Updates in the role of the tumor microenvironment cellular crosstalk and genetic signatures in diffuse large B-cell lymphoma: a narrative review.

BACKGROUND AND OBJECTIVE: The tumor microenvironment (TME) is known to exert a significant impact on disease biology and convey prognostic and therapeutic implications in several hematopoietic neoplasms, including diffuse large B-cell lymphoma (DLBCL). Recent discoveries have yielded new information regarding the genetic signatures of the TME. This study aims to review the updates on the cellular markers and genetics of various components of the TME in DLBCL influencing tumor behavior and patients' responses to treatment and discuss the novel treatment modalities available for the patients. METHODS: We systematically reviewed the literature in Medline for DLBCL-related articles on gene expression studies of TME. Forty-seven articles were identified and included that were published between Apr 2006 and Apr 2023. KEY CONTENT AND FINDINGS: We review the key components of the TME including the endothelial cells, myofibroblasts and mast cells, and discuss their biologic roles, with a particular focus on elements of their crosstalk relevant to DLBCL. We also review the genetic changes in lymphocytes and macrophages in TME of DLBCL. Increased understanding of emergent molecular alterations may hopefully allow improved prognostication and translational discoveries which will benefit patients with aggressive B-cell lymphomas. CONCLUSIONS: Combining cell of origin and TME as a risk stratification/prognostication system could provide more effective targeted therapeutic regiments. Identifying TME-targeted therapies will happen after providing the TME markers in the DLBCLs.

Efficient measurement of multiple ventricular assist device patient-reported outcomes: Creation of a 20-item profile from the MCS A-QOL study.

BACKGROUND: Patient-reported outcome (PRO) measures of distinct concepts are often put together into patient profile assessments. When brief, profile assessments can decrease respondent burden and increase measure completion rates. In this report, we describe the creation of 5 self-reported 4-item short forms and the Mechanical Circulatory Support: Measures of Adjustment and Quality of Life (MCS A-QOL) 20-item profile to assess PROs specific to adjustment and health-related quality of life (HRQOL) among patients who undergo left ventricular assist device (LVAD) implantation. METHODS: Using a cross-sectional sample of patients (n = 620) who underwent LVAD implantation at 12 U.S. sites or participated in the MyLVAD.com support group, we created 5 4-item short forms: Satisfaction with Treatment, ventricular assist device (VAD) Team Communication, Being Bothered by VAD Self-care and Limitations, Self-efficacy Regarding VAD self-care, and Stigma, which we combined into a 20-item profile. Analyses included intercorrelations among measures, Cronbach's alpha (i.e., internal consistency reliability)/score-level-specific reliability, and construct validity. RESULTS: The 620 patients were mean age = 57 years, 78% male, 70% White, and 56% on destination therapy LVADs. Intercorrelations among the 5 4-item measures were low to moderate (≤0.50), indicating they are associated yet largely distinct, and correlations with calibrated measures and 6-item short forms were ≥0.76, indicating their ability to reflect full-item bank scores. Internal consistency reliability for the 5 4-item short forms ranged from acceptable (≥0.70) to good (≥0.80). Construct validity was demonstrated for these measures. CONCLUSIONS: Our 5 4-item short forms are reliable and valid and may be used individually or together as a 20-item profile to assess adjustment and HRQOL in patients who undergo LVAD implantation.

Using SCENTinel® to predict SARS-CoV-2 infection: insights from a community sample during dominance of Delta and Omicron variants.

