Active Residents in Care Homes (ARCH) : a holistic approach to promoting and encouraging meaningful activity for residents living in care homes (innovative practice)

The active residents in care homes intervention aim to promote meaningful activity among care home residents. Residents, family members and staff from three residential care homes in South London are participating. It is a whole systems approach which involves formal and 'on the floor' training to empower care home staff to facilitate activity. Training is delivered by two occupational therapists, a physiotherapist and a rehabilitation assistant. This paper describes the active residents in care homes intervention, the evaluation methods and discusses some preliminary findings

High mobility group box 1 in human cancer

High mobility group box 1 (HMGB1) is an extremely versatile protein that is located predominantly in the nucleus of quiescent eukaryotic cells, where it is critically involved in maintaining genomic structure and function. During cellular stress, however, this multifaceted, cytokine-like protein undergoes posttranslational modifications that promote its translocation to the cytosol, from where it is released extracellularly, either actively or passively, according to cell type and stressor. In the extracellular milieu, HMGB1 triggers innate inflammatory responses that may be beneficial or harmful, depending on the magnitude and duration of release of this pro-inflammatory protein at sites of tissue injury. Heightened awareness of the potentially harmful activities of HMGB1, together with a considerable body of innovative, recent research, have revealed that excessive production of HMGB1, resulting from misdirected, chronic inflammatory responses, appears to contribute to all the stages of tumorigenesis. In the setting of established cancers, the production of HMGB1 by tumor cells per se may also exacerbate inflammation-related immunosuppression. These pro-inflammatory mechanisms of HMGB1-orchestrated tumorigenesis, as well as the prognostic potential of detection of elevated expression of this protein in the tumor microenvironment, represent the major thrusts of this review.http://www.mdpi.com/journal/cellspm2020Immunolog

Hyaluronan turnover and hypoxic brown adipocytic differentiation are co-localized with ossification in calcified human aortic valves

The calcification process in aortic stenosis has garnered considerable interest but only limited investigation into selected signaling pathways. This study investigated mechanisms related to hypoxia, hyaluronan homeostasis, brown adipocytic differentiation, and ossification within calcified valves. Surgically explanted calcified aortic valves (nﾠ=ﾠ14) were immunostained for markers relevant to these mechanisms and evaluated in the center (NodCtr) and edge (NodEdge) of the calcified nodule (NodCtr), tissue directly surrounding nodule (NodSurr); center and tissue surrounding small ﾓprenodulesﾔ (PreNod, PreNodSurr); and normal fibrosa layer (CollFibr). Pearson correlations were determined between staining intensities of markers within regions. Ossification markers primarily localized to NodCtr and NodEdge, along with markers related to hyaluronan turnover and hypoxia. Markers of brown adipocytic differentiation were frequently co-localized with markers of hypoxia. In NodCtr and NodSurr, brown fat and ossification markers correlated with hyaluronidase-1, whereas these markers, as well as hypoxia, correlated with hyaluronan synthases in NodEdge. The protein product of tumor necrosis factor-? stimulated gene-6 strongly correlated with ossification markers and hyaluronidase in the regions surrounding the nodules (NodSurr, PreNodSurr). In conclusion, this study suggests roles for hyaluronan homeostasis and the promotion of hypoxia by cells demonstrating brown fat markers in calcific aortic valve disease

Systemic immune dysregulation in early breast cancer is associated with decreased plasma levels of both soluble co-inhibitory and co-stimulatory immune checkpoint molecules

