Discordant Responses Research Articles

Development of predictive models for pathological response status in breast cancer after neoadjuvant therapy based on peripheral blood inflammatory indexes

BackgroundAchieving a pathological complete response (pCR) after neoadjuvant therapy (NAT) is considered to be a critical factor for a favourable prognosis in breast cancer. However, discordant pathological complete response (DpCR), characterised by isolated responses in the breast or axillary, represents an intermediate pathological response category between no response and complete response. This study aims to investigate predictive factors and develop models based on peripheral blood inflammatory indexes to more accurately predict NAT outcomes.MethodA total of 789 eligible patients were enrolled in this retrospective study. The patients were randomized into training and validation cohort according to a 7:3 ratio. Lasso and uni/multivariable logistic regression analysis were applied to identify the predictor variables. Two Nomograms combining clinico-pathologic features and peripheral blood inflammatory indexes were developed.ResultMolecular Subtype, HALP, P53, and FAR were used to construct the predictive models for traditional non pCR (T-NpCR) and total-pCR (TpCR). The T-NpCR group was divided into DpCR and non pCR (NpCR) subgroups to construct a new model to more accurately predict NAT outcomes. cN, HALP, FAR, Molecular Subtype, and RMC were used to construct the predictive models for NpCR and DpCR. The receiver operating characteristic (ROC) curves indicate that the model exhibits robust predictive capacity. Clinical Impact Curves (CIC) and Decision Curve Analysis (DCA) indicate that the models present a superior clinical utility.ConclusionHALP and FAR were identified as peripheral blood inflammatory index predictors for accurately predicting NAT outcomes.

Evaluation of CMV T-cell Mediated Immunity in Children with CMV DNAemia After Allogeneic Hematopoietic Cell Transplantation

Abstract Background Cytomegalovirus (CMV) is among the most common infectious complications following allogeneic hematopoietic cell transplantation (allo-HCT). A commercially available CMV T-cell immune panel (CMV-TCIP, Viracor®), reported as percentages of CMV-specific interferon gamma releasing CD4 and CD8 cells (%CMV-CD4 or %CMV-CD8 IFN-γ), may be used to assess CMV cell-mediated immunity (CMV-CMI). However, the utility of this assay among pediatric allo-HCT recipients remains unknown. Methods A retrospective analysis among pediatric allo-HCT recipients (age ≤18 years) from 1/2020 to 11/2023 who developed CMV DNAemia and had CMV-TCIP testing was performed. Per institutional protocol, weekly quantitative plasma CMV PCR was performed until day +100. Clinically significant CMV infection (csCMVi) was defined as CMV viral load (VL) ≥500IU/ml and pre-emptive therapy (PET) was provided for csCMVi. The most frequent indications for CMV-TCIP testing were to evaluate CMV-CMI to inform the need of CMV virus-specific T-cell therapy (CMV-VST) in the setting of resistant/refractory CMV, to monitor CMV-CMI as a proxy of VST expansion post CMV-VST, or to evaluate the need of ongoing secondary antiviral prophylaxis. A %CMV-CD4 or %CMV-CD8 IFN-γ ≤0.2% was categorized as a poor response, whereas a result >0.2% was classified as an adequate response. Specimens with insufficient quality, high background, or discrepant results from %CMV-CD4 or %CMV-CD8 were classified as a discordant response. Demographics, underlying condition, HCT type, conditioning regimen, antiviral agents and use of VST, VL, and CMV-TCIP results were recorded. Descriptive and nonparametric statistics (median, interquartile range [IQR]) were used for analysis. Results Twenty-seven CMV-TCIP results from 10 unique allo-HCT recipients were analyzed. The median age at transplant was 8.5 years (IQR 2.75-14.3), predominantly for hematologic malignancy (70%). CMV donor/recipient (D/R) serostatus were D+/R+ (60%), D-/R+ (30%) and D+/R- (10%). CMV DNAemia developed post-HCT in 80% (8/10) with median onset of 4 days post-HCT (IQR 3-40) and 2 subjects had known DNAemia prior to HCT. Nine (90%) subjects were started on PET for csCMVi, whereas 1 (10%) received antiviral therapy when VL was <500IU/ml. The first CMV-TCIP was obtained at median of 112 days (IQR 42-130) post-HCT. Despite appropriate antiviral therapy, patients with a peak VL ≥500 IU/mL (obtained within 1 week before and after CMV-TCIP testing) demonstrated significantly lower absolute CD4 (median 12 vs. 198 cells/uL, p=0.02) and CD8 (median 79 vs. 443 cells/uL, p=0.04) counts and %CMV-CD4 IFN-γ (0.04% vs. 0.36%, p=0.02) compared to those with a peak VL <500 IU/mL. Conclusion Our results suggest that CMV-CMI, particularly %CMV-CD4 IFN-γ >0.2%, was observed concurrently with downward trending VL, and may serve as a proxy of VST expansion in patients receiving CMV-VSTs. Figure 1A. The distribution of peak VLs over time based on %CMV-CD4 and %CMV-CD8 IFN-γ are demonstrated in Figure 1B. CMV peak VLs were lower with TCIP testing results reported as adequate combined responses compared to those with poor combined responses. In five subjects (50%) who received CMV-VSTs as part of CMV therapy, increased %CMV-CD4 and %CMV-CD8 IFN-γ were observed post-infusion with an observed downward trend in VL.

