Therapist specific factors were felt to be as, or more, important than the technique used to treat patients. When discussing the sources they used, therapists preferred to use their clinical experience or their patients' experience to make clinical decisions. Theoretical or practical information was preferred to empirical research. The presentation of information was felt to be important to encourage the implementation of research, and therapists also felt tools such as outcome measures and manuals were too rigid to be useful. Finally, patients' choice of treatment was felt to be important in treatment decisions. CONCLUSIONS: The views of therapists were heterogeneous, but this study highlighted some of the barriers to closing the gap between science and practice. This knowledge can be used to increase the translation of science into practice.

Hedgehog pathway inhibitor saridegib (IPI-926) increases lifespan in a mouse medulloblastoma model.

The Sonic Hedgehog (Shh) pathway drives a subset of medulloblastomas, a malignant neuroectodermal brain cancer, and other cancers. Small-molecule Shh pathway inhibitors have induced tumor regression in mice and patients with medulloblastoma; however, drug resistance rapidly emerges, in some cases via de novo mutation of the drug target. Here we assess the response and resistance mechanisms to the natural product derivative saridegib in an aggressive Shh-driven mouse medulloblastoma model. In this model, saridegib treatment induced tumor reduction and significantly prolonged survival. Furthermore, the effect of saridegib on tumor-initiating capacity was demonstrated by reduced tumor incidence, slower growth, and spontaneous tumor regression that occurred in allografts generated from previously treated autochthonous medulloblastomas compared with those from untreated donors. Saridegib, a known P-glycoprotein (Pgp) substrate, induced Pgp activity in treated tumors, which likely contributed to emergence of drug resistance. Unlike other Smoothened (Smo) inhibitors, the drug resistance was neither mutation-dependent nor Gli2 amplification-dependent, and saridegib was found to be active in cells with the D473H point mutation that rendered them resistant to another Smo inhibitor, GDC-0449. The fivefold increase in lifespan in mice treated with saridegib as a single agent compares favorably with both targeted and cytotoxic therapies. The absence of genetic mutations that confer resistance distinguishes saridegib from other Smo inhibitors.