Introduction: Based on a large body of previous research suggesting that smell loss was a predictor of COVID-19, we investigated the ability of SCENTinel®, a newly validated rapid olfactory test that assesses odor detection, intensity, and identification, to predict SARS-CoV-2 infection in a community sample. Methods: Between April 5, 2021, and July 5, 2022, 1,979 individuals took one SCENTinel® test, completed at least one physician-ordered SARS-CoV-2 PCR test, and endorsed a list of self-reported symptoms. Results: Among the of SCENTinel® subtests, the self-rated odor intensity score, especially when dichotomized using a previously established threshold, was the strongest predictor of SARS-CoV-2 infection. SCENTinel® had high specificity and negative predictive value, indicating that those who passed SCENTinel® likely did not have a SARS-CoV-2 infection. Predictability of the SCENTinel® performance was stronger when the SARS-CoV-2 Delta variant was dominant rather than when the SARS-CoV-2 Omicron variant was dominant. Additionally, SCENTinel® predicted SARS-CoV-2 positivity better than using a self-reported symptom checklist alone. Discussion: These results indicate that SCENTinel® is a rapid assessment tool that can be used for population-level screening to monitor abrupt changes in olfactory function, and to evaluate spread of viral infections like SARS-CoV-2 that often have smell loss as a symptom.

New Dizziness Impact Measures of Positional, Functional, and Emotional Status Were Supported for Reliability, Validity, and Efficiency.

Objective: To calibrate the 25 items from the Dizziness Handicap Inventory (DHI) patient-reported outcome measure (PROM), using item response theory (IRT), into 1 or more item banks, and assess reliability, validity, and administration efficiency of scores derived from computerized adaptive test (CAT) or short form (SF) administration modes. Design: Retrospective cohort study. Setting: Outpatient rehabilitation clinics. Participants: Patients (N=28,815; women=69%; mean age [SD]=60 [18]) included in a large national dataset and assessed for dizziness-related conditions who responded to all DHI items at intake. Interventions: Not applicable. Main Outcome Measures: IRT model assumptions of unidimensionality, local item independence, item fit, and presence of differential item functioning (DIF) were evaluated. Generated scores were assessed for reliability, validity, and administration efficiency. Results: Patients were treated in 976 clinics from 49 US states for either vestibular-, brain injury-, or neck-related impairments. Three unidimensional item banks were calibrated, creating 3 distinct PROMs for Dizziness Functional Status (DFS, 13 items), Dizziness Positional Status (DPS, 4 items), and Dizziness Emotional Status (DES, 6 items). Two items did not fit into any domain. A DFS-CAT and a DFS 7-item SF were developed. Except for 2 items by age groups and 1 item by main impairment, no items were flagged for DIF; DIF impact was negligible. Median reliability estimates were 0.91, 0.72, and 0.79 for the DFS, DPS, and DES, respectively. Scores discriminated between patient groups in clinically logical ways and had a large effect size (>0.8), with acceptable floor and ceiling effects (<15%), except for a floor effect for DPS (20.4%). DFS-CAT scores were generated using a median of 8 items; they correlated highly with full-bank scores (r=0.99). Conclusion: The 3 dizziness impact PROMs demonstrated moderate to high reliability, were valid, and highly responsive to change; thus, they are suitable for research and routine clinical administration.

Treatment of secondary CNS lymphoma using CD19-targeted chimeric antigen receptor (CAR) T cells.

BACKGROUND: Aggressive B cell lymphoma with secondary central nervous system (CNS) involvement (SCNSL) carries a dismal prognosis. Chimeric antigen receptor (CAR) T cells (CAR-T) targeting CD19 have revolutionized the treatment for B cell lymphomas; however, only single cases with CNS manifestations successfully treated with CD19 CAR-T have been reported. METHODS: We prospectively enrolled 4 patients with SCNSL into our study to assess clinical responses and monitor T cell immunity. RESULTS: Two of four SNCSL patients responded to the CD19-targeted CAR-T. Only one patient showed a substantial expansion of peripheral (PB) CAR-T cells with an almost 100-fold increase within the first week after CAR-T. The same patient also showed marked neurotoxicity and progression of the SNCSL despite continuous surface expression of CD19 on the lymphoma cells and an accumulation of CD4+ central memory-type CAR-T cells in the CNS. Our studies indicate that the local production of chemokine IP-10, possibly through its receptor CXCR3 expressed on our patient's CAR-T, could potentially have mediated the local accumulation of functionally suboptimal anti-tumor T cells. CONCLUSIONS: Our results demonstrate expansion and homing of CAR-T cells into the CNS in SNCSL patients. Local production of chemokines such as IP-10 may support CNS infiltration by CAR-T cells but also carry the potential of amplifying local toxicity. Future studies investigating numbers, phenotype, and function of CAR-T in the different body compartments of SNSCL patients receiving CAR-T will help to improve local delivery of "fit" and highly tumor-reactive CAR-T with low off-target reactivity into the CNS.

