Disrupting Roquin-1 interaction with Regnase-1 induces autoimmunity and enhances antitumor responses.

Roquin and Regnase-1 proteins bind and post-transcriptionally regulate proinflammatory target messenger RNAs to maintain immune homeostasis. Either the sanroque mutation in Roquin-1 or loss of Regnase-1 cause systemic lupus erythematosus-like phenotypes. Analyzing mice with T cells that lack expression of Roquin-1, its paralog Roquin-2 and Regnase-1 proteins, we detect overlapping or unique phenotypes by comparing individual and combined inactivation. These comprised spontaneous activation, metabolic reprogramming and persistence of T cells leading to autoimmunity. Here, we define an interaction surface in Roquin-1 for binding to Regnase-1 that included the sanroque residue. Mutations in Roquin-1 impairing this interaction and cooperative regulation of targets induced T follicular helper cells, germinal center B cells and autoantibody formation. These mutations also improved the functionality of tumor-specific T cells by promoting their accumulation in the tumor and reducing expression of exhaustion markers. Our data reveal the physical interaction of Roquin-1 with Regnase-1 as a hub to control self-reactivity and effector functions in immune cell therapies.

Myeloid-Cell-Derived VEGF Maintains Brain Glucose Uptake and Limits Cognitive Impairment in Obesity.

High-fat diet (HFD) feeding induces rapid reprogramming of systemic metabolism. Here, we demonstrate that HFD feeding of mice downregulates glucose transporter (GLUT)-1 expression in blood-brain barrier (BBB) vascular endothelial cells (BECs) and reduces brain glucose uptake. Upon prolonged HFD feeding, GLUT1 expression is restored, which is paralleled by increased expression of vascular endothelial growth factor (VEGF) in macrophages at the BBB. In turn, inducible reduction of GLUT1 expression specifically in BECs reduces brain glucose uptake and increases VEGF serum concentrations in lean mice. Conversely, myeloid-cell-specific deletion of VEGF in VEGF(Δmyel) mice impairs BBB-GLUT1 expression, brain glucose uptake, and memory formation in obese, but not in lean mice. Moreover, obese VEGF(Δmyel) mice exhibit exaggerated progression of cognitive decline and neuroinflammation on an Alzheimer's disease background. These experiments reveal that transient, HFD-elicited reduction of brain glucose uptake initiates a compensatory increase of VEGF production and assign obesity-associated macrophage activation a homeostatic role to restore cerebral glucose metabolism, preserve cognitive function, and limit neurodegeneration in obesity.

NK cells link obesity-induced adipose stress to inflammation and insulin resistance.

An important cause of obesity-induced insulin resistance is chronic systemic inflammation originating in visceral adipose tissue (VAT). VAT inflammation is associated with the accumulation of proinflammatory macrophages in adipose tissue, but the immunological signals that trigger their accumulation remain unknown. We found that a phenotypically distinct population of tissue-resident natural killer (NK) cells represented a crucial link between obesity-induced adipose stress and VAT inflammation. Obesity drove the upregulation of ligands of the NK cell-activating receptor NCR1 on adipocytes; this stimulated NK cell proliferation and interferon-γ (IFN-γ) production, which in turn triggered the differentiation of proinflammatory macrophages and promoted insulin resistance. Deficiency of NK cells, NCR1 or IFN-γ prevented the accumulation of proinflammatory macrophages in VAT and greatly ameliorated insulin sensitivity. Thus NK cells are key regulators of macrophage polarization and insulin resistance in response to obesity-induced adipocyte stress.

Signaling by IL-6 promotes alternative activation of macrophages to limit endotoxemia and obesity-associated resistance to insulin.

Obesity and resistance to insulin are closely associated with the development of low-grade inflammation. Interleukin 6 (IL-6) is linked to obesity-associated inflammation; however, its role in this context remains controversial. Here we found that mice with an inactivated gene encoding the IL-6Rα chain of the receptor for IL-6 in myeloid cells (Il6ra(Δmyel) mice) developed exaggerated deterioration of glucose homeostasis during diet-induced obesity, due to enhanced resistance to insulin. Tissues targeted by insulin showed increased inflammation and a shift in macrophage polarization. IL-6 induced expression of the receptor for IL-4 and augmented the response to IL-4 in macrophages in a cell-autonomous manner. Il6ra(Δmyel) mice were resistant to IL-4-mediated alternative polarization of macrophages and exhibited enhanced susceptibility to lipopolysaccharide (LPS)-induced endotoxemia. Our results identify signaling via IL-6 as an important determinant of the alternative activation of macrophages and assign an unexpected homeostatic role to IL-6 in limiting inflammation.