Breast cancer cells exploit the up-regulation or down-regulation of immune checkpoint proteins to evade anti-tumor immune responses. To explore the possible involvement of this mechanism in promoting systemic immunosuppression, the pre-treatment levels of soluble co-inhibitory and co-stimulatory immune checkpoint molecules, as well as those of cytokines, chemokines, and growth factors were measured in 98 newly diagnosed breast cancer patients and compared with those of 45 healthy controls using multiplex bead array and ELISA technologies. Plasma concentrations of the co-stimulatory immune checkpoints, GITR, GITRL, CD27, CD28, CD40, CD80, CD86 and ICOS, as well as the co-inhibitory molecules, PD-L1, CTLA-4 and TIM-3, were all significantly lower in early breast cancer patients compared to healthy controls, as were those of HVEM and sTLR-2, whereas the plasma concentrations of CX3CL1 (fractalkine), CCL5 (RANTES) and those of the growth factors, M-CSF, FGF-21 and GDF-15 were significantly increased. However, when analyzed according to the patients’ breast cancer characteristics, these being triple negative breast cancer (TNBC) vs. non-TNBC, tumor size, stage, nodal status and age, no significant differences were detected between the plasma levels of the various immune checkpoint molecules, cytokines, chemokines and growth factors. Additionally, none of these biomarkers correlated with pathological complete response. This study has identified low plasma levels of soluble co-stimulatory and co-inhibitory immune checkpoint molecules in newly diagnosed, non-metastatic breast cancer patients compared to healthy controls, which is a novel finding seemingly consistent with a state of systemic immune dysregulation. Plausible mechanisms include an association with elevated levels of M-CSF and CCL5, implicating the involvement of immune suppressor cells of the M2-macrophage/monocyte phenotype as possible drivers of this state of systemic immune quiescence/dysregulation.The Cancer Association of South Africa (CANSA).https://www.frontiersin.org/journals/immunologydm2022Immunolog

Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3

DATA AVAILABILITY STATEMENT : The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.SUPPLEMETARY MATERIAL : SUPPLEMENTARY FIGURE 1 Box and whisker plots depicting the progressive changes in the median plasma concentrations (with 95% confidence limits) of three co-inhibitory immune checkpoints (BTLA, CTLA-4 and PD-1) throughout the course of neoadjuvant chemotherapy (NAC) (pre-treatment/diagnosis, post-NAC and post-surgery) in relation to the corresponding median values of the control subjects. The p values represent the comparison between pre-treatment/ diagnosis and post-NAC values.SUPPLEMENTARY FIGURE 2 Box and whisker plots depicting the progressive changes in the median plasma concentrations (with 95% confidence limits) of the remaining four co-stimulatory immune checkpoints (CD28, CD40, CD86 and GITRL) throughout the course of neoadjuvant chemotherapy (NAC) (pretreatment/ diagnosis, post-NAC and post-surgery) in relation to the corresponding median values of the control subjects. The p values represent the comparison between the pre-treatment/diagnosis and post- NAC values.SUPPLEMENTARY FIGURE 3 Box and whisker plots depicting the progressive changes in the median plasma concentrations (with 95% confidence limits) of the two dual-activity immune checkpoints (TLR-2 and HVEM) throughout the course of neoadjuvant chemotherapy (NAC) (pre-treatment/diagnosis, post-NAC and post-surgery) in relation to the corresponding median values of the control subjects. The p values represent the comparison between the pre-treatment/ diagnosis and post-NAC values.SUPPLEMENTARY FIGURE 4 Histological photomicrographs of pre-treatment tissue of a patient who attained a pathological complete response. (A) x20 Magnification: Core biopsy hematoxylin and eosin (H&E) stained slide breast carcinoma no special type (NST), prior to therapy. (B) X10 Magnification: Positive ECadherin immunoperoxidase stain of tumor confirming ductal differentiation. (C) x20 Magnification: Estrogen receptor immunoperoxidase stain of tumor, showing no staining (ER negative).SUPPLEMENTARY FIGURE 5 Histological photomicrographs of pre-treatment tissue of a patient who attained a pathological complete response. (A) x20 Magnification: Progesterone receptor immunoperoxidase stain of tumor (PR negative). (B) x20 Magnification: HER2 immunoperoxidase stain of tumor (HER2 negative). (C) x20 Magnification :Ki67 immunoperoxidase stain of tumor (90% of tumor cells staining positive).SUPPLEMENTARY FIGURE 6 Histological photomicrographs of post-surgery tissue obtained during surgery of a patient who attained a pathological complete response. (A) X10 Magnification: Tumor bed post chemotherapy showing stromal fibrosis and dystrophic calcification with NO tumor cells H&E. (B) X10 Magnification: Tumor bed post chemotherapy showing loose fibrovascular response and elastosis with NO tumor cells H&E. (C) x20 Magnification: MNF116 (broad pancytokeratin) immunoperoxidase stain of tumor bed post chemotherapy showing NO residual staining tumor cells.Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p<0.021-p<0.0001; and p<0.008-p<0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p<0.04-p<0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PDL1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p<0.03 and p<0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC.The Cancer Association of South Africa (CANSA).http://www.frontiersin.org/Oncologyam2024ImmunologySDG-03:Good heatlh and well-bein