Novel measures to assess ventricular assist device patient-reported outcomes: Findings from the MCS A-QOL study.

BACKGROUND: Generic and heart failure-specific measures do not capture unique aspects of living with a ventricular assist device (VAD). Using state-of-the-science psychometric measurement methods, we developed a measurement system to assess post-ventricular assist device adjustment and health-related quality of life (HRQOL). METHODS: Patients were recruited from 10/26/16-2/29/20 from 12 U.S. VAD programs. We created a dataset of participants (n = 620) enrolled before left (L)VAD implantation, with data at 3- or 6- months post-implantation (group1 [n = 154]), and participants enrolled after LVAD implantation, with data at one timepoint (group 2 [n = 466]). We constructed 5 item banks: 3 modified from existing measures and 2 new measures. Analyses included item response theory (IRT) modeling, differential item functioning tests for systematic measurement bias, and indicators of reliability and validity. RESULTS: Of 620 participants, 56% (n = 345) were implanted as destination therapy, 51% (n = 316) were <12 months post-implantation, mean age = 57.3 years, 78% (n = 485) male, 70% (n = 433) White, 58% (n = 353) married/partnered, and 58% (n = 357) with >high school education. We developed 5 new VAD item banks/measures: 6-item VAD Team Communication; 12-item Self-efficacy Regarding VAD Self-care; 11-item Being Bothered by VAD Self-care and Limitations; 7-item Satisfaction with Treatment; and 11-item Stigma. Cronbach's alpha reliability ranged from good (≥0.80) to excellent (≥0.90) for item banks/measures. All measures, except VAD Team Communication, demonstrated at least moderate correlations (≥0.30) with construct validity indicators. CONCLUSIONS: These measures meet IRT modeling assumptions and requirements; scores demonstrate reliability and validity. Use of these measures may assist VAD clinicians to inform patients about VADs as a treatment option and guide post-VAD interventions.

Psychometric Properties of the Spinal Cord Injury-Quality of Life (SCI-QOL) Resilience Short Form in a Sample With Spinal Cord Injury.

OBJECTIVE: To explore the psychometric properties (eg, data distribution characteristics, convergent or discriminant validity, internal consistency reliability) of the Spinal Cord Injury-Quality of Life measurement system (SCI-QOL) Resilience 8-item short form (SF) in comparison to the criterion standard resilience measure, Connor Davidson Resilience Scale (CD-RISC) in a sample of individuals with spinal cord injury (SCI). DESIGN: Descriptive statistics were calculated to examine variable data distribution characteristics. Correlation analyses were conducted for convergent and discriminant validity. Reliability statistics were calculated for resilience and other validity measures. SETTING: General community. PARTICIPANTS: Individuals with SCI (N=202; 51.5% male, 48% female). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Patient-Reported Outcomes Measurement Information System measures (depression, anxiety, ability to participate in social roles and activities, pain intensity, fatigue, sleep disturbance), SCI-QOL short forms (SF) (resilience, positive affect and well-being, mobility), CD-RISC, National Institutes of Health Toolbox for Assessment of Neurological and Behavioral Function - perceived stress (NIH Toolbox-perceived stress), and the Satisfaction with Life Scale were administered. RESULTS: The mean and SD for the SCI-QOL Resilience SF (mean=48.60; SD=8.20) approximated the normative mean (mean=50, SD=10). The SCI-QOL Resilience SF scores were essentially normally distributed though somewhat kurtotic, with skew=-0.17 and excess kurtosis=1.4; internal consistency reliability was good (Cronbach's alpha=0.89). Convergent validity was supported by significant moderate correlations in expected directions between the SCI-QOL Resilience SF and measures of CD-RISC resilience, depressive symptoms, anxiety, social participation, positive affect and well-being, stress, and satisfaction with life. Discriminant validity was supported by small non-significant correlations between the SCI-QOL Resilience SF and age, sex, injury level, time since injury, pain intensity, mobility, sleep disturbance, and fatigue. CONCLUSION: The SCI-QOL Resilience SF demonstrated good convergent and discriminant validity. Our study showed that the SCI-QOL Resilience SF is a psychometrically valid tool that can reliably estimate levels of resilience in the SCI population.