STING agonism turns human T cells into interferon-producing cells but impedes their functionality.

The cGAS-STING (cyclic GMP-AMP synthase-stimulator of interferon genes) axis is the predominant DNA sensing system in cells of the innate immune system. However, human T cells also express high levels of STING, while its role and physiological trigger remain largely unknown. Here, we show that the cGAS-STING pathway is indeed functional in human primary T cells. In the presence of a TCR-engaging signal, both cGAS and STING activation switches T cells into type I interferon-producing cells. However, T cell function is severely compromised following STING activation, as evidenced by increased cell death, decreased proliferation, and impaired metabolism. Interestingly, these different phenotypes bifurcate at the level of STING. While antiviral immunity and cell death require the transcription factor interferon regulatory factor 3 (IRF3), decreased proliferation is mediated by STING independently of IRF3. In summary, we demonstrate that human T cells possess a functional cGAS-STING signaling pathway that can contribute to antiviral immunity. However, regardless of its potential antiviral role, the activation of the cGAS-STING pathway negatively affects T cell function at multiple levels. Taken together, these results could help inform the future development of cGAS-STING-targeted immunotherapies.

Comparative performance of scFv-based anti-BCMA CAR formats for improved T cell therapy in multiple myeloma.

In multiple myeloma (MM), B cell maturation antigen (BCMA)-directed CAR T cells have emerged as a novel therapy with potential for long-term disease control. Anti-BCMA CAR T cells with a CD8-based transmembrane (TM) and CD137 (41BB) as intracellular costimulatory domain are in routine clinical use. As the CAR construct architecture can differentially impact performance and efficacy, the optimal construction of a BCMA-targeting CAR remains to be elucidated. Here, we hypothesized that varying the constituents of the CAR structure known to impact performance could shed light on how to improve established anti-BCMA CAR constructs. CD8TM.41BBIC-based anti-BCMA CAR vectors with either a long linker or a short linker between the light and heavy scFv chain, CD28TM.41BBIC-based and CD28TM.CD28IC-based anti-BCMA CAR vector systems were used in primary human T cells. MM cell lines were used as target cells. The short linker anti-BCMA CAR demonstrated higher cytokine production, whereas in vitro cytotoxicity, T cell differentiation upon activation and proliferation were superior for the CD28TM.CD28IC-based CAR. While CD28TM.CD28IC-based CAR T cells killed MM cells faster, the persistence of 41BBIC-based constructs was superior in vivo. While CD28 and 41BB costimulation come with different in vitro and in vivo advantages, this did not translate into a superior outcome for either tested model. In conclusion, this study showcases the need to study the influence of different CAR architectures based on an identical scFv individually. It indicates that current scFv-based anti-BCMA CAR with clinical utility may already be at their functional optimum regarding the known structural variations of the scFv linker.

Beyond CAR T cells: exploring alternative cell sources for CAR-like cellular therapies.

Chimeric antigen receptor (CAR)-T cell therapy has led to remarkable clinical outcomes in the treatment of hematological malignancies. However, challenges remain, such as limited infiltration into solid tumors, inadequate persistence, systemic toxicities, and manufacturing insufficiencies. The use of alternative cell sources for CAR-based therapies, such as natural killer cells (NK), macrophages (MΦ), invariant Natural Killer T (iNKT) cells, γδT cells, neutrophils, and induced pluripotent stem cells (iPSC), has emerged as a promising avenue. By harnessing these cells' inherent cytotoxic mechanisms and incorporating CAR technology, common CAR-T cell-related limitations can be effectively mitigated. We herein present an overview of the tumoricidal mechanisms, CAR designs, and manufacturing processes of CAR-NK cells, CAR-MΦ, CAR-iNKT cells, CAR-γδT cells, CAR-neutrophils, and iPSC-derived CAR-cells, outlining the advantages, limitations, and potential solutions of these therapeutic strategies.

