Evaluation and Management of Deficiency of Adenosine Deaminase 2: An International Consensus Statement.

Importance: Deficiency of adenosine deaminase 2 (DADA2) is a recessively inherited disease characterized by systemic vasculitis, early-onset stroke, bone marrow failure, and/or immunodeficiency affecting both children and adults. DADA2 is among the more common monogenic autoinflammatory diseases, with an estimate of more than 35 000 cases worldwide, but currently, there are no guidelines for diagnostic evaluation or management. Objective: To review the available evidence and develop multidisciplinary consensus statements for the evaluation and management of DADA2. Evidence Review: The DADA2 Consensus Committee developed research questions based on data collected from the International Meetings on DADA2 organized by the DADA2 Foundation in 2016, 2018, and 2020. A comprehensive literature review was performed for articles published prior to 2022. Thirty-two consensus statements were generated using a modified Delphi process, and evidence was graded using the Oxford Center for Evidence-Based Medicine Levels of Evidence. Findings: The DADA2 Consensus Committee, comprising 3 patient representatives and 35 international experts from 18 countries, developed consensus statements for (1) diagnostic testing, (2) screening, (3) clinical and laboratory evaluation, and (4) management of DADA2 based on disease phenotype. Additional consensus statements related to the evaluation and treatment of individuals with DADA2 who are presymptomatic and carriers were generated. Areas with insufficient evidence were identified, and questions for future research were outlined. Conclusions and Relevance: DADA2 is a potentially fatal disease that requires early diagnosis and treatment. By summarizing key evidence and expert opinions, these consensus statements provide a framework to facilitate diagnostic evaluation and management of DADA2.

Novel methodology to quantify dehydration in head and neck cancer radiotherapy using DIXON MRI.

INTRODUCTION: Head and neck cancer (HNC) patients are at risk of weight change, due to inadequate nutrition intake or dehydration, when receiving radiotherapy (RT). This study aimed to develop methodology to measure water content changes on magnetic resonance imaging (MRI) scans of the head and neck region over the course of RT. METHODS: Retrospective datasets of 54 patients were analysed. Eligible patients had been treated for HNC with cisplatin chemoradiation (CRT) or RT alone and underwent a minimum of 2 MRI scans from weeks 0, 3 and 6 of their treatment. Anatomical regions consisting of ≥90% water, on T2-weighted DIXON MRI sequences, were contoured. Water volume changes of all patients were evaluated, within an anatomically standardised external volume, by comparing the absolute water fraction volume (cc) (VEx90WF) and relative water fraction volume (%) (RelVEx90WF) at weeks 0 and 6 of RT. RESULTS: There was a statistically significant difference between the RelVEx90WF at weeks 0 and 6 (P = 0.005). However, no statistically significant difference was identified between weeks 0 and 6 VEx90WF (P = 0.064). There were no statistically significant differences identified between patients who received CRT versus RT alone. CONCLUSION: This study developed a novel method for measuring changes in water fraction volumes over time, using T2-weighted DIXON MRIs. The methodology created in this study requires further validation through phantom imaging, with known fat and water values.

Assessing patient-reported symptom burden of long-term head and neck cancer survivors at annual surveillance in survivorship clinic.

BACKGROUND: This study reports long-term head and neck cancer (HNC) patient-reported symptoms using the MD Anderson Symptom Inventory Head and Neck Cancer Module (MDASI-HN) in a large cohort of HNC survivors. METHODS: MDASI-HN results were prospectively collected from an institutional survivorship database. Associations with clinicopathologic data were analyzed using χ2 , Mann-Whitney, and univariate regression. RESULTS: Nine hundred and twenty-eight patients were included. Forty-six percent had oropharyngeal primary tumors. Eighty-two percent had squamous cell carcinoma. Fifty-six percent of patients had ablative surgery and 81% had radiation therapy as a component of treatment. The most severe symptoms were xerostomia and dysphagia. Symptom scores were worst for hypopharynx and varied by subsite. Patients treated with chemoradiation or surgery followed by radiation ± chemotherapy reported the worst symptoms while patient treated with surgery plus radiation ± chemotherapy reported the worst interference. CONCLUSION: HNC survivors describe their long-term symptom burden and inform efforts to improve care many years into survivorship.

Blenderized Tube Feeding: A Survey of Dietitians' Perspectives, Education, and Perceived Competence.

Increasingly, patients and their caregivers desire blenderized tube feeding (BTF) as an alternative or adjunct to commercial enteral formula. Although dietitians are central in the care of tube fed patients, they do not necessarily have training or experience with BTF and may therefore find it challenging to manage the nutrition of patients who opt for this enteral nutrition approach. To describe dietitians' perspectives, perceived competence, and education on BTF, a cross-sectional survey was conducted by use of an original questionnaire. Dietitians with the authority to practice enteral nutrition in the province of British Columbia, Canada, were included in the study (n = 715). Of the 221 respondents (31% response rate), 28% reported being knowledgeable about BTF, and 24% reported confidence managing patients on BTF. Few agreed they had the expertise to design, administer, or teach administration of BTF (29%, 15%, and 24%, respectively). In regards to education, 27% of respondents did not have BTF education of any kind, and those with BTF education reported it to be primarily derived from informal sources such as self-directed study and learning from colleagues or patients. These results indicate that among dietitians, formal BTF education is uncommon, and there is limited perceived competence on BTF practice.