Arthroplasty-Related Pseudotumor of the Scapula: Case Report and Review of the Literature.

Arthroplasty-related pseudotumors are nonneoplastic and noninfectious inflammatory masses that are typically associated with adverse reaction to metal debris. Pseudotumors most commonly occur in the setting of metal-on-metal joint replacements at the hip. However, the presentation of pseudotumor at the shoulder is exceedingly rare. In this article, we reported a case of arthroplasty-related pseudotumor of the scapula. Clinical history, radiologic signs, and tissue analysis are described. Knowledge of this rare diagnosis will support clinical decision making for teams of radiologists, pathologists, oncologists, and orthopaedic surgeons who provide care for patients presenting with suspicious shoulder masses.

Cytogenetics and molecular genetics of myelodysplastic neoplasms.

According to the 2022 World Health Organization (WHO) Classification (5th edition), the term myelodysplastic neoplasms (abbreviated MDS) has been introduced to replace myelodysplastic syndromes. MDS are a group of clonal hematopoietic stem cell diseases characterized by cytopenia(s), dysplasia in one or more of lineages, ineffective hematopoiesis, and an increased risk of progression to bone marrow failure or to acute myeloid leukemia (AML). Current NCCN guidelines and recent review articles have provided in depth discussion on the clinical diagnosis and management of MDS. This review will focus on discussion of the WHO and International Consensus Classification (ICC) updates on the role of cytogenetics and molecular genetics in the diagnosis and risk stratification of MDS.

Psychometric properties of the mock interview rating scale for autistic transition-age youth.

Background: Employment is a major contributor to quality of life. However, autistic people are often unemployed and underemployed. One potential barrier to employment is the job interview. However, the availability of psychometrically-evaluated assessments of job interviewing skills is limited for autism services providers and researchers. Objective: We analyzed the psychometric properties of the Mock Interview Rating Scale that was adapted for research with autistic transition-age youth (A-MIRS; a comprehensive assessment of video-recorded job interview role-play scenarios using anchor-based ratings for 14 scripted job scenarios). Methods: Eighty-five transition-age youth with autism completed one of two randomized controlled trials to test the effectiveness of two interventions focused on job interview skills. All participants completed a single job interview role-play at pre-test that was scored by raters using the A-MIRS. We analyzed the structure of the A-MIRS using classical test theory, which involved conducting both exploratory and confirmatory factor analyzes, Rasch model analysis and calibration techniques. We then assessed internal consistency, inter-rater reliability, and test-retest reliability. Pearson correlations were used to assess the A-MIRS' construct, convergent, divergent, criterion, and predictive validities by comparing it to demographic, clinical, cognitive, work history measures, and employment outcomes. Results: Results revealed an 11-item unidimensional construct with strong internal consistency, inter-rater reliability, and test-retest reliability. Construct [pragmatic social skills (r = 0.61, p < 0.001), self-reported interview skills (r = 0.34, p = 0.001)], divergent [e.g., age (r = -0.13, p = 0.26), race (r = 0.02, p = 0.87)], and predictive validities [competitive employment (r = 0.31, p = 0.03)] received initial support via study correlations, while convergent [e.g., intrinsic motivation (r = 0.32, p = 0.007), job interview anxiety (r = -0.19, p = 0.08)] and criterion [e.g., prior employment (r = 0.22, p = 0.046), current employment (r = 0.21, p = 0.054)] validities were limited. Conclusion: The psychometric properties of the 11-item A-MIRS ranged from strong-to-acceptable, indicating it may have utility as a reliable and valid method for assessing the job interview skills of autistic transition-age youth.

