Citations

Abstract Altered Bone Marrow (BM) Plasma Amino Acid (AA) Composition Reflects Microenvironmental Remodeling in Patients with Multiple Myeloma (MM) compared to Monoclonal Gammopathy of Unknown Significance (MGUS) Michael Egan, Yogesh Chawla, Puja Dey, Dragan Jevremovic, Taro Hitosugi, Shaji Kumar and Wilson Gonsalves BACKGROUND: MYC overexpression, a hallmark of progression from MGUS to MM, drives metabolic reprogramming, including enhanced AA uptake and utilization. However, the contribution of AAs to disease progression from MGUS to MM remains poorly defined. In this study, we comprehensively profiled AA levels in the BM plasma of MGUS and MM patients to determine whether shifts in the availability of specific AAs reflect microenvironmental remodeling and evolving metabolic demands of malignant plasma cells (PCs). METHODS: AA profiles of BM plasma samples—reflective of the BM microenvironment—from two different cohorts of patients with either MGUS or MM (Cohort #1: 49 MGUS and 50 newly diagnosed MM (NDMM) and Cohort #2: 50 MGUS and 64 NDMM) were acquired using liquid chromatography (LC) coupled with tandem mass spectrometry (MS). Individual AA were quantified by MS using single-point quantification with isotopically labeled internal standards of AAs. Individual relative and quantitative AA data were analyzed for differences between the groups using the parametric t-test, and significance was defined as p < 0.05. We utilized a Pearson correlation coefficient method to determine the association of the percentage of clonal PCs in the BM to the levels of the AAs. The areas under the curve (AUC) of receiver operating characteristic (ROC) analyses were created on the web-based tool MetaboAnalyst 6.0 to determine the ability of quantitative AA levels to be utilized as a model to distinguish MGUS vs. MM. RESULTS: In BM plasma samples from cohort #1, using a global untargeted metabolite profiling, we identified 28 AAs and their metabolites out of the 1,089 known metabolites detected. A targeted quantification of these AAs was performed in the same samples to validate any observed differences between the groups. Both aspartate and glycine were found to be more abundant in NDMM compared to MGUS in both untargeted and targeted assays. In contrast,12 AAs (branched chain AAs: valine, leucine and isoleucine, aromatic AAs: tryptophan, kynurenine, tyrosine and phenylalanine; essential AAs: threonine and lysine; non-essential AAs: ornithine, citrulline and asparagine) were found to be less abundant in NDMM compared to MGUS. We then validated the presence of these differences using targeted quantification of AAs in the BM plasma samples from cohort #2. Aspartate was the only AA consistently found to be present at higher levels in NDMM vs. MGUS. Whereas, 8 AAs—threonine, valine, citrulline, tyrosine, tryptophan, isoleucine, phenylalanine, and kynurenine—were consistently lower in NDMM vs. MGUS. We observed a statistically significant positive correlation between the concentration of aspartate and the percentage of clonal PCs present in the BM (r = 0.56). In contrast, there were statistically significant negative correlations between the concentrations of all 8 AAs consistently lower in NDMM vs. MGUS and the percentage of clonal PCs in the BM: threonine (r = -0.41), valine (r = -0.35), citrulline (r = -0.37), tyrosine (r = -0.28), tryptophan (r = -0.31), isoleucine (r = -0.21), phenylalanine (r = -0.19), and kynurenine (r = -0.19). Using only the quantitative concentrations of the 9 AAs that were significantly different between NDMM and MGUS across both patient cohorts, we performed ROC analyses to develop predictive models distinguishing NDMM from MGUS. In cohort #1, the models yielded AUC values ranging from 0.738 to 0.785, while in cohort #2, AUC values ranged from 0.798 to 0.835, depending on the number of AAs included in the model. CONCLUSIONS: Several AAs are present at significantly different levels in the BM plasma of patients with NDMM compared to MGUS. These findings support the emerging role of AA availability, across a diverse set of AAs, in the pathogenesis and progression of MGUS to MM. Future studies are warranted to validate these observations and to determine whether alterations in the BM AA landscape can be leveraged for diagnostic or therapeutic strategies.