Active Residents in Care Homes (ARCH) : study protocol to investigate the implementation and outcomes of a whole-systems activity programme in residential care homes for older people

OBJECTIVES: To evaluate the effectiveness, acceptability and costs of Active Residents in Care Homes, ARCH - a programme aiming to increase opportunities for activity in older care home residents. DESIGN: Feasibility study. SETTING: Residential care homes for older people. PARTICIPANTS: 10-15 residents, staff and family members will be recruited in each of the three participating care homes. INTERVENTION: ARCH is a 12-month 'whole-systems' programme implemented by occupational therapists and physiotherapists. They will conduct a comprehensive assessment of each care home, considering the physical environment, working practices and organisation structure as well as residents' individual needs, and recommend ways to address barriers and increase residents' activity levels. The therapists will then work with staff to improve understanding of the issues, instigate training, environmental, organisational and working practice changes as necessary. MAIN OUTCOME MEASURES: Residents' activity levels, health and quality of life will be tested using several measures to see which are practicable and appropriate for this population in this context. This includes: Assessment of Physical Activity in Frail Older People; Pool Activity Level Checklist; Dementia Care Mapping observations; and EQ-5D-5L. Residents will be assessed prior to programme implementation then 4- and 12-months post-implementation. Semi-structured interviews will explore the experiences of residents, staff, family members and therapists. CONCLUSIONS: Providing evidence of effectiveness and acceptability of ARCH, and documenting factors that impede/facilitate implementation will help us identify ways to enhance the care and quality of life of older people in residential care, and our understanding of how to implement them

A prospective, real‑world, multinational study of febrile neutropenia (FN) occurrence in oncology patients receiving chemotherapy with intermediate risk of FN : a MASCC neutropenia, infection, and myelosuppression study group initiative

DATA AVAILABILITY : Novartis supports the publication of scientifically rigorous analysis that is relevant to patient care, regardless of a positive or negative outcome. Qualified external researchers can request access to anonymized patient-level data, respecting patient-informed consent, through www. clini calst udyda tareq uest. com, according to requirements noted on the web portal.PURPOSE : Limited knowledge is available on the incidence of febrile neutropenia (FN) in intermediate-risk patients and the rationale for use of granulocyte colony-stimulating factor (G-CSF) in these patients. We aimed to estimate the rate at which patients associated with intermediate risk (10–20%) of FN would develop ≥ 1 episode of FN with a commonly used chemotherapy regimen in clinical practice. METHODS : This prospective, real-world, observational, multinational, multicenter study (December 2016–October 2019) recruited patients with solid tumors or Hodgkin’s/non-Hodgkin’s lymphoma. Patients receiving chemotherapy with intermediate risk of FN, but not G-CSF as primary prophylaxis were included and observed for the duration of the chemotherapy (≤ 6 cycles and ≤ 30 days after the last chemotherapy administration). RESULTS : In total, 364 patients (median age, 56 years) with 1601 cycles of chemotherapy were included in the analysis. The incidence of FN was 5% in cycle 1, 3% in cycles 2–3, and 1% in cycles 4–6. The rate of patients with ≥ 1 episode of FN was 9%, and 59% of FN events were reported during cycle 1. The rate of grade 4 neutropenia in cycle 1 was 11%, and 15% of patients experienced ≥ 1 episode of grade 4 neutropenia. CONCLUSIONS : Overall, the incidence of FN was low, with a high incidence in cycle 1 and a decrease in the subsequent cycles. These results provide the real FN risk for common chemotherapy regimens in patients generally excluded from clinical trials. Prophylactic G-CSF in intermediate-risk patients could be considered as per clinician’s judgement.Open access funding provided by University of Pretoria. This work was supported by research funding from Novartis Pharma AG, Basel, Switzerland.https://www.springer.com/journal/520am2024ImmunologySDG-03:Good heatlh and well-bein

Dysregulation of systemic soluble immune checkpoints in early breast cancer is attenuated following administration of neoadjuvant chemotherapy and is associated with recovery of CD27, CD28, CD40, CD80, ICOS and GITR and substantially increased levels of PD-L1, LAG-3 and TIM-3