T-cell exhaustion induced by continuous bispecific molecule exposure is ameliorated by treatment-free intervals.

T-cell-recruiting bispecific molecule therapy has yielded promising results in patients with hematologic malignancies; however, resistance and subsequent relapse remains a major challenge. T-cell exhaustion induced by persistent antigen stimulation or tonic receptor signaling has been reported to compromise outcomes of T-cell-based immunotherapies. The impact of continuous exposure to bispecifics on T-cell function, however, remains poorly understood. In relapsed/refractory B-cell precursor acute lymphoblastic leukemia patients, 28-day continuous infusion with the CD19xCD3 bispecific molecule blinatumomab led to declining T-cell function. In an in vitro model system, mimicking 28-day continuous infusion with the half-life-extended CD19xCD3 bispecific AMG 562, we identified hallmark features of exhaustion arising over time. Continuous AMG 562 exposure induced progressive loss of T-cell function (day 7 vs day 28 mean specific lysis: 88.4% vs 8.6%; n = 6; P = .0003). Treatment-free intervals (TFIs), achieved by AMG 562 withdrawal, were identified as a powerful strategy for counteracting exhaustion. TFIs induced strong functional reinvigoration of T cells (continuous vs TFI-specific lysis on day 14: 34.9% vs 93.4%; n = 6; P < .0001) and transcriptional reprogramming. Furthermore, use of a TFI led to improved T-cell expansion and tumor control in vivo. Our data demonstrate the relevance of T-cell exhaustion in bispecific antibody therapy and highlight that T cells can be functionally and transcriptionally rejuvenated with TFIs. In view of the growing number of bispecific molecules being evaluated in clinical trials, our findings emphasize the need to consider and evaluate TFIs in application schedules to improve clinical outcomes.

Post-transplant-cyclophosphamide and short-term Everolimus as graft-versus-host-prophylaxis in patients with relapsed/refractory lymphoma and myeloma-Final results of the phase II OCTET-EVER trial.

BACKGROUND: Conditioning regimens and the choice of immunosuppression have substantial impact on immune reconstitution after allogeneic hematopoietic stem cell transplantation (aHSCT). The pivotal mechanism to maintain remission is the induction of the graft-versus-tumor effect. Relapse as well as graft versus host disease remain common. Classic immunosuppressive strategies implementing calcineurin inhibitors (CNI) have significant toxicities, hamper the immune recovery, and reduce the anti-cancer immune response. METHODS: We designed a phase II clinical trial for patients with relapsed and refractory lymphoid malignancies undergoing aHSCT using a CNI-free approach consisting of post-transplant cyclophosphamide (PTCy) and short-term Everolimus after reduced-intensity conditioning and matched peripheral blood stem cell transplantation. The results of the 19 planned patients are presented. Primary endpoint is the cumulative incidence and severity of acute GvHD. RESULTS: Overall incidence of acute GvHD was 53% with no grade III or IV. Cumulative incidence of NRM at 1, 2, and 4 years was 11%, 11%, and 16%, respectively, with a median follow-up of 43 months. Cumulative incidence of relapse was 32%, 32%, and 42% at 1, 2, and 4 years after transplant, respectively. Four out of six early relapses were multiple myeloma patients. Overall survival was 79%, 74%, and 62% at 1, 2, and 4 years. GvHD-relapse-free-survival was 47% after 3 years. CONCLUSIONS: Using PTCy and short-term Everolimus is safe with low rates of aGvHD and no severe aGvHD or cGvHD translating into a low rate of non-relapse mortality. Our results in this difficult to treat patient population are encouraging and warrant further studies.

CD33 BiTE® molecule-mediated immune synapse formation and subsequent T-cell activation is determined by the expression profile of activating and inhibitory checkpoint molecules on AML cells.