The Sigmoid Colon as an Unusual Primary Site of T Cell Lymphoma in a Patient Presenting With Brain Metastasis.

Intestinal T-cell lymphomas are an uncommon type of gastrointestinal malignancy, primarily found in the stomach and small bowel. The liver represents the most common distant organ for metastasis in gastrointestinal malignancies, followed by the lungs. Brain and muscular metastases are rare. We present intestinal T-cell lymphoma with a primary site in the sigmoid colon and metastasis to the brain, meninges, and psoas muscle. Biopsy of the malignant mass confirmed intestinal T-cell lymphoma. To our knowledge, this is the first colon T-cell lymphoma with primary brain and meningeal metastasis with another uncommon site of muscular metastasis.

Lower Quadrant Edema Patient-Reported Outcome Measure Is Reliable, Valid, and Efficient for Patients With Lymphatic and Venous Disorders.

OBJECTIVE: The main aims of this study were: (1) to create a patient-reported outcome measure (PROM) item bank for measuring the impact of lower quadrant edema (LQE) on physical function using item response theory and (2) to assess reliability, validity, and administration efficiency of LQE PROM scores based on computerized adaptive test (CAT) and the reliability of a 10-item short form (SF). METHODS: This retrospective study included data from patients treated in outpatient rehabilitation clinics for lower quadrant edema who responded to all 30 candidate items at intake. Item response theory model assumptions of unidimensionality, local item independence, item fit, and presence of differential item functioning (DIF) were evaluated. LQE-CAT-generated scores were assessed for reliability, validity, and administration efficiency. LQE-SF-generated scores were assessed for reliability. RESULTS: The total cohort included 4894 patients (mean [SD] age = 65 [14] years; range = 14-89 years). A set of 20 items was selected for the item bank based on support for its unidimensionality and fit to the item response theory model, with reliability estimates greater than 0.92 for CAT and SF administration modes. No items demonstrated DIF with respect to tested variables. After controlling for scores at intake, scores discriminated among multiple patient groups in clinically logical ways with better outcomes observed for patients who were younger with less chronic symptoms and fewer comorbidities. Scores were responsive to change but the effect size was small (0.4). There were negligible floor and ceiling effects. CAT administration of the item bank required an average of 6.1 items (median = 5). Scores correlated highly with full-bank scores (Pearson correlation coefficient = 0.98). CONCLUSION: Scores on the LQE PROM were reliable, valid, and efficient for assessing perceived physical function of patients with lower quadrant edema. The LQE, CAT, and SF are suitable for research and routine clinical care. Reasons for the small effect size for change scores should be studied. IMPACT: The newly developed LQE PROM was reliable and valid and offered efficient administration modes for assessing perceived physical function of patients with LQE, both for research and routine clinical care in busy outpatient rehabilitation settings. As an item response theory-based measure, the LQE PROM allows administration of condition-specific functional questions with low response burden for patients. The 10-item LQE-SF offers a feasible alternative administration mode when CAT administration is not available. This study supports a transition to PROMs that are based on modern measurement approaches to achieve the combined benefits of high accuracy and efficiency.

Myeloid madness: assessing diagnostic inconsistency between the new WHO and ICC schemes for myelodysplastic/myeloproliferative neoplasms.

The classification of haematological neoplasms recently underwent revision, generating two separate schemes-the International Consensus Classification and the fifth edition of the WHO classification. The new division into separate classification systems presents challenges for haematopathologists, haematologists/oncologists and patients. While it is too early to assess the full clinical impact, we sought to identify diagnostic discordance which may arise from applying separate classification schemes in myeloid neoplasia, and particularly in the challenging category of myelodysplastic syndrome/myeloproliferative neoplasms. A review of 64 such cases found 1 case with a significant discrepancy between the WHO and International Consensus Classification systems, and 9 cases with nominal discrepancies. Confusion from the use of conflicting diagnostic terms represents a potential source of patient harm, increased pathologist workload and burnout and erosion of clinician and patient trust.