Small-molecule inhibition of prostaglandin E receptor 2 impairs cyclooxygenase-associated malignant glioma growth.

BACKGROUND AND PURPOSE: An up-regulation of COX-2 in malignant gliomas causes excessive synthesis of PGE2 , which is thought to facilitate brain tumour growth and invasion. However, which downstream PGE2 receptor subtype (i.e., EP1 -EP4 ) directly contributes to COX activity-promoted glioma growth remains largely unknown. EXPERIMENTAL APPROACH: Using a publicly available database from The Cancer Genome Atlas research network, we compared the expression of PGE2 signalling-associated genes in human lower grade glioma and glioblastoma multiforme (GBM) samples. The Kaplan-Meier analysis was performed to determine the relationship between their expression and survival probability. A time-resolved FRET method was used to identify the EP subtype that mediates COX-2/PGE2 -initiated cAMP signalling in human GBM cells. Taking advantage of a recently identified novel selective bioavailable brain-permeable small-molecule antagonist, we studied the effect of pharmacological inhibition of the EP2 receptor on glioma cell growth in vitro and in vivo. KEY RESULTS: The EP2 receptor is a key Gαs -coupled receptor that mediates COX-2/PGE2 -initiated cAMP signalling pathways in human malignant glioma cells. Inhibition of EP2 receptors reduced COX-2 activity-driven GBM cell proliferation, invasion, and migration and caused cell cycle arrest at G0-G1 and apoptosis of GBM cells. Glioma cell growth in vivo was also substantially decreased by post-treatment with an EP2 antagonist in both subcutaneous and intracranial tumour models. CONCLUSION AND IMPLICATIONS: Taken together, our results suggest that PGE2 signalling via the EP2 receptor increases the malignant potential of human glioma cells and might represent a novel therapeutic target for GBM.

Public Policy and Health Informatics.

OBJECTIVES: To provide an overview of the history of electronic health policy and identify significant laws that influence health informatics. DATA SOURCES: US Department of Health and Human Services. CONCLUSION: The development of health information technology has influenced the process for delivering health care. Public policy and regulations are an important part of health informatics and establish the structure of electronic health systems. Regulatory bodies of the government initiate policies to ease the execution of electronic health record implementation. These same bureaucratic entities regulate the system to protect the rights of the patients and providers. IMPLICATIONS FOR NURSING PRACTICE: Nurses should have an overall understanding of the system behind health informatics and be able to advocate for change. Nurses can utilize this information to optimize the use of health informatics and campaign for safe, effective, and efficient health information technology.

Cyclooxygenase-2 contributes to oxidopamine-mediated neuronal inflammation and injury via the prostaglandin E2 receptor EP2 subtype.

Cyclooxygenase-2 (COX-2) triggers pro-inflammatory processes that can aggravate neuronal degeneration and functional impairments in many neurological conditions, mainly via producing prostaglandin E2 (PGE2) that activates four membrane receptors, EP1-EP4. However, which EP receptor is the culprit of COX-2/PGE2-mediated neuronal inflammation and degeneration remains largely unclear and presumably depends on the insult types and responding components. Herein, we demonstrated that COX-2 was induced and showed nuclear translocation in two neuronal cell lines - mouse Neuro-2a and human SH-SY5Y - after treatment with neurotoxin 6-hydroxydopamine (6-OHDA), leading to the biosynthesis of PGE2 and upregulation of pro-inflammatory cytokine interleukin-1ß. Inhibiting COX-2 or microsomal prostaglandin E synthase-1 suppressed the 6-OHDA-triggered PGE2 production in these cells. Treatment with PGE2 or EP2 selective agonist butaprost, but not EP4 agonist CAY10598, increased cAMP response in both cell lines. PGE2-initiated cAMP production in these cells was blocked by our recently developed novel selective EP2 antagonists - TG4-155 and TG6-10-1, but not by EP4 selective antagonist GW627368X. The 6-OHDA-promoted cytotoxicity was largely blocked by TG4-155, TG6-10-1 or COX-2 selective inhibitor celecoxib, but not by GW627368X. Our results suggest that PGE2 receptor EP2 is a key mediator of COX-2 activity-initiated cAMP signaling in Neuro-2a and SH-SY5Y cells following 6-OHDA treatment, and contributes to oxidopamine-mediated neurotoxicity.

Nutritional status, management and clinical outcomes in patients with esophageal and gastro-oesophageal cancers: A descriptive study.