Bispecific T-cell engager (BiTE®) molecules recruit T cells to cancer cells through CD3ε binding, independently of T-cell receptor (TCR) specificity. Whereas physiological T-cell activation is dependent on signal 1 (TCR engagement) and signal 2 (co-stimulation), BiTE molecule-mediated T-cell activation occurs without additional co-stimulation. As co-stimulatory and inhibitory molecules modulate the strength and nature of T-cell responses, we studied the impact of the expression profile of those molecules on target cells for BiTE molecule-mediated T-cell activation in the context of acute myeloid leukemia (AML). Accordingly, we created a novel in vitro model system using murine Ba/F3 cells transduced with human CD33 ± CD86 ± PD-L1. T-cell fitness was assessed by T-cell function assays in co-cultures and immune synapse formation by applying a CD33 BiTE molecule (AMG 330). Using our cell-based model platform, we found that the expression of positive co-stimulatory molecules on target cells markedly enhanced BiTE molecule-mediated T-cell activation. The initiation and stability of the immune synapse between T cells and target cells were significantly increased through the expression of CD86 on target cells. By contrast, the co-inhibitory molecule PD-L1 impaired the stability of BiTE molecule-induced immune synapses and subsequent T-cell responses. We validated our findings in primary T-cell-AML co-cultures, demonstrating a PD-L1-mediated reduction in redirected T-cell activation. The addition of the immunomodulatory drug (IMiD) lenalidomide to co-cultures led to stabilization of immune synapses and improved subsequent T-cell responses. We conclude that target cells modulate CD33 BiTE molecule-dependent T-cell activation and hence, combinatorial strategies might contribute to enhanced efficacy.

Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults.

BACKGROUND: Allogeneic haematopoietic stem cell transplantation (SCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after an allogeneic SCT, is the result of host tissues being attacked by donor immune cells. It affects more than half of the patients after transplant either as acute and or chronic GVHD. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATGs), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation. OBJECTIVES: To assess the effect of ATG used for the prevention of GVHD in patients undergoing allogeneic SCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, non-relapse mortality, graft failure and adverse events. SEARCH METHODS: For this update we searched the CENTRAL, MEDLINE, Embase, trial registers and conference proceedings on the 18th November 2022 along with reference checking and contacting study authors to identify additional studies. We did not apply language restrictions. SELECTION CRITERIA: We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic SCT. The selection criteria were modified from the previous version of this review. Paediatric studies and studies where patients aged < 18 years constituted more than 20 % of the total number were excluded. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration for data collection, extraction and analyses. MAIN RESULTS: For this update we included seven new RCTs, leading to a total of ten studies investigating 1413 participants. All patients had a haematological condition which warranted an allogeneic SCT. The risk of bias was estimated as low for seven and unclear for three studies. ATG probably has little or no influence on overall survival (HR (hazard ratio) 0.93 (95 % confidence interval (CI) 0.77 to 1.13, nine studies, n = 1249, moderate-certainty evidence)). Estimated absolute effect: 430 surviving people per 1000 people not receiving ATG compared to 456 people surviving per 1000 people receiving the intervention (95 % CI 385 to 522 per 1000 people). ATG results in a reduction in acute GVHD II to IV with relative risk (RR) 0.68 (95 % CI 0.60 to 0.79, 10 studies, n = 1413, high-certainty evidence). Estimated absolute effect: 418 acute GVHD II to IV per 1000 people not receiving ATG compared to 285 per 1000 people receiving the intervention (95 % CI 251 to 331 per 1000 people). Addition of ATG results in a reduction of overall chronic GvHD with a RR of 0.53 (95 % CI 0.45 to 0.61, eight studies, n = 1273, high-certainty evidence). Estimated absolute effect: 506 chronic GVHD per 1000 people not receiving ATG compared to 268 per 1000 people receiving the intervention (95 % CI 228 to 369 per 1000 people). Further data on severe acute GVHD and extensive chronic GVHD are available in the manuscript. ATG probably slightly increases the incidence of relapse with a RR of 1.21 (95 % CI 0.99 to 1.49, eight studies,  n =1315, moderate-certainty evidence). Non relapse mortality is probably slightly or not affected by ATG with an HR of 0.86 (95 % CI 0.67 to 1.11, nine studies, n=1370, moderate-certainty evidence).   ATG prophylaxis may result in no increase in graft failure with a RR of 1.55 (95 % CI 0.54 to 4.44, eight studies, n = 1240, low-certainty evidence).  Adverse events could not be analysed due to the serious heterogeneity in the reporting between the studies, which limited comparability (moderate-certainty evidence) and are reported in a descriptive manner.   Subgroup analyses on ATG types, doses and donor type are available in the manuscript. AUTHORS' CONCLUSIONS: This systematic review suggests that the addition of ATG during allogeneic SCT probably has little or no influence on overall survival. ATG results in a reduction in the incidence and severity of acute and chronic GvHD. ATG intervention probably slightly increases the incidence of relapse and probably does not affect the non relapse mortality. Graft failure may not be affected by ATG prophylaxis. Analysis of data on adverse events was reported in a narrative manner. A limitation for the analysis was the imprecision in reporting between the studies thereby reducing the confidence in the certainty of evidence.