Whole body magnetic resonance imaging (WB MRI) in the diagnosis and evaluation of the effectiveness of treatment of metastatic prostate cancer: Met-RADS-P system standards

INTRODUCTION: Whole-body magnetic resonance imaging (WB MRI) including diffusion-weighted imaging (DWI) is increasingly used in clinical practice. For metastatic prostate cancer, the radiologic reporting and data system Met-RADS-P (METastasis Reporting and Data System for Prostate Cancer) has been proposed to determine the prevalence of the metastatic process and subsequently evaluate the response to specific treatment based on WB MRI data.OBJECTIVE: To present an overview of the methodological aspects of WB MRI in patients with metastatic prostate cancer in relation to the Met-RADS-P system, to outline its terminology and principles for assessing study results, and to discuss the possibilities of its clinical use.MATERIALS AND METHODS: A search was conducted for publications for the period from January 1, 2017 to December 1, 2023 in Russian and English in the electronic databases eLibrary, Medline, PubMed, using the keywords: «диффузионно-взвешенная томография всего тела», «метастатический рак предстательной железы», «Met-RADS-P», «Whole Body MRI, WB MRI», «Whole Body DWI, WB DWI», «metastatic prostate cancer», supplemented by examination of references in the retrieved articles.RESULTS: Based on the literature data and our own experience, WB MRI protocols in patients with metastatic prostate cancer are described, the algorithm of MR image analysis, the criteria for evaluating the response of metastatic foci in the skeleton, lymph nodes, and internal organs, and the response assessment categories according to the RAC (response assessment categories) scale, as well as summarize the results and discuss the prospects for the clinical use of Met-RADS-P.DISCUSSION: The few publications in the literature using the Met-RADS-P system primarily concern the assessment of its reliability (inter-reader agreement). The authors conclude that it is appropriate to use it in monitoring metastases in patients with castration-resistant prostate cancer, emphasizing the clinical importance of identifying discordant responses after therapy. They also note the obstacles to the widespread introduction of WB MRI imaging into clinical practice, including the duration of the examination procedure and the large volume of diagnostic data that requires significant time for analysis and reporting, which can be overcome by automating the assessment of MR images using artificial intelligence.CONCLUSION: The Met-RADS-P system systematizes the approach to performing and describing WB MRI in patients with advanced prostate cancer, allowing the technique to be reproduced on virtually any modern scanner, from the scan protocol to a standardized report of findings. This makes the WB MRI technique reproducible in a variety of medical settings, and therefore increases its value. Nevertheless, Met-RADS-P is a relatively new system and requires large multicenter clinical trials to confirm its efficacy and representativeness, as well as to level out its shortcomings.

Psychobiological Stress Response Profiles in Current and Remitted Depression: A Person-Centered, Multisystem Approach

BackgroundA dysregulated stress response, including exaggerated affective reactivity and abnormal hypothalamic–pituitary–adrenal (HPA) axis responsivity, has been implicated in the etiology, maintenance and relapse of major depressive disorder (MDD). Among adolescents, discordant affective and physiological stress response profiles have been linked to negative affective outcomes and increased risk for psychopathology. Whether these findings extend to adults with varying degree of MDD risk is unclear, as are possible links to various risk factors. MethodsWe used a person-centered, multisystem approach in a sample of 119 unmedicated adults with current or remitted MDD, as well as individuals without past MDD to evaluate psychobiological stress response profiles. Multi-trajectory modeling was applied to positive affect, negative affect, and salivary cortisol (CORT) levels in response to the Maastricht Acute Stress Test. ResultsAnalyses identified four within-person profiles, one typical, Normative (n=32, 26.9%); and three atypical: CORT Hyperreactivity Affective Stability (n=17, 14.3%), CORT Hyporeactivity Affective Reactivity #1 (n=45, 37.8%), and CORT Hyporeactivity Affective Reactivity #2 (n=25, 21.0%). Validating the assumption of a Normative profile and increased risk for psychopathology in non-normative stress-response profiles, coherent associations emerged between stress response profiles and clinical status, depression severity, anhedonia, perceived stress, childhood adversity and reports of well-being, suggesting increased risk for psychopathology for individuals with a hyperreactive or discordant hyporeactive stress response profiles. ConclusionThis work advances our understanding of stress response mechanisms in MDD and underscores the potential of targeted interventions to enhance resilience and reduce psychopathology based on individual stress response profiles.

