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Trials with second generation CD19 chimeric antigen receptors (CAR) T-cells report unprecedented responses but are associated with risk of cytokine release syndrome (CRS). Instead, we studied the use of donor Epstein–Barr virus-specific T-cells (EBV CTL) transduced with a first generation CD19CAR, relying on the endogenous T-cell receptor for proliferation. We conducted a multi-center phase I/II study of donor CD19CAR transduced EBV CTL in pediatric acute lymphoblastic leukaemia (ALL). Patients were eligible pre-emptively if they developed molecular relapse (>5 × 10 −4 ) post first stem cell transplant (SCT), or prophylactically post second SCT. An initial cohort showed poor expansion/persistence. We therefore investigated EBV-directed vaccination to enhance expansion/persistence. Eleven patients were treated. No CRS, neurotoxicity or graft versus host disease (GVHD) was observed. At 1 month, 5 patients were in CR (4 continuing, 1 de novo ), 1 PR, 3 had stable disease and 3 no response. At a median follow-up of 12 months, 10 of 11 have relapsed, 2 are alive with disease and 1 alive in CR 3 years. Although CD19CAR CTL expansion was poor, persistence was enhanced by vaccination. Median persistence was 0 (range: 0–28) days without vaccination compared to 56 (range: 0–221) days with vaccination ( P =0.06). This study demonstrates the feasibility of multi-center studies of CAR T cell therapy and the potential for enhancing persistence with vaccination.

Primary hemophagocytic lymphohistiocytosis, a rare genetic immune disorder characterized by hyperinflammation, manifests in infancy and is associated with high mortality. In a study involving 34 children, an antibody to interferon-γ (emapalumab) produced responses in 65%; it served as a bridge to marrow transplantation in 70% of those who had received previous treatment.

Mrp8 and Mrp14 are endogenous alarmins amplifying inflammation via Toll‐like receptor‐4 (TLR‐4) activation. Due to their pro‐inflammatory properties, alarmins are supposed to enhance adaptive immunity via activation of dendritic cells (DCs). In contrast, analysing a model of allergic contact dermatitis (ACD) we observed a more severe disease outcome in Mrp8/14‐deficient compared to wild‐type mice. This unexpected phenotype was associated with an enhanced T‐cell response due to an accelerated maturation of DCs in Mrp8/14‐deficient mice. Accordingly, Mrp8, the active component of the heterocomplex, inhibits early DC maturation and antigen presentation in a TLR‐4‐dependent manner. Transfer of DCs purified from the local lymph nodes of sensitized Mrp8/14‐deficient to wild‐type mice determined the outcome of ACD. Our results link a pro‐inflammatory role of the endogenous TLR‐4 ligand Mrp8/14 to a regulatory function in adaptive immunity, which shows some similarities with the ‘hygiene hypothesis’ regarding continuous TLR‐4 stimulation and decreased risk of allergy. Mrp8/14, an amplifier of innate immune responses, has distinct roles in the adaptive immune system, preventing its hyper‐activation by regulating dendritic cell maturation and antigen presentation.

The rate of ara-cytosine triphosphate (ara-CTP) accumulation and its retention has been correlated with 1-beta-D-arabinofuranosylcytosine (ara-C)-mediated toxicity and clinical outcome in childhood and adult leukemia. We tested to what extent preincubation with the ribonucleotide reductase inhibitors fludarabine (F-ara-A) and hydroxyurea (HU) enhanced ara-CTP levels in two human myeloid (HL-60, CMK) and two lymphoblastic leukemia cell lines (MOLT-4, BLIN-1) and also in blasts from 28 children with acute leukemia (AML: 14, ALL: 14). Incubation experiments carried out with cell lines showed F-ara-A and HU to be equipotent in increasing ara-CTP levels. The highest increase was observed in HL-60 cells whereas preincubation had no modulatory effect in MOLT-4 cells. Accordingly, modulation of intracellular ara-CTP levels differed between the subtypes of childhood acute leukemia: whereas in T-ALL (five) preincubation with F-ara-A and HU had no effect on intracellular ara-C metabolism, increased ara-CTP levels were seen in some cases of pre-B-ALL (seven). In myelogenous blasts (12) clinically relevant enhancement of ara-C toxification was regularly obtained with both, F-ara-A (1.9-fold) and HU (1.5-fold). In conclusion, our data suggest that combinations of ara-C and ribonucleotide reductase inhibitors are apt to increase ara-CTP levels depending on the individual cell type and its sensitivity towards ara-C modulators.