Exercise interventions for adults with cancer receiving radiation therapy alone.

BACKGROUND: Radiation therapy (RT) is given to about half of all people with cancer. RT alone is used to treat various cancers at different stages. Although it is a local treatment, systemic symptoms may occur. Cancer- or treatment-related side effects can lead to a reduction in physical activity, physical performance, and quality of life (QoL). The literature suggests that physical exercise can reduce the risk of various side effects of cancer and cancer treatments, cancer-specific mortality, recurrence of cancer, and all-cause mortality. OBJECTIVES: To evaluate the benefits and harms of exercise plus standard care compared with standard care alone in adults with cancer receiving RT alone. SEARCH METHODS: We searched CENTRAL, MEDLINE (Ovid), Embase (Ovid), CINAHL, conference proceedings and trial registries up to 26 October 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that enrolled people who were receiving RT without adjuvant systemic treatment for any type or stage of cancer. We considered any type of exercise intervention, defined as a planned, structured, repetitive, objective-oriented physical activity programme in addition to standard care. We excluded exercise interventions that involved physiotherapy alone, relaxation programmes, and multimodal approaches that combined exercise with other non-standard interventions such as nutritional restriction. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and the GRADE approach for assessing the certainty of the evidence. Our primary outcome was fatigue and the secondary outcomes were QoL, physical performance, psychosocial effects, overall survival, return to work, anthropometric measurements, and adverse events. MAIN RESULTS: Database searching identified 5875 records, of which 430 were duplicates. We excluded 5324 records and the remaining 121 references were assessed for eligibility. We included three two-arm RCTs with 130 participants. Cancer types were breast and prostate cancer. Both treatment groups received the same standard care, but the exercise groups also participated in supervised exercise programmes several times per week while undergoing RT. Exercise interventions included warm-up, treadmill walking (in addition to cycling and stretching and strengthening exercises in one study), and cool-down. In some analysed endpoints (fatigue, physical performance, QoL), there were baseline differences between exercise and control groups. We were unable to pool the results of the different studies owing to substantial clinical heterogeneity. All three studies measured fatigue. Our analyses, presented below, showed that exercise may reduce fatigue (positive SMD values signify less fatigue; low certainty). • Standardised mean difference (SMD) 0.96, 95% confidence interval (CI) 0.27 to 1.64; 37 participants (fatigue measured with Brief Fatigue Inventory (BFI)) • SMD 2.42, 95% CI 1.71 to 3.13; 54 participants (fatigue measured with BFI) • SMD 1.44, 95% CI 0.46 to 2.42; 21 participants (fatigue measured with revised Piper Fatigue Scale) All three studies measured QoL, although one provided insufficient data for analysis. Our analyses, presented below, showed that exercise may have little or no effect on QoL (positive SMD values signify better QoL; low certainty). • SMD 0.40, 95% CI -0.26 to 1.05; 37 participants (QoL measured with Functional Assessment of Cancer Therapy-Prostate) • SMD 0.47, 95% CI -0.40 to 1.34; 21 participants (QoL measured with World Health Organization QoL questionnaire (WHOQOL-BREF)) All three studies measured physical performance. Our analyses of two studies, presented below, showed that exercise may improve physical performance, but we are very unsure about the results (positive SMD values signify better physical performance; very low certainty) • SMD 1.25, 95% CI 0.54 to 1.97; 37 participants (shoulder mobility and pain measured on a visual analogue scale) • SMD⁠⁠⁠⁠⁠⁠ 3.13 (95% CI 2.32 to 3.95; 54 participants (physical performance measured with the six-minute walk test) Our analyses of data from the third study showed that exercise may have little or no effect on physical performance measured with the stand-and-sit test, but we are very unsure about the results (SMD 0.00, 95% CI -0.86 to 0.86, positive SMD values signify better physical performance; 21 participants; very low certainty). Two studies measured psychosocial effects. Our analyses (presented below) showed that exercise may have little or no effect on psychosocial effects, but we are very unsure about the results (positive SMD values signify better psychosocial well-being; very low certainty). • SMD 0.48, 95% CI -0.18 to 1.13; 37 participants (psychosocial effects measured on the WHOQOL-BREF social subscale) • SMD 0.29, 95% CI -0.57 to 1.15; 21 participants (psychosocial effects measured with the Beck Depression Inventory) Two studies recorded adverse events related to the exercise programmes and reported no events. We estimated the certainty of the evidence as very low. No studies reported adverse events unrelated to exercise. No studies reported the other outcomes we intended to analyse (overall survival, anthropometric measurements, return to work). AUTHORS' CONCLUSIONS: There is little evidence on the effects of exercise interventions in people with cancer who are receiving RT alone. While all included studies reported benefits for the exercise intervention groups in all assessed outcomes, our analyses did not consistently support this evidence. There was low-certainty evidence that exercise improved fatigue in all three studies. Regarding physical performance, our analysis showed very low-certainty evidence of a difference favouring exercise in two studies, and very low-certainty evidence of no difference in one study. We found very low-certainty evidence of little or no difference between the effects of exercise and no exercise on quality of life or psychosocial effects. We downgraded the certainty of the evidence for possible outcome reporting bias, imprecision due to small sample sizes in a small number of studies, and indirectness of outcomes. In summary, exercise may have some beneficial outcomes in people with cancer who are receiving RT alone, but the evidence supporting this statement is of low certainty. There is a need for high-quality research on this topic.