Collaborative Large Language Models for Automated Data Extraction in Living Systematic Reviews.

Data extraction from the published literature is the most laborious step in conducting living systematic reviews (LSRs). We aim to build a generalizable, automated data extraction workflow leveraging large language models (LLMs) that mimics the real-world two-reviewer process. A dataset of 10 clinical trials (22 publications) from a published LSR was used, focusing on 23 variables related to trial, population, and outcomes data. The dataset was split into prompt development (n=5) and held-out test sets (n=17). GPT-4-turbo and Claude-3-Opus were used for data extraction. Responses from the two LLMs were compared for concordance. In instances with discordance, original responses from each LLM were provided to the other LLM for cross-critique. Evaluation metrics, including accuracy, were used to assess performance against the manually curated gold standard. In the prompt development set, 110 (96%) responses were concordant, achieving an accuracy of 0.99 against the gold standard. In the test set, 342 (87%) responses were concordant. The accuracy of the concordant responses was 0.94. The accuracy of the discordant responses was 0.41 for GPT-4-turbo and 0.50 for Claude-3-Opus. Of the 49 discordant responses, 25 (51%) became concordant after cross-critique, with an increase in accuracy to 0.76. Concordant responses by the LLMs are likely to be accurate. In instances of discordant responses, cross-critique can further increase the accuracy. Large language models, when simulated in a collaborative, two-reviewer workflow, can extract data with reasonable performance, enabling truly 'living' systematic reviews.

Alignment of parent-proxy report and teen self-report of adverse childhood experiences among U.S. teens

PurposeData on adverse childhood experiences (ACEs) among teens is collected using a single informant, a parent-proxy, or teen self-report. Little is known about alignment between these approaches. MethodsSurveys were administered online to teens ages 15–17 and their parents (n = 522 dyads) using the AmeriSpeak panel. We present descriptive statistics on the prevalence and measures agreement for 18 ACEs based on teen self-report and parent-proxy report. We fit multivariable models examining associations between teen and household demographic characteristics and discordance in ACE report. ResultsBased on teen-self report and parent-proxy report, cumulative and individual ACE prevalence was overall similar. However, discordance was found in individual ACE reports within teen-parent dyads (discordance ranged: 2.9–21.2 %). Lowest agreement was among ACEs related to abuse, neglect, and violence victimization and highest among household challenges. Furthermore, parent-teen dyads with LGB+ youth (vs. heterosexual) and Black, Hispanic, and multiracial or another race (vs. White) youth were more likely to have discordant responses among several ACEs. ConclusionsSurveillance and programmatic efforts should consider the type of ACE and the reporter when using data to inform prevention strategies. Teen self-report for abuse, neglect, and violence victimization and community challenges ACEs are particularly important to capture.

Intra-epidermal electrically evoked potentials are sensitive to detect degenerative cervical myelopathy suggesting their spinothalamic propagation

ObjectiveDegenerative cervical myelopathy (DCM) is a centromedullary spinal cord disorder mainly affecting crossing fibers. While contact heat evoked potentials (CHEPs) are sensitive in detecting DCM by testing spinothalamic integrity, somatosensory evoked potentials (dSSEPs) show unaffected dorsal column conduction. Intra-epidermal electrically evoked potentials (IEEPs) have unknown spinal propagation after noxious stimulation. We investigated (1) the spinothalamic tract propagation and (2) the discriminative power in detecting spinal pathology of IEEPs compared to CHEPs and dSSEPs in DCM. MethodsDCM was diagnosed by neurological examination regarding stenosis (MRI). Stimulation of C6, C8, and T4 dermatomes yielded dSSEPs, CHEPs, and IEEPs. (1) Spinal propagation was assessed through concordant or discordant responses, and (2) discriminative power was determined using receiver operating characteristic curves (ROC). ResultsTwenty-seven patients (8F, 56 ± 12yrs) with DCM were analyzed and compared to age-matched healthy controls. IEEPs were abnormal in 43–54%, CHEPs in 37–69%, and dSSEPs in 4–12%. IEEPs showed high concordance with abnormalities of CHEPs (62–69%). ROC analyses showed good discriminative power of CHEPs and IEEPs contrary to dSSEPs. ConclusionsThe concordance of abnormal responses of CHEPs and IEEPs contrary to dSSEPs suggests spinothalamic propagation of IEEPs. SignificanceMinimal differences between CHEPs and IEEPs suggest complementary potential by the combined testing of spinothalamic tract integrity.

Comparison of two survey methods for estimating unplanned pregnancy, Bangladesh.

