The health care experience of adults with metabolic dysfunction-associated steatohepatitis and influence of PNPLA3: A qualitative study.

BACKGROUND: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive form of metabolic dysfunction-associated steatotic liver disease, for which there is limited information about patient experience, including the patient journey. METHODS: In this study, we conducted interviews with patients with MASH to qualitatively evaluate the patient journey and help elucidate the experiences of this patient population. We also investigated if the patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M variant (non-Hispanic) or being of Hispanic ethnicity may influence patient experiences because these 2 subgroups develop advanced liver disease more frequently than other patient groups. RESULTS: One-to-one interviews were conducted with 28 adults (with PNPLA3 I148M genetic variant, n = 10; Hispanic, n = 8) living in the United States who had been diagnosed with MASH with liver fibrosis. Patients were asked open-ended questions about their experiences before, at, and after their diagnosis. The data collected found that patients experienced a long process of misdiagnoses before their diagnosis of MASH, a lack of clear information provided by clinicians, and limited accessibility to support groups. Hispanic patients reported "impact on family/friends" (75%) and "fear of disease progression" (75%) more frequently than the other patient cohorts interviewed. This is the first report of "fear of progression" in patients with MASH. No patients who were White and had the PNPLA3 I148M variant reported nausea/vomiting, in contrast to other patient cohorts. CONCLUSIONS: This qualitative study identified key aspects of the patient journey that are important for clinical providers and medical teams to recognize. We also propose a new algorithm that could be developed to help screen relatives of patients who are found to carry the PNPLA3 I148M variant.

Patient-reported outcomes with durvalumab, with or without tremelimumab, plus chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (POSEIDON).

OBJECTIVES: In the phase 3 POSEIDON study, first-line tremelimumab plus durvalumab and chemotherapy significantly improved overall survival and progression-free survival versus chemotherapy in metastatic non-small-cell lung cancer (NSCLC). We present patient-reported outcomes (PROs). PATIENTS AND METHODS: Treatment-naïve patients were randomized 1:1:1 to tremelimumab plus durvalumab and chemotherapy, durvalumab plus chemotherapy, or chemotherapy. PROs (prespecified secondary endpoints) were assessed using the European Organisation for Research and Treatment of Cancer 30-item core quality of life questionnaire version 3 (QLQ-C30) and its 13-item lung cancer module (QLQ-LC13). We analyzed time to deterioration (TTD) of symptoms, functioning, and global health status/quality of life (QoL) from randomization by log-rank test and improvement rates by logistic regression. RESULTS: 972/1013 (96 %) patients randomized completed baseline QLQ-C30 and QLQ-LC13 questionnaires, with scores comparable between treatment arms. Patients receiving tremelimumab plus durvalumab and chemotherapy versus chemotherapy had longer median TTD for all PRO items. Hazard ratios for TTD favored tremelimumab plus durvalumab and chemotherapy for all items except diarrhea; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, cognitive functioning, pain, nausea/vomiting, insomnia, constipation, hemoptysis, dyspnea, and pain in other parts. For durvalumab plus chemotherapy, median TTD was longer versus chemotherapy for all items except nausea/vomiting and diarrhea. Hazard ratios favored durvalumab plus chemotherapy for all items except appetite loss; 95 % confidence intervals did not cross 1.0 for global health status/QoL, physical functioning, role functioning, dyspnea, and pain in other parts. For both immunotherapy plus chemotherapy arms, improvement rates in all PRO items were numerically higher versus chemotherapy, with odds ratios > 1. CONCLUSIONS: Tremelimumab plus durvalumab and chemotherapy delayed deterioration in symptoms, functioning, and global health status/QoL compared with chemotherapy. Together with significant improvements in survival, these results support tremelimumab plus durvalumab and chemotherapy as a first-line treatment option in metastatic NSCLC.

Health-Related Quality of Life Outcomes in Patients with Resected Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer Who Received Adjuvant Osimertinib in the Phase III ADAURA Trial.

PURPOSE: In the phase III ADAURA trial, adjuvant treatment with osimertinib versus placebo, with/without prior adjuvant chemotherapy, resulted in a statistically significant and clinically meaningful disease-free survival benefit in completely resected stage IB-IIIA EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). We report health-related quality of life (HRQoL) outcomes from ADAURA. PATIENTS AND METHODS: Patients randomized 1:1 received oral osimertinib 80 mg or placebo for 3 years or until recurrence/discontinuation. HRQoL (secondary endpoint) was measured using the Short Form-36 (SF-36) health survey at baseline, 12, and 24 weeks, then every 24 weeks until recurrence or treatment completion/discontinuation. Exploratory analyses of SF-36 score changes from baseline until week 96 and time to deterioration (TTD) were performed in the overall population (stage IB-IIIA; N = 682). Clinically meaningful changes were defined using the SF-36 manual. RESULTS: Baseline physical/mental component summary (PCS/MCS) scores were comparable between osimertinib and placebo (range, 46-47) and maintained to Week 96, with no clinically meaningful differences between arms; difference in adjusted least squares (LS) mean [95% confidence intervals (CI), -1.18 (-2.02 to -0.34) and -1.34 (-2.40 to -0.28), for PCS and MCS, respectively. There were no differences between arms for TTD of PCS and MCS; HR, 1.17 (95% CI, 0.82-1.67) and HR, 0.98 (95% CI, 0.70-1.39), respectively. CONCLUSIONS: HRQoL was maintained with adjuvant osimertinib in patients with stage IB-IIIA EGFRm NSCLC, who were disease-free after complete resection, with no clinically meaningful differences versus placebo, further supporting adjuvant osimertinib as a new treatment in this setting. See related commentary by Patil and Bunn, p. 2204.