Distinct distribution patterns of exercise-induced natural killer cell mobilization into the circulation and tumor tissue of patients with prostate cancer.

The mobilization and activation of natural killer (NK) cells have been proposed as key mechanisms promoting anti-oncogenic effects of physical exercise. Although mouse models have proven that physical exercise recruits NK cells to tumor tissue and inhibits tumor growth, this preclinical finding has not been transferred to the clinical setting yet. In this first-in-human study, we found that physical exercise mobilizes and redistributes NK cells, especially those with a cytotoxic phenotype, in line with preclinical models. However, physical exercise did not increase NK cell tumor infiltrates. Future studies should carefully distinguish between acute and chronic exercise modalities and should be encouraged to investigate more immune-responsive tumor entities.

Early weight loss is an independent risk factor for shorter survival and increased side effects in patients with metastatic colorectal cancer undergoing first-line treatment within the randomized Phase III trial FIRE-3 (AIO KRK-0306).

Body weight loss is frequently regarded as negatively related to outcomes in patients with malignancies. This retrospective analysis of the FIRE-3 study evaluated the evolution of body weight in patients with metastatic colorectal cancer (mCRC). FIRE-3 evaluated first-line FOLFIRI (folinic acid, fluorouracil and irinotecan) plus cetuximab or bevacizumab in mCRC patients with RAS-WT tumors (ie, wild-type in KRAS and NRAS exons 2-4). The prognostic and predictive relevance of early weight loss (EWL) regarding patient outcomes and treatment side effects were evaluated. Retrospective data on body weight during first 6 months of treatment were evaluated (N = 326). To correlate with efficacy endpoints and treatment side effects, patients were grouped according to clinically significant EWL ≥5% and <5% at Month 3. Age constituted the only significant predictor of EWL following a linear relationship with the corresponding log odds ratio (P = .016). EWL was significantly associated with the incident frequencies of diarrhea, edema, fatigue, nausea and vomiting. Further, a multivariate analysis revealed EWL to be an independent negative prognostic factor for overall survival (32.4 vs 21.1 months; hazard ratio [HR]: 1.64; 95% confidence interval [CI] = 1.13-2.38; P = .0098) and progression-free survival (11.8 vs 9.0 months; HR: 1.72; 95% CI = 1.18-2.5; P = .0048). In conclusion, EWL during systemic treatment against mCRC is significantly associated with patient age. Patients exhibiting EWL had worse survival and higher frequencies of adverse events. Early preventative measures targeted at weight maintenance should be evaluated, especially in elderly patients being at highest risk of EWL.