AIM: The aims of this study were to investigate the nutritional management practice and nutritional status of patients with oesophageal and gastro-oesophageal cancers, and to propose strategies for improving their nutritional and clinical outcomes. METHODS: All patients diagnosed with oesophageal and gastro-oesophageal cancers and treated with chemotherapy and/or radiotherapy at the Liverpool Cancer Therapy Centre (between August 2010 and February 2014) were included in this retrospective study. Patient and tumour characteristics, nutritional status and management were compared to clinical outcomes. RESULTS: A total of 69 patients met the inclusion criteria. The median weight loss prior to treatment commencement was 10.5% (Interquartile Range (IQR) = 6.6-15.4). A decline in nutritional status continued throughout the treatment course. The median percentage of weight loss during treatment was 3.53% (IQR = 0.00-6.84). Seven and 19 patients required nutrition intervention using a feeding tube or stent insertion to manage dysphagia, respectively. In patients treated with a curative intent, radiotherapy was completed in 100% of those with a nasogastric tube insertion as compared to 80% who had a stent insertion. There was a higher percentage of patients from culturally and linguistically diverse (CALD) background, experiencing significant weight loss when compared with their non-CALD counterparts (P = 0.04). CONCLUSIONS: Patients with oesophageal and gastro-oesophageal cancers commonly present with significant weight loss and this continues during the course of their anti-cancer treatment. A standardised protocol of nutrition management for these cancer patients is recommended, focusing on assisting patients from CALD backgrounds.

Oncogenic Characterization and Pharmacologic Sensitivity of Activating Fibroblast Growth Factor Receptor (FGFR) Genetic Alterations to the Selective FGFR Inhibitor Erdafitinib.

Fibroblast growth factor receptor (FGFR) genetic alterations are frequently observed in cancer, suggesting that FGFR inhibition may be a promising therapy in patients harboring these lesions. Identification of predictive and pharmacodynamic biomarkers to select and monitor patients most likely to respond to FGFR inhibition will be the key to clinical development of this class of agents. Sensitivity to FGFR inhibition and correlation with FGFR pathway activation status were determined in molecularly annotated panels of cancer cell lines and xenograft models. Pathway inhibition in response to FGFR inhibitor treatment was assessed in cell lines (both in vitro and in vivo) and in samples from patients treated with the FGFR inhibitor JNJ-42756493 (erdafitinib). Frequency of FGFR aberrations was assessed in a panel of NSCLC, breast, prostate, ovarian, colorectal, and melanoma human tumor tissue samples. FGFR translocations and gene amplifications present in clinical specimens were shown to display potent transforming activity associated with constitutive pathway activation. Tumor cells expressing these FGFR activating mutants displayed sensitivity to the selective FGFR inhibitor erdafitinib and resulted in suppression of FGFR phosphorylation and downstream signal transduction. Clinically, patients receiving erdafitinib showed decreased Erk phosphorylation in tumor biopsies and elevation of serum phosphate. In a phase I study, a heavily pretreated bladder cancer patient with an FGFR3-TACC3 translocation experienced a partial response when treated with erdafitinib. This preclinical study confirmed pharmacodynamics and identified new predictive biomarkers to FGFR inhibition with erdafitinib and supports further clinical evaluation of this compound in patients with FGFR genetic alterations. Mol Cancer Ther; 16(8); 1717-26. ©2017 AACR.

Impact of a brief exercise program on the physical and psychosocial health of prostate cancer survivors: A pilot study.

AIM: It is well established that exercise is beneficial for prostate cancer survivors. The challenge for health professionals is to create effective strategies to encourage survivors to exercise in the community. Many community exercise programs are brief in duration (e.g. <5 exercise sessions); whilst evidence for the efficacy of exercise within the literature are derived from exercise programs ≥8 weeks in duration, it is unknown if health benefits can be obtained from a shorter program. This study examined the effect of a four-session individualized and supervised exercise program on the physical and psychosocial health of prostate cancer survivors. METHODS: Fifty-one prostate cancer survivors (mean age 69±7 years) were prescribed 1 h, individualized, supervised exercise sessions once weekly for 4 weeks. Participants were encouraged to increase their physical activity levels outside of the exercise sessions. Objective measures of muscular strength, exercise capacity, physical function and flexibility; and self-reported general, disease-specific and psychosocial health were assessed at baseline and following the intervention. RESULTS: Improvements were observed in muscle strength (leg press 17.6 percent; P < 0.001), exercise capacity (400-m walk 9.3 percent; P < 0.001), physical function (repeated chair stands 20.1 percent, usual gait speed 19.3 percent, timed up-and-go 15.0 percent; P < 0.001), flexibility (chair sit and reach +2.9 cm; P < 0.001) and positive well-being (P = 0.014) following the exercise program. CONCLUSION: A four-session exercise program significantly improved the muscular strength, exercise capacity, physical function and positive well-being of prostate cancer survivors. This short-duration exercise program is safe and feasible for prostate cancer survivors and a randomized controlled trial is now required to determine whether a similar individualized exercise regimen improves physical health and mental well-being over the short, medium and long term.