To compare the prevalence of unintended pregnancy measured by the Demographic and Health Survey (DHS) and the London Measure of Unplanned Pregnancy in Bangladesh, and explore the extent of discordance between the measures and the factors associated with the discordance. In 2023, we conducted a cross-sectional survey in four randomly selected districts in Bangladesh: Kurigram, Mymensingh, Pabna and Satkhira. We randomly selected 20 hospitals, five from each district. We collected data from 1200 women who had recently delivered a baby and were visiting the hospitals for postnatal care. We interviewed the women about their pregnancy intention in their last pregnancy using questions in the DHS and the London Measure of Unplanned Pregnancy and examined the discordance in their responses. We used multivariable logistic regression analysis to identify factors associated with discordant responses in reported pregnancy intention. The prevalence of unintended pregnancy was 24.3% (292/1200) using the DHS measure and 31.0% (373/1200) using the London Measure of Unplanned Pregnancy. Discordance in responses to pregnancy intention between the two measures was 27.1% (325/1200). Factors associated with discordance were older age, female sex of the last child born, having more than two children, being in a poorer wealth quintile, living in a rural area and living in Kurigram district. The prevalence of unintended pregnancy in Bangladesh measured by the DHS measure may be an underestimate, suggesting that the adverse effects of unintended pregnancy are greater than realized and emphasizing the need to bolster Bangladesh's family planning programme.

DIPG-60. OPERATIVE PERFORMANCE OF RAPNO DIPG CRITERIA FOR IMAGING REVIEW- A STUDY FROM THE INTERNATIONAL DIPG/DMG REGISTRY (IDIPGR)

Abstract BACKGROUND The Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group for diffuse intrinsic pontine glioma (DIPG) recently published its recommendations. Response criteria incorporate radiologic findings, neurologic status, and use of concurrent steroids and antiangiogenic drugs to define response. To test the operative performance of the imaging component, we retrospectively applied RAPNO DIPG recommendations to a convenience sample of 46 patients enrolled in the International DIPG/DMG Registry(IDIPGR). METHODS MRIs were independently reviewed by 2 pediatric neuro-radiologists. These measurements were analyzed utilizing RAPNO DIPG imaging criteria to categorize the response as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). For PR evaluation, each MRI was compared to the baseline MRI, and for PD evaluation, each MRI was compared to the MRI with the smallest cross-sectional measurement. The response category for each MRI was compared between 2 neuro-radiologists and was classified as concordant if they agreed, minor discordant if one reported SD and the other reported PR or PD, and major discordant if one reported PR and the other reported PD. RESULTS A total of 276 paired MRIs were analyzed. Sixty-seven percent of the time, the analyzed response assessment was concordant. In 33% discordant reads, 26% were minor discordant, and 7% were major discordant. There were no CRs reported. Further analysis of minor discordant cases showed that 62% of these cases were within 10% of the boundary for PR or PD. The median difference between 2 neuro-radiologists’ long axis measurements was 2 mm (range 0-27mm) and short axis measurements was 2mm (range 0-29mm). These small differences in measurements account for all discordant response categories between 2 neuro-oncologists. CONCLUSION This study demonstrated that RAPNO DIPG imaging criteria can be successfully applied with high concordance between readers. When discordant, measurements were largely at the boundaries of response type.

Assessing ChatGPT's potential as a clinical resource for medical oncologists: An evaluation with board-style questions and real-world patient cases.

e13628 Background: ChatGPT is a conversational artificial intelligence (AI) model that learns from massive text-based datasets and then responds to user input, which often involves completing tasks or answering questions. Recent studies showed ChatGPT’s success in passing multiple specialty medical licensing and board examinations, showcasing its promising capabilities in the medical domain. Here, we investigated ChatGPT's potential as a swift and reliable information source for medical oncologists using board examination style questions and real patient cases. Methods: We randomly selected 121 board-style questions from the American Society of Clinical Oncology Self-Evaluation Program (ASCO SEP). The questions were entered into ChatGPT in both multiple-choice (MC) and open-ended (OE) prompts. ChatGPT’s answers and explanations were evaluated for accuracy and concordance. Non-inferiority analysis was performed with power of 80% at α = 0.05 and non-inferiority margin set at 70% correct answers given the historical board exam pass rate of about 65% correct answers. For subgroup analysis, the questions were categorized by tested competency and primary tumor pathology. ChatGPT was also given 10 questions derived from real patient cases. We compared its responses to the answers provided by experienced oncologists to determine accuracy and practical applicability. Results: ChatGPT answered 75 (62.0%) MC queries correctly. Among the correctly answered queries, 2 responses contained faulty explanations. Such inaccurate or discordant explanations were found in 26 of the 46 incorrectly answered queries. In OE prompts, ChatGPT answered 53 (43.8%) questions correctly with correct explanations for all. Of the 68 incorrect responses, 32 of them contained inaccurate or discordant explanations. Subgroup analysis suggested varying performance across the categories. The best performance was seen with malignant hematology (81.8% of MC and 72.8% of OE prompts answered correctly) while the weakest performance was seen with genitourinary malignancies (60% of MC and 20% of OE prompts answered correctly). As for the real-world patient case questions, responses from ChatGPT and the clinicians were concordant in 5 questions. None of the discordant responses contained inaccurate information while 80% of the concordant responses contained sufficient details to assist with patient management decisions. Conclusions: ChatGPT's performance fell short of the non-inferiority margin, highlighting the challenges with incorporating AI in the rapidly evolving field of medical oncology. Despite the limitations, ChatGPT’s partial success, in both board-style and real-world patient care questions, affirms its potential for clinical utility in future.