Checkpoint-inhibitor induced Polyserositis with Edema.

BACKGROUND: As immune checkpoint inhibitors (ICI) are increasingly being used due to effectiveness in various tumor entities, rare side effects occur more frequently. Pericardial effusion has been reported in patients with advanced non-small cell lung cancer (NSCLC) after or under treatment with immune checkpoint inhibitors. However, knowledge about serositis and edemas induced by checkpoint inhibitors in other tumor entities is scarce. METHODS AND RESULTS: Four cases with sudden onset of checkpoint inhibitor induced serositis (irSerositis) are presented including one patient with metastatic cervical cancer, two with metastatic melanoma and one with non-small cell lung cancer (NSCLC). In all cases treatment with steroids was successful in the beginning, but did not lead to complete recovery of the patients. All patients required multiple punctures. Three of the patients presented with additional peripheral edema; in one patient only the lower extremities were affected, whereas the entire body, even face and eyelids were involved in the other patients. In all patients serositis was accompanied by other immune-related adverse events (irAEs). CONCLUSION: ICI-induced serositis and effusions are complex to diagnose and treat and might be underdiagnosed. For differentiation from malignant serositis pathology of the punctured fluid can be helpful (lymphocytes vs. malignant cells). Identifying irSerositis as early as possible is essential since steroids can improve symptoms.

Increased visceral fat distribution and body composition impact cytokine release syndrome onset and severity after CD19 chimeric antigen receptor T-cell therapy in advanced B-cell malignancies.

Chimeric antigen receptor T-cell (CAR-T) therapy is associated with a distinct toxicity profile that includes cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). CRS is characterized by the release of pro-inflammatory cytokines such as interleukin 6 (IL-6) and is closely linked to CAR-T expansion and bystander cells like monocytes/macrophages. In other hyperinflammatory states, obesity contributes to inflammatory cascades and acts as a risk factor for disease severity. We aimed to study the influence of anthropometric and body composition (BC) measurements on CAR-T-related immunotoxicity in 64 patients receiving CD19-directed CAR-T for relapsed/refractory Bcell malignancies. Patients with grade ≥2 CRS presented with a significantly higher median body mass index (BMI), waist circumference, waist-to-height ratio (WtHR) and visceral adipose tissue (VAT). These parameters were also found to be associated with an earlier CRS onset. Other adipose deposits and muscle mass did not differ between patients with grade 0-1 CRS versus grade ≥2 CRS. Moreover, BC parameters did not influence ICANS severity or onset. In a multivariate binary logistic regression incorporating known risk factors of immunotoxicity, the factors BMI, waist circumference, WtHR and VAT increased the probability of grade ≥2 CRS. Receiver operating characteristic analyses were utilized to determine optimal discriminatory thresholds for these parameters. Patients above these thresholds displayed markedly increased peak IL-6 levels. Our data imply that increased body composition and VAT in particular represent an additional risk factor for severe and early CRS. These findings carry implications for risk-stratification prior to CD19 CAR-T and may be integrated into established risk models.

Two-dimensional CT measurements enable assessment of body composition on head and neck CT.

OBJECTIVES: The aim of this study was to evaluate whether simple 2D measurements in axial slices of head and neck CT examinations correlate with generally established measurements of body composition in abdominal CT at the height of the third lumbar vertebra and thus allow for an estimation of muscle and fat masses. METHODS: One hundred twenty-two patients who underwent concurrent CT of the head and neck and the abdomen between July 2016 and July 2020 were retrospectively included. For a subset of 30 patients, additional bioelectrical impedance analysis (BIA) was available. Areas of paraspinal muscles at the height of the third (C3) and fifth cervical vertebrae (C5) as well as the total cross-sectional area at the height of C3 and at the submandibular level were correlated with the results of abdominal measurements and BIA. Furthermore, intra- and interreader variabilities of all measurements were assessed. RESULTS: Regarding adipose tissue, good correlations were found between the total cross-sectional area of the patient's body at the submandibular level and at the height of C3 between both abdominal measurements and BIA results (r = 0.8-0.92; all p < 0.001). Regarding muscle, the total paraspinal muscle area at the height of C3 and C5 showed strong correlations with abdominal measurements and moderate to strong correlations with BIA results (r = 0.44-0.80; all p < 0.001), with the muscle area on C5 yielding slightly higher correlations. CONCLUSIONS: Body composition information can be obtained with comparable reliability from head and neck CT using simple biplanar measurements as from abdominal CT. KEY POINTS: • The total paraspinal muscle area at the height of C3 and C5 correlates strongly with abdominal muscle mass. • The total cross-sectional area at the submandibular level and at the height of C3 shows good correlations with abdominal fat mass. • The described measurements facilitate a rapid, opportunistic assessment of relevant body composition parameters.