Introduction: Patients with cognitive impairments, who may be unable to engage in traditional psychotherapies, may require support through non-cognitive interventions. This review synthesizes the existing literature to assess the evidence base for these interventions and to propose future directions for research. Methods: A comprehensive literature search was conducted across seven electronic databases on October 17, 2024. Eligible studies assessed psychological, emotional, social, or spiritual outcomes. Results: Seventy-three studies were included, conducted across 18 countries. Music therapy and art therapy had the strongest empirical support, with consistent effects on distress, emotional expression, social and spiritual connectedness, and finding meaning. Other approaches, including movement therapy, spiritual interventions, and pet therapy, showed promising but preliminary results. Aromatherapy and massage therapy yielded mixed findings, while energy-based methods lacked robust evidence. Most studies had a high risk of bias, primarily due to confounding. Few interventions were conducted with patients with cognitive impairments, despite their potential relevance. Conclusion: A variety of interventions compatible with cognitive impairment show promise in palliative care settings. However, existing empirical support is constrained by bias and a lack of research in cognitively-impaired populations.

Abstract Rationale Immune checkpoint inhibitors (ICI) have become standard care for many cancers. Their mechanism of action mediates immune related adverse events including ICI pneumonitis. Diagnosis of this is difficult to differentiate from infectious and radiation pneumonitis as it is a diagnosis of exclusion often requiring bronchoscopy and imaging interpreted by expert radiologists. This study investigates the use of CALIPER, a computer-aided lung informatics program, in identifying differences between Computed Tomography (CT) patterns in ICI, radiation, and infectious pneumonitis that may aid in diagnosis noninvasively. Methods CT images of ten patients with ICI pneumonitis, ten patients with infectious pneumonitis, and nine patients with radiation pneumonitis, all diagnosed by clinical expertise and evaluation with bronchoalveolar lavage, were analyzed with CALIPER. CALIPER classified each CT voxel into either vessel-related structures (VRS), normal, mild low-attenuation area (LAA), moderate LAA, severe LAA, reticular (R), honeycomb (HC) or ground-glass (GG) features. Each lung was divided into upper, middle, and lower lobes. Exploratory analyses explored the relationship between CALIPER components and diagnosis, comparing ICI and radiation pneumonitis with infectious pneumonitis. Diagnosis was analyzed using multinomial logistic regression adjusted for presence of pleural effusion. Additionally, diagnosis was assessed as infectious versus a pooled group of radiation and ICI pneumonitis and analyzed using logistic regression adjusted for pleural effusion. Due to the exploratory nature of analysis, no correction was applied for multiplicity of testing. Results Twenty-nine patients were analyzed. ICI pneumonitis patients had less moderate low attenuation in the left upper (p = 0.016) and middle peripheral lung (p = 0.038), and radiation pneumonitis patients had less moderate low attenuation in the left upper peripheral lung (p = 0.031). When comparing the pooled group of ICI and radiation pneumonitis images with infectious pneumonitis, there was more moderate LAA in left upper (0.012) and middle (0.034) peripheral lung in the pooled group compared to infectious pneumonitis. There was no association with VRS, GG, HC, R, mild, or severe LAA patterns. Conclusions Although areas of moderate low attenuation were more prevalent for infectious pneumonitis, these results taken in the context of low sample size, exploratory analysis, and lack of clinical reasoning to support these findings make them likely insignificant. Based on this limited exploratory analysis, it is unlikely that we can solely use CALIPER as noninvasive evaluation to differentiate radiation and ICI pneumonitis from infectious pneumonitis. This highlights the need for a more robust program to aid in noninvasive diagnosis.

Abstract We describe a patient with self-induced inhalational pulmonary talcosis originally diagnosed as asthma. A 35-year-old female respiratory technologist developed severe asthma that was refractory to steroids and methotrexate. An open lung biopsy specimen showed scattered aggregates of refractile golden crystals within membranous and respiratory bronchioles. The particles ranged in size from 30 to 100 μm and were birefringent when viewed with polarized light. Following review of the lung biopsy specimen, the patient admitted to regularly inhaling large amounts of hospital baby powder. Analysis of the lung biopsy specimen and a sample of the hospital baby powder by x-ray energy dispersion showed identical spectroscopic peaks, including elemental peaks for magnesium silicate. Many patients with self-induced illness lack the picturesque symptomatology classically attributed to Munchausen syndrome. Awareness of these more subtle and varied patterns of presentation may aid in earlier recognition.