The relationship between imaging features, therapeutic response, and overall survival in pediatric diffuse intrinsic pontine glioma

We aimed to evaluate the relationship between imaging features, therapeutic responses (comparative cross-product and volumetric measurements), and overall survival (OS) in pediatric diffuse intrinsic pontine glioma (DIPG). A total of 134 patients (≤ 18 years) diagnosed with DIPG were included. Univariate and multivariate analyses were performed to evaluate correlations of clinical and imaging features and therapeutic responses with OS. The correlation between cross-product (CP) and volume thresholds in partial response (PR) was evaluated by linear regression. The log-rank test was used to compare OS patients with discordant therapeutic response classifications and those with concordant classifications. In univariate analysis, characteristics related to worse OS included lower Karnofsky, larger extrapontine extension, ring-enhancement, necrosis, non-PR, and increased ring enhancement post-radiotherapy. In the multivariate analysis, Karnofsky, necrosis, extrapontine extension, and therapeutic response can predict OS. A 25% CP reduction (PR) correlated with a 32% volume reduction (R2 = 0.888). Eight patients had discordant therapeutic response classifications according to CP (25%) and volume (32%). This eight patients’ median survival time was 13.0 months, significantly higher than that in the non-PR group (8.9 months), in which responses were consistently classified as non-PR based on CP (25%) and volume (32%). We identified correlations between imaging features, therapeutic responses, and OS; this information is crucial for future clinical trials. Tumor volume may represent the DIPG growth pattern more accurately than CP measurement and can be used to evaluate therapeutic response.

Abstract 7518: Neoadjuvant-adjuvant pembrolizumab in resectable advanced basal cell carcinoma of the head and neck: An open-label, single-arm, phase 1b trial

Abstract Introduction: BCC is a common form of skin cancer that shares treatment-related aspects with the more well-studied skin malignancy, melanoma, including sensitivity to anti-PD-1/PD-L1 immunotherapy. However, despite major advances in peri-operative immunotherapy for melanoma, little is known regarding these strategies in BCC. This phase 1B, single-arm study evaluated neoadjuvant-adjuvant treatment with pembrolizumab (PEMBRO) together with standard of care (SOC) resection in advanced BCC of the head and neck. Methods: Eligible patients had resectable, locally advanced BCC of the head and neck, defined by at least one of the following high-risk characteristics: a measurement of ≥ 20 mm, indication for post-operative radiation, or perineural invasion (PNI) in multiple nerves. Patients were naive to hedgehog inhibitors (HHI) and had an ECOG of 0 or 1. All patients received IV PEMBRO at a dose of 200 mg every 3 weeks for a total of 4 cycles, then within 4 weeks underwent a SOC resection followed by adjuvant PEMBRO until a total of 17 cycles was completed. After the 30-day post treatment safety follow-up visit, patients were followed for up to 5 years post-operatively. The primary endpoint was pathological response rate. Secondary endpoints included RECIST response by radiographic or physical exam, adverse events (AE), and recurrence-free survival (RFS). Results: 13 patients were enrolled in the trial from July 2020 to May 2023, and received at least one dose of PEMBRO. Two patients withdrew from the trial after one dose of PEMBRO, one following treatment-related G3 hepatitis and a second due to an unrelated medical complication (cholecystitis). Out of 11 patients undergoing surgical resection, 10 patients received 4 out of 4 and 1 patient received 3 out of 4 planned cycles of neoadjuvant PEMBRO (investigator preference without new related AE). Pathological complete response (pCR) was observed in 3 patients (23%). For those with RECIST measurable disease, 2 patients demonstrated a complete response (CR), 1 patient a partial response (PR), and 5 patients showed stable disease (SD). Two patients had progressive disease (PD). One patient with a complete pathologic response had a discordant RECIST response with PD noted radiographically. All 13 patients experienced at least one AE of G1 or 2. The highest grade of related AEs were noted in 2 patients with grade 3 hepatitis and pruritus respectively that resolved with supportive therapy. As of November 2023, the median follow-up time is 17.6 months with no recurrences noted. Conclusions: Neoadjuvant-adjuvant PEMBRO shows promising efficacy and an acceptable safety profile in resectable advanced BCC of the head and neck. Given these positive results and the healthcare burden BCC accounts for, these findings warrant further study. Citation Format: Grace M. Jones, James Isaacs, Lucy Boyce Kennedy, Jennifer Ko, Allison Vidimos, Alok Vij, Christine Poblete-Lopez, Jennifer Lucas, Yee Peng Phoon, Melissa McEnery-Stonelake, Jon Meine, Thach-Giao Truong, Pauline Funchain, Brian Gastman. Neoadjuvant-adjuvant pembrolizumab in resectable advanced basal cell carcinoma of the head and neck: An open-label, single-arm, phase 1b trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7518.