Neoadjuvant chemotherapy (NAC) may alter the immune landscape of patients with early breast cancer (BC), potentially setting the scene for more effective implementation of checkpoint-targeted immunotherapy. This issue has been investigated in the current study in which alterations in the plasma concentrations of 16 soluble co-stimulatory and co-inhibitory, immune checkpoints were measured sequentially in a cohort of newly diagnosed, early BC patients (n=72), pre-treatment, post-NAC and post-surgery using a Multiplex® bead array platform. Relative to a group of healthy control subjects (n=45), the median pre-treatment levels of five co-stimulatory (CD27, CD40, GITRL, ICOS, GITR) and three co-inhibitory (TIM-3, CTLA-4, PD-L1) soluble checkpoints were significantly lower in the BC patients vs. controls (p&lt;0.021-p&lt;0.0001; and p&lt;0.008-p&lt;0.00001, respectively). Following NAC, the plasma levels of six soluble co-stimulatory checkpoints (CD28, CD40, ICOS, CD27, CD80, GITR), all involved in activation of CD8+ cytotoxic T cells, were significantly increased (p&lt;0.04-p&lt;0.00001), comparable with control values and remained at these levels post-surgery. Of the soluble co-inhibitory checkpoints, three (LAG-3, PD-L1, TIM-3) increased significantly post-NAC, reaching levels significantly greater than those of the control group. PD-1 remained unchanged, while BTLA and CTLA-4 decreased significantly (p&lt;0.03 and p&lt;0.00001, respectively). Normalization of soluble co-stimulatory immune checkpoints is seemingly indicative of reversal of systemic immune dysregulation following administration of NAC in early BC, while recovery of immune homeostasis may explain the increased levels of several negative checkpoint proteins, albeit with the exceptions of CTLA-4 and PD-1. Although a pathological complete response (pCR) was documented in 61% of patients (mostly triple-negative BC), surprisingly, none of the soluble immune checkpoints correlated with the pCR, either pre-treatment or post-NAC. Nevertheless, in the case of the co-stimulatory ICMs, these novel findings are indicative of the immune-restorative potential of NAC in early BC, while in the case of the co-inhibitory ICMs, elevated levels of soluble PD-L1, LAG-3 and TIM-3 post-NAC underscore the augmentative immunotherapeutic promise of targeting these molecules, either individually or in combination, as a strategy, which may contribute to the improved management of early BC

Tumor-Infiltrating Lymphocytes (TILs) in Early Breast Cancer Patients: High CD3+, CD8+, and Immunoscore Are Associated with a Pathological Complete Response

Background: Tumor-infiltrating lymphocytes are associated with a better prognosis in early triple-negative breast cancer (TNBC). These cells can be enumerated in situ by the &ldquo;Immunoscore Clinical Research&rdquo; (ISCR). The original Immunoscore&reg; is a prognostic tool that categorizes the densities of CD3+ and CD8+ cells in both the invasive margin (IM) and center of the tumor (CT) in localized colon cancer, yielding a five-tiered classification (0&ndash;4). We evaluated the prognostic potential of ISCR and pathological complete response (pCR) following neoadjuvant chemotherapy (NACT). Methods: The cohort included 53 TNBC, 32 luminal BC, and 18 HER2-positive BC patients undergoing NACT. Pre-treatment tumor biopsies were immune-stained for CD3+ and CD8+ T-cell markers. Quantitative analysis of these cells in different tumor locations was performed using computer-assisted image analysis. Results: The pCR rate was 44%. Univariate analysis showed that primary tumor size, estrogen-receptor negative, progesterone-receptor negative, luminal vs. HER2-positive vs. TNBC, high Ki-67, high densities (cells/mm2) of CD3 CT, CD8+ CT, CD3+ IM, and CD8+ IM cells were associated with a high pCR. ISCR was associated with pCR following NACT. A multivariate model consisting of ISCR and the significant variables from the univariate analysis showed a significant trend for ISCR; however, the low sample size did not provide enough power for the model to be included in this study. Conclusions: These results revealed a significant prognostic role for the spatial distributions of the CD3+, and CD8+ lymphocytes, as well as the ISCR in relation to pCR following NACT