BMI-related cortical morphometry changes are associated with altered white matter structure.

BACKGROUND: While gross measures of brain structure have shown alterations with increasing body mass index (BMI), the extent and nature of such changes has varied substantially across studies. Here, we sought to determine whether small-scale morphometric measures might prove more sensitive and reliable than larger scale measures and whether they might offer a valuable opportunity to link cortical changes to underlying white matter changes. To examine this, we explored the association of BMI with millimetre-scale Gaussian curvature, in addition to standard measures of morphometry such as cortical thickness, surface area and mean curvature. We also assessed the volume and integrity of the white matter, using white matter signal intensity and fractional anisotropy (FA). We hypothesised that BMI would be linked to small-scale changes in Gaussian curvature and that this phenomenon would be mediated by changes in the integrity of the underlying white matter. METHODS: The association of global measures of T1-weighted cortical morphometry with BMI was examined using linear regression and mediation analyses in two independent groups of healthy young to middle aged human subjects (n1 = 52, n2 = 202). In a third dataset of (n3 = 897), which included diffusion tensor images, we sought to replicate the significant associations established in the first two datasets, and examine the potential mechanistic link between BMI-associated cortical changes and global FA. RESULTS: Gaussian curvature of the white matter surface showed a significant, positive association with BMI across all three independent datasets. This effect was mediated by a negative association between the integrity of the white matter and BMI. CONCLUSIONS: Increasing BMI is associated with changes in white matter microstructure in young to middle-aged healthy adults. Our results are consistent with a model whereby BMI-linked cortical changes are mediated by the effects of BMI on white matter microstructure.

Failure of sucrose replacement with the non-nutritive sweetener erythritol to alter GLP-1 or PYY release or test meal size in lean or obese people.

There is considerable interest in the effect of foods containing high intensity sweeteners on satiation. However, less is known about low-calorie bulk sweeteners such as erythritol. In this randomized three-way crossover study, we studied 10 lean and 10 obese volunteers who consumed three test meals on separate occasions: (a) control sucrose meal; (b) isovolumic meal with partial replacement of sucrose by erythritol; (c) isocaloric meal which contained more erythritol but equivalent calories to the control meal. We measured gut hormone levels, hunger and satiety scores, ad libitum food intake, sucrose preference and intake after the manipulations. There was a greater post-prandial excursion in glucose and insulin levels after sucrose than after the erythritol meals. There was no difference in GLP-1/PYY levels or subsequent energy intake and sucrose preference between sucrose control and isovolumic erythritol meals. In lean (but not obese) participants, hunger decreased to a greater extent after the isocaloric erythritol meal compared to the control meal (p = 0.003) reflecting the larger volume of this meal. Replacing sucrose with erythritol leads to comparable hunger and satiety scores, GLP-1 and PYY levels, and subsequent sucrose preference and intake.

The Presence of Real Food Usurps Hypothetical Health Value Judgment in Overweight People.

To develop more ecologically valid models of the neurobiology of obesity, it is critical to determine how the neural processes involved in food-related decision-making translate into real-world eating behaviors. We examined the relationship between goal-directed valuations of food images in the MRI scanner and food consumption at a subsequent ad libitum buffet meal. We observed that 23 lean and 40 overweight human participants showed similar patterns of value-based neural responses to health and taste attributes of foods. In both groups, these value-based responses in the ventromedial PFC were predictive of subsequent consumption at the buffet. However, overweight participants consumed a greater proportion of unhealthy foods. This was not predicted by in-scanner choices or neural response. Moreover, in overweight participants alone, impulsivity scores predicted greater consumption of unhealthy foods. Overall, our findings suggest that, while the hypothetical valuation of the health of foods is predictive of eating behavior in both lean and overweight people, it is only the real-world food choices that clearly distinguish them.

Dopamine modulates the neural representation of subjective value of food in hungry subjects.

Although there is a rich literature on the role of dopamine in value learning, much less is known about its role in using established value estimations to shape decision-making. Here we investigated the effect of dopaminergic modulation on value-based decision-making for food items in fasted healthy human participants. The Becker-deGroot-Marschak auction, which assesses subjective value, was examined in conjunction with pharmacological fMRI using a dopaminergic agonist and an antagonist. We found that dopamine enhanced the neural response to value in the inferior parietal gyrus/intraparietal sulcus, and that this effect predominated toward the end of the valuation process when an action was needed to record the value. Our results suggest that dopamine is involved in acting upon the decision, providing additional insight to the mechanisms underlying impaired decision-making in healthy individuals and clinical populations with reduced dopamine levels.

Studying food reward and motivation in humans.

A key challenge in studying reward processing in humans is to go beyond subjective self-report measures and quantify different aspects of reward such as hedonics, motivation, and goal value in more objective ways. This is particularly relevant for the understanding of overeating and obesity as well as their potential treatments. In this paper are described a set of measures of food-related motivation using handgrip force as a motivational measure. These methods can be used to examine changes in food related motivation with metabolic (satiety) and pharmacological manipulations and can be used to evaluate interventions targeted at overeating and obesity. However to understand food-related decision making in the complex food environment it is essential to be able to ascertain the reward goal values that guide the decisions and behavioral choices that people make. These values are hidden but it is possible to ascertain them more objectively using metrics such as the willingness to pay and a method for this is described. Both these sets of methods provide quantitative measures of motivation and goal value that can be compared within and between individuals.