Discordant responses of bone formation and absorption markers in Japanese infants with vitamin D deficiency: a comprehensive matched case-control study.

Vitamin D deficiency during infancy has been associated with increased bone turnover rate and bone mineral loss. However, few studies have examined bone turnover markers (BTMs) for both bone formation and resorption in infants with vitamin D deficiency. Here, we analyzed serum concentrations of 25OHD, intact parathormone (iPTH), and BTMs including total alkaline phosphatase (ALP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), and serum type I collagen N-telopeptide (NTx) as well as basic clinical characteristics of 456 infants (626 samples) aged less than 12mo born at Saitama City Hospital, Japan (latitude 35.9° North) between January 2021 and December 2022. One hundred sixteen infants (147 samples) were classified as having vitamin D deficiency (25OHD < 12.0ng/mL), and 340 infants (479 samples) had sufficient vitamin D levels (25OHD ≥ 12.0ng/mL). In addition to 25OHD and ALP, both TRACP-5b and sNTx were measured in 331 infants (418 samples), while 90 infants (105 samples) had only TRACP-5b measured and 101 infants (103 samples) had only sNTx measured. Statistical comparison of 104 subjects each in the vitamin D deficiency and sufficiency groups after matching for the background characteristics revealed that the vitamin D deficiency group had significantly higher levels of ALP and iPTH compared with the sufficiency group (P = <.0001, .0012, respectively). However, no significant differences were found in TRACP-5b and NTx levels between the 2 groups (P = .19, .08, respectively). Our findings suggest discordant responses between bone formation and resorption markers in subclinical vitamin D deficiency during infancy.

Interim FDG-PET improves treatment failure prediction in primary central nervous system lymphoma: An LOC network prospective multicentric study.

The purpose of our study was to assess the predictive and prognostic role of 2-18F-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/MRI during high-dose methotrexate-based chemotherapy (HD-MBC) in de novo primary central nervous system lymphoma (PCNSL) patients aged 60 and above. This prospective multicentric ancillary study included 65 immunocompetent patients who received induction HD-MBC as part of the BLOCAGE01 phase III trial. FDG-PET/MRI were acquired at baseline, post 2 cycles (PET/MRI2), and posttreatment (PET/MRI3). FDG-PET response was dichotomized with "positive" indicating persistent tumor uptake higher than the contralateral mirroring brain region. Performances of FDG-PET and International PCNSL Collaborative Group criteria in predicting induction response, progression-free survival (PFS), and overall survival (OS) were compared. Of the 48 PET2 scans performed, 9 were positive and aligned with a partial response (PR) on MRI2. Among these, 8 (89%) progressed by the end of the induction phase. In contrast, 35/39 (90%) of PET2-negative patients achieved complete response (CR). Among the 18 discordant responses at interim (PETCR/MRIPR), 83% ultimately achieved CR. Eighty-seven percent of the PET2-negative patients were disease free at 6 months versus 11% of the PET2-positive patients (P < .001). The MRI2 response did not significantly differentiate patients based on their PFS, regardless of whether they were in CR or PR. Both PET2 and MRI2 independently predicted OS in multivariate analysis, with PET2 showing a stronger association. Our study highlights the potential of interim FDG-PET for early management of PCNSL patients. Response-driven treatment based on PET2 may guide future clinical trials. LOCALYZE, NCT03582254, ancillary of phase III clinical trial BLOCAGE01, NCT02313389 (Registered July 10, 2018-retrospectively registered) https://clinicaltrials.gov/ct2/show/NCT03582254?term=LOCALYZE&draw=2&rank=1.

Brief Report: In cART-Treated HIV-Infected Patients, Immunologic Failure Is Associated With a High Myeloid-Derived Suppressor Cell Frequency.

During HIV infection, effective combined antiretroviral therapy suppresses viral replication and restores the number of circulating CD4+ T cells. However, 15%-30% of treated patients show a discordant response to combined antiretroviral therapy. Myeloid-derived suppressor cells (MDSC) are expanded in HIV+ patients; to better understand the role of MDSC on CD4 T-cell recovery, we evaluated the frequency of MDSC in HIV+ patients under combined antiretroviral therapy and its association with immunologic response. We enrolled 60 HIV+ patients, including complete responders (R, n = 44), virologic nonresponders (VNR, n = 5), and immunologic nonresponders (INR, n = 11). The frequency of circulating MDSC and the percentage of activated and naïve CD4 T cells were evaluated by flow cytometry. Plasmatic cytokine levels were analyzed by automated ELISA. As previously observed, polymorphonuclear MDSC (PMN-MDSC) frequency was higher in HIV+ patients compared with healthy donors. Furthermore, PMN-MDSC percentage was higher in INR than R patients, and a significant association between MDSC frequency and immunologic failure was confirmed by a receiver operator characteristic analysis. Accordingly, an inverse correlation was found between the percentages of PMN-MDSC and naïve CD4 T cells. A positive correlation was observed between PMN-MDSC frequency and the percentage of human leucocyte antigen locus DR + CD4 T cells and the plasmatic level of IL-1β and IL-8. Our results show that a high frequency of PMN-MDSC persists in INR, possibly because of immune activation, contributing to CD4 T-cell recovery failure. These findings further highlight the detrimental role of MDSC during HIV infection, suggesting these cells as a possible new therapeutic target.