Disseminated or relapsed Ewing sarcoma (EwS) has remained fatal in the majority of patients. A promising approach to preventing relapse after conventional therapy is to establish tumor antigen-specific immune control. Efficient and specific T cell memory against the tumor depends on the expansion of rare T cells with native specificity against target antigens overexpressed by the tumor. Candidate antigens in EwS include six-transmembrane epithelial antigen of the prostate-1 (STEAP1), and the human cancer/testis antigens X-antigen family member 1 (XAGE1) and preferentially expressed antigen in melanoma (PRAME). Here, we screened normal donors and EwS patients for the presence of circulating T cells reactive with overlapping peptide libraries of these antigens by IFN-γ Elispot analysis. The majority of 22 healthy donors lacked detectable memory T cell responses against STEAP1, XAGE1 and PRAME. Moreover, ex vivo detection of T cells specific for these antigens in both blood and bone marrow were limited to a minority of EwS patients and required nonspecific T cell prestimulation. Cytotoxic T cells specific for the tumor-associated antigens were efficiently and reliably generated by in vitro priming using professional antigen-presenting cells and optimized cytokine stimulation; however, these T cells failed to interact with native antigen processed by target cells and with EwS cells expressing the antigen. We conclude that EwS-associated antigens fail to induce efficient T cell receptor (TCR)-mediated antitumor immune responses even under optimized conditions. Strategies based on TCR engineering could provide a more effective means to manipulating T cell immunity toward targeted elimination of tumor cells.

Background Previous studies have demonstrated high complication rates after harvest of iliac crest bone grafts. This study was undertaken to compare the morbidity related to the harvest of anterior iliac crest bone graft with that related to the harvest of posterior iliac crest bone graft and to determine differences in functional outcome.Methods The medical records of eighty-eight consecutive patients who had undergone a total of 108 iliac crest bone-grafting procedures for the treatment of chronic osteomyelitis from 1991 to 1998 were retrospectively reviewed. Demographic characteristics, the location of the harvest, the volume of bone graft that was harvested, the estimated blood loss, and postoperative complications were recorded. Fifty-eight patients completed a questionnaire pertaining to postoperative and residual pain, sensory disturbances, functional limitations, cosmetic appearance, and overall satisfaction with the bone-graft harvesting procedure.Results Sixty-six anterior and forty-two posterior bone-graft harvest sites were evaluated at a minimum of two years after the operation. A major complication was associated with 8% (five) of the sixty-six anterior sites and 2% (one) of the forty-two posterior sites. The rates of minor complications were 15% (ten) and 0%, respectively. In the series as a whole, there were ten minor complications (9%) and six major complications (6%). The rates of both minor complications (p = 0.006) and all complications (p = 0.004) were significantly higher after the anterior harvest procedures than they were after the posterior procedures. The postoperative pain at the donor site was significantly more severe (p = 0.0016) and of significantly greater duration (p = 0.0017) after the anterior harvests. No patient reported functional limitations at the latest follow-up evaluation.ConclusionsIn this series, the complication rate was lower than those previously reported by other investigators. Harvest of a posterior iliac crest bone graft was associated with a significantly lower risk of postoperative complications. On the basis of the results of this study, we recommend that iliac crest bone graft be harvested posteriorly whenever possible.

Disseminated Ewing sarcoma remains a fatal disease despite advanced multimodal treatment regimens. Immunotherapies as well as novel drugs and biologicals are currently being explored to eliminate minimal residual disease after conventional therapy thereby rescuing patients at a high risk for relapse. Insights into the interactions between novel therapies provide the basis for the development of effective combination strategies. We investigated the effects of the aminobisphosphonate zoledronic acid (ZA) on the in vitro expansion of human natural killer (NK) cells and their cytolytic activity against Ewing sarcoma cells. ZA significantly impaired the in vitro expansion of activated NK cells from both healthy donors and Ewing sarcoma patients in a dose-dependent manner. Expression of differentiation markers and activating receptors was unaffected by the drug. Activated NK cells from both healthy donors and patients had potent degranulation responses to Ewing sarcoma cells. In the presence of ZA at concentrations reflecting pharmaceutical serum levels, the in vitro antitumor activity of NK cells from Ewing sarcoma patients was significantly impaired. We conclude that ZA can impede in vitro NK cell expansion and cytolytic NK cell responses to Ewing sarcoma. These observations raise caution against the combination of adoptive NK cell transfer with ZA maintenance therapy in Ewing sarcoma. Future studies aim to identify potentiating interactions of novel drugs with cellular therapies.