Long-term physical training in adolescent sprint and middle distance swimmers alters the composition of circulating T and NK cells which correlates with soluble ICAM-1 serum concentrations.

PURPOSE: It remains unknown how different training intensities and volumes chronically impact circulating lymphocytes and cellular adhesion molecules. First, we aimed to monitor changes in NK and T cells over a training season and relate these to training load. Second, we analyzed effects of training differences between swimmers on these cells. Finally, we examined if changes in lymphocytes were associated with sICAM-1 concentrations. METHODS: We analyzed weekly training volume, training intensity, proportions of T and NK cells and serum sICAM-1 in eight sprint (SS) and seven middle-distance swimmers (MID) at three points over a 16-week training period: at the start (t0), after 7 weeks of increased training load (t7) and after 16 weeks, including 5-day taper (t16). RESULTS: Training volume of all swimmers was statistically higher and training intensity lower from t0-t7 compared to t7-t16 (p = 0.001). Secondly, training intensity was statistically higher in SS from t0-t7 (p = 0.004) and t7-t16 (p = 0.015), while MID had a statistically higher training volume from t7-t16 (p = 0.04). From t0-t7, NK (p = 0.06) and CD45RA+CD45RO+CD4+ cells (p < 0.001) statistically decreased, while CD45RA-CD45RO+CD4+ cells (p = 0.024) statistically increased. In a subgroup analysis, SS showed statistically larger increases in NK cells from t7-t16 than MID (p = 0.012). Lastly, sICAM-1 concentrations were associated with changes in CD45RA-CDRO+CD4+ cells (r = - 0.656, p = 0.08). CONCLUSION: These results indicate that intensified training in swimmers resulted in transient changes in T and NK cells. Further, NK cells are sensitive to high training volumes. Lastly, sICAM-1 concentrations may be associated with the migration and maturation of CD4+ cells in athletes.

Single-slice CT measurements allow for accurate assessment of sarcopenia and body composition.

OBJECTIVES: To evaluate the correlation between simple planimetric measurements in axial computed tomography (CT) slices and measurements of patient body composition and anthropometric data performed with bioelectrical impedance analysis (BIA) and metric clinical assessments. METHODS: In this prospective cross-sectional study, we analyzed data of a cohort of 62 consecutive, untreated adult patients with advanced malignant melanoma who underwent concurrent BIA assessments at their radiologic baseline staging by CT between July 2016 and October 2017. To assess muscle and adipose tissue mass, we analyzed the areas of the paraspinal muscles as well as the cross-sectional total patient area in a single CT slice at the height of the third lumbar vertebra. These measurements were subsequently correlated with anthropometric (body weight) and body composition parameters derived from BIA (muscle mass, fat mass, fat-free mass, and visceral fat mass). Linear regression models were built to allow for estimation of each parameter based on CT measurements. RESULTS: Linear regression models allowed for accurate prediction of patient body weight (adjusted R2 = 0.886), absolute muscle mass (adjusted R2 = 0.866), fat-free mass (adjusted R2 = 0.855), and total as well as visceral fat mass (adjusted R2 = 0.887 and 0.839, respectively). CONCLUSIONS: Our data suggest that patient body composition can accurately and quantitatively be determined by using simple measurements in a single axial CT slice. This could be useful in various medical and scientific settings, where the knowledge of the patient's anthropometric parameters is not immediately or easily available. KEY POINTS: • Easy to perform measurements on a single CT slice highly correlate with clinically valuable parameters of body composition. • Body composition data were acquired using bioelectrical impedance analysis to correlate CT measurements with a non-imaging-based method, which is frequently lacking in previous studies. • The obtained equations facilitate a quick, opportunistic assessment of relevant parameters of body composition.