Survey Uses May Influence Survey Responses.

Traditional validation processes for psychological surveys tend to focus on analyzing item responses instead of the cognitive processes that participants use to generate these responses. When screening for invalid responses, researchers typically focus on participants who manipulate their answers for personal gain or respond carelessly. In this paper, we introduce a new invalid response process, discordant responding, that arises when participants disagree with the use of the survey and discuss similarities and differences between this response style and protective responding. Results show that nearly all participants reflect on the intended uses of an assessment when responding to items and may decline to respond or modify their responses if they are not comfortable with the way the results will be used. Incidentally, we also find that participants may misread survey instructions if they are not interactive. We introduce a short screener to detect invalid responses, the discordant response identifiers (DRI), which provides researchers with a simple validity tool to use when validating surveys. Finally, we provide recommendations about how researchers may use these findings to design surveys that reduce this response manipulation in the first place.

Factors Underlying Impaired Organ Recovery Despite a Deep Hematologic Response in Patients with Systemic AL Amyloidosis

Background: Amyloid-mediated organ dysfunction is the main determinant of survival for patients with light chain (AL) amyloidosis. Reducing the production of amyloidogenic light chains with plasma cell-directed therapy is a prerequisite for organ response. Despite achieving a hematologic complete response (hemCR), some patients have enduring organ dysfunction. A better grasp of the mechanisms underlying organ recovery is needed, especially as attention moves to novel therapeutics that trigger removal of existing amyloid deposits, and as graded organ response criteria to gauge improvement more precisely than traditional binary systems are adopted. Aims: We designed this study to identify the (1) rates of organ non-response and (2) possible reasons for impaired organ recovery in patients with AL amyloidosis with hemCR after treatment. Methods: Patients with biopsy confirmed AL amyloidosis who presented to our center for post-treatment assessment between February 2019 and June 2023 were included if they had major organ involvement (heart, kidney and/or liver) and were evaluable for organ response (Palladini, 2012). Graded cardiac response was assessed by validated criteria (Muchtar, 2022). We excluded patients who received amyloid fibril-targeted antibody therapies. To eliminate the possibility of insufficient hematologic response as a confounder for organ non-response, we focused only on patients with hemCR. Organ response was measured as best response &amp;gt;3 months from hemCR achievement. Reasons for organ non-response were postulated by our multidisciplinary team after extensive workup and review of clinical data. Results: Among 143 patients with hemCR, the median age at diagnosis was 58 years (range 30-78); 94 (66%) were male; and 24 (17%) identified as non-white race. Kidney, heart and liver involvement was present in 117 (82%), 68 (48%) and 17 (12%) patients, respectively; 54 (38%) had ≥2 major organs affected. Final treatment granting hemCR was high-dose melphalan and stem cell transplantation for 49 (34%); bortezomib-based for 37 (26%); daratumumab monotherapy for 31 (22%); daratumumab-CyBorD for 18 (13%); and an immunomodulatory drug for 8 (6%) patients; 58 (41%) required ≥2 lines of therapy to achieve hemCR. Failure to attain organ response was observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) of patients with kidney, heart and liver involvement, respectively. Of 42 patients with both kidney and heart involvement, 21 (50%) had concordant responses of both organs; 6 (14%) had concordant non-responses; and 15 (36%) had discordant responses. Among 49 heart responders, 14 (29%) attained CarCR (nadir BNP ≤80 pg/mL); 16 (33%) CarVGPR (&amp;gt;60% reduction); and 19 (39%) CarPR (31-60% reduction); 40/77 (52%) kidney responders attained proteinuria &amp;lt;500 mg/24h. Clinical features of organ non-responders in relation to responders are reported in Table 1. Notably, kidney non-responders had more advanced disease at baseline, whereas heart non-responders more often had lambda-typic amyloidogenic light chains. Among kidney non-responders, 2 had stable and another 2 had rising proteinuria level; the remaining 36 had improved proteinuria but were categorized as non-response due to &amp;gt;25% worsening of eGFR. Among heart non-responders, 5 had stable elevation of BNP and 14 experienced organ progression (BNP increase &amp;gt;30% and &amp;gt;50 pg/mL); 2 required heart transplantation. The two most common factors believed to underlie kidney non-response were permanent kidney damage at diagnosis needing dialysis and treatment-related toxicity (Table 2). For 10 (25%) kidney non-responders, there was no apparent explanation, 7 of whom had detectable measurable residual disease (MRD) by multiparametric flow cytometry. Most cases of heart non-response had no apparent explanation; 6 of these 8 patients had detectable MRD. Conclusions: Despite effective treatment of the plasma cell clone, a considerable number of patients with AL amyloidosis in hemCR have enduring organ dysfunction. We found that the reasons for organ non-response differed across organ systems. Response was not always concordant for all involved organs, suggesting heterogeneity in organ biology in terms of mechanisms for amyloid-mediated injury and intrinsic ability to repair. Careful scrutiny of reasons for organ non-response is warranted before providing further hematologic treatments, which may be ineffective for organ recovery.