Background: In animals, some phthalates impair male reproductive development and function. Epidemiological studies have reported inconsistent evidence of associations between phthalates and markers of human testicular function. Objectives: We aimed to provide estimates of the effects of phthalate exposure on reproductive hormone levels and semen quality in healthy men. Methods: A total of 881 men gave urine, serum, and semen samples. Serum levels of testosterone, estradiol (E2), sex hormone-binding globulin (SHBG), luteinizing hormone (LH), follicle-stimulating hormone (FSH), and inhibin-B; semen quality; and urinary concentrations of 14 phthalate metabolites, including metabolites of di(2-ethylhexyl) phthalate (DEHP) and diisononyl phthalate (DiNP), were assessed. The proportions of DEHP and DiNP excreted as their respective primary metabolites [mono(2-ethylhexyl) phthalate (MEHP) and mono-isononyl phthalate (MiNP)] were calculated and expressed as percentages (%MEHP and %MiNP, respectively). Results: The free androgen index was 15% lower [95% confidence interval (CI): -23, -8%] for men in the highest %MiNP quartile compared to the lowest quartile (p < 0.001) after adjusting for confounders, and 9% lower (95% CI: -16, -1%) in the highest %MEHP quartile (p = 0.02). %MEHP and %MiNP were negatively associated with the ratio of testosterone/LH and testosterone/FSH. %MEHP was negatively associated with total testosterone, free testosterone, and ratio of testosterone/E2. %MiNP was positively associated with SHBG. There was little evidence of associations between urinary phthalate metabolites or sums of phthalates with reproductive hormones or semen quality Conclusion: Our data suggest that both testosterone production and pituitary—hypothalamic feedback may be compromised in individuals excreting a high proportion of primary metabolites of long-chained phthalates relative to the proportion of secondary metabolites.

Background Osteoarthritis (OA) is a joint disease with a high worldwide prevalence, often leading to replacement surgery. However, despite the high success rate of replacement surgery, some patients fail to experience the intended benefits. Given the importance of patient involvement, this trial aims to assess the effect of shared decision-making (SDM) on decisional quality for patients with severe OA. Specifically, it investigates whether an in-consult patient decision aid (PtDA) enhances decisional quality, involvement, and health outcomes for patients with severe hip or knee OA. Methods This protocol outlines a pragmatic two-armed multicentre cluster-randomised controlled trial (C-RCT), chosen for its ability to assess the combined effect of shared decision-making (SDM) and a newly developed in-consult patient decision aid (PtDA) in routine clinical practice. The PtDA is a tool designed to help patients make informed decisions during the consultation by providing personalised treatment options, benefits, and risks. The C-RCT design is particularly well-suited to this context, as it effectively minimises contamination and bias across treatment groups. A total of 19 orthopaedic surgeons will be randomised 1:1, stratified by centre, to either continue standard consultations without the PtDA or implement SDM using the PtDA. The trial will recruit 615 patients with severe hip or knee OA. Outcomes will be measured at one week, three months, and 12 months post treatment start. The primary outcome, decisional quality, will be assessed using the Hip/Knee OA Decision Quality Instrument, focusing on patients being well-informed and receiving their preferred treatment. The secondary outcomes include patient involvement in the decision-making process and consultation durations. The tertiary outcomes include patients’ satisfaction, regret and health-related outcomes. The primary outcome will be analysed using a multilevel mixed-effects logistic regression with surgeons as random effects reporting odds ratios with 95% confidence intervals. Discussion This study aims to contribute insights into the use of SDM facilitated by a PtDA and its impact on improving decisional quality for future patients with hip or knee OA. Trial registration www.ClinicalTrials.gov (NCT05972525), Data of registration: 06.08.2023.

Abstract Background The prevalence and risk factors for infection with enteropathogens in dogs frequenting dog parks have been poorly documented, and infected dogs can pose a potential zoonotic risk for owners. Hypothesis/Objectives To determine the prevalence and risk factors of infection with enteropathogens and zoonotic Giardia strains in dogs attending dog parks in Northern California and to compare results of fecal flotation procedures performed at a commercial and university parasitology laboratory. Animals Three-hundred dogs attending 3 regional dog parks in Northern California. Methods Prospective study. Fresh fecal specimens were collected from all dogs, scored for consistency, and owners completed a questionnaire. Specimens were analyzed by fecal centrifugation flotation, DFA, and PCR for detection of 11 enteropathogens. Giardia genotyping was performed for assemblage determination. Results Enteropathogens were detected in 114/300 dogs (38%), of which 62 (54%) did not have diarrhea. Frequency of dog park attendance correlated significantly with fecal consistency (P = .0039), but did not correlate with enteropathogen detection. Twenty-seven dogs (9%) were infected with Giardia, and genotyping revealed nonzoonotic assemblages C and D. The frequency of Giardia detection on fecal flotation was significantly lower at the commercial laboratory versus the university laboratory (P = .013), and PCR for Giardia was negative in 11/27 dogs (41%) that were positive on fecal flotation