The Stroke Upper and Lower Extremity Physical Function Measures Were Supported for Score Reliability, Validity, and Administration Efficiency for Patients Poststroke.

OBJECTIVE: The aims of this study were to (1) evaluate the suitability of newly developed items for calibration into 2 item banks for stroke upper extremity (SUE) and stroke lower extremity (SLE) physical function (PF) patient-reported outcome measures (PROMs) and to (2) assess score reliability and validity and PROM administration efficiency based on computerized adaptive testing (CAT). METHODS: A retrospective longitudinal study involving patients poststroke who were treated in outpatient rehabilitation clinics and responded to 28 and 25 region-specific candidate items addressing tasks related to upper or lower extremity PF, respectively, was conducted. Item response theory (IRT) model assumptions of unidimensionality, local independence, item fit, and presence of differential item functioning were evaluated. CAT-generated scores were assessed for reliability, validity, and administration efficiency, and 10-item short forms were assessed for reliability. RESULTS: Cohorts consisted of 2017 patients with stroke involving the upper extremity and 2107 patients with stroke involving the lower extremity (mean age [SD]: SUE = 62 [14] and SLE = 63 [14]; range = 14-89). Two solutions (SUE: 28-item; SLE: 24-item) supported unidimensionality and fit to the IRT model, with reliability estimates >0.93 for all administration modes. No items demonstrated differential item functioning. Scores discriminated among multiple patient groups in clinically logical ways, with better outcomes observed for patients who were younger, were male, had less chronicity, and had fewer comorbidities. The SUE and SLE, respectively, had 1 and 0.3% floor effects and 4.3 and 1.1% ceiling effects. Change score effect sizes were 0.5 (SUE) and 0.6 (SLE). Simulated CAT scores required an average of 6 (SUE) and 5.6 (SLE) items (median = 5). CONCLUSION: The stroke upper extremity and stroke lower extremity PROM scores were reliable, valid, and efficient and had moderate change effect sizes for assessing PF as perceived by patients poststroke with upper and lower extremity impairments. Scores had negligible floor and acceptable ceiling effects. Based on these results, the stroke PROMs are suitable for research and routine clinical practice. IMPACT: As IRT-based measures, these PROMs support clinical practice guideline recommendations for the use of outcome measures in neurologic physical therapy and the administration of condition-specific functional questions with low response burden for patients. The 10-item short forms offer a feasible alternative administration mode when CAT administration is not available.

Chimeric antigen receptor (CAR) T cells for the treatment of a kidney transplant patient with post-transplant lymphoproliferative disorder (PTLD).

Post-transplant lymphoproliferative disorder (PTLD) is a potentially fatal complication following kidney transplantation, and there is a critical and unmet need for PTLD treatments associated with more pronounced and durable responses. To date, reports on the use of CD19-targeted chimeric antigen receptor (CAR) T (CAR-T) cells in patients after solid organ transplant (SOT) have been anecdotal, clinical presentations and outcomes have been heterogenous, and a longitudinal analysis of CAR-T cell expansion and persistence in PTLD patients has not been reported. Our report describes a patient with a history of renal transplant who received CD19-directed CAR-T cell therapy for the treatment of refractory PTLD, diffuse large B cell lymphoma (DLBCL)-type. We show that even with the background of prolonged immunosuppression for SOT, it is possible to generate autologous CAR-T products capable of expansion and persistence in vivo, without evidence of excess T-cell exhaustion. Our data indicate that CAR-T cells generated from a SOT recipient with PTLD can yield deep remissions without increased toxicity or renal allograft dysfunction. Future clinical studies should build on these findings to investigate CAR-T therapy, including longitudinal monitoring of CAR-T phenotype and function, for PTLD in SOT recipients.