Communication and fear of recurrence in colorectal cancer survivors and their partners.

502 Background: Little is known about how colorectal (CRC) survivors and their partners communicate about cancer or about their fears of recurrence. CRC survivors who are discordant with their partner in communication about cancer and fear of recurrence may have worse health-related quality of life (HrQoL), but this is not known. Methods: From 2019-2020 we surveyed survivors of stage III CRC diagnosed 2014-2018 at an academic cancer center, a community oncology practice, and the Georgia cancer registry, and their domestic partners. We measured dyadic communication about cancer using the 23-item Lewis Mutuality and Interpersonal Sensitivity Scale (MIS). To measure fear of recurrence, we asked survivors and partners 3 questions about how often worry about recurrence has a negative psychosocial impact in their life. We measured survivors’ HrQoL using the PROMIS-29+2 profile, v 2.1. We used bivariate analyses and multivariable logistic regressions to 1) compare paired survivor and partner responses to individual items about communication in the MIS and compare fear of recurrence scores, 2) describe characteristics of dyads who were discordant in communication and fear of recurrence, 3) assess associations between survivors’ HrQoL and discordance in communication and fear of recurrence. Results: 501/986 eligible survivors returned surveys (51% response rate). 428 survivors (86%) had a partner; 311 partners (73%) returned surveys. We analyzed data from 307 paired survivor-partner dyads. Survivors were mostly &gt; age 50 (88%), male (64%), white (77%) and had at least some college education (77%). 6/23 MIS items (23%) evoked discordant responses in ≥30% of dyads (Table). Most dyads were concordant in responses to fear of recurrence questions. Greater dyadic discordance in communication and fear of recurrence was differentially associated (p&lt;0.05) with some survivor factors and partner factors (communication: female survivor gender and greater partner education; recurrence: younger survivor age). Worse survivor HRQoL was associated with greater discordance in fear of recurrence (p&lt;0.01) but not with discordance in communication (p=0.55). Conclusions: There is dyadic discordance in communication about negative feelings, sadness, and fear about the cancer. Dyadic discordance in fear of recurrence is associated with worse survivor HRQoL. Clinicians should be aware of and acknowledge negative feelings and fear during surveillance.[Table: see text]

PREPONDERANCE EFFECT OF TH1 CYTOKINES IN HIV PATIENTS UNDERGOING HAART

Infection with HIV results in discordant immunological response characterized by dysregualtion of cytokines and adecrease in CD4+ T cells. As HIV progresses to AIDS, there is a switch in Th1 to Th2 cytokines. In this study, plasmacytokine levels were compared between newly diagnosed HIV-positive HAART naïve patients and HAART undergoingpatients. Additionally, the association between plasma cytokine levels and CD4+ T cell count was examined. 160 HIVpositiveindividuals were enrolled for the study, of which 80 were HAART naïve and 80 were undergoing HAART forover six months since diagnosis. The plasma cytokine levels of IFN Ɣ, IL 2, IL 4 and IL 10 were analysed using ELISAand CD4+ T cell counts were assessed using flow cytometry. Comparing the HAART naïve patients to HAARTundergoing group, the plasma cytokine concentrations of IL 4 and IL 10 was considerably higher in HAART naïvepatients while IFN Ɣ and IL 2 concentration was greater in HAART undergoing patients. Similarly, while examining therelationship between CD4+ T cells and plasma cytokine levels, it was discovered that IFN Ɣ significantly correlated withCD4+ T cells in HAART-naive individuals as opposed to IL 2, IL 4, and IL 10. Therefore, an increase in Th1 cytokinesover Th2 cytokines and the restoration of immune response are indicators of successful anti-retroviral therapy

Peritumoral Immune-suppressive Mechanisms Impede Intratumoral Lymphocyte Infiltration into Colorectal Cancer Liver versus Lung Metastases.

Our results demonstrate that functional status and spatial distribution of immune cells vary significantly across different metastatic sites in MSS colorectal cancer. These findings suggest that metastatic site-dependent immune contexture may underlie discordant responses to ICI therapy in patients with MSS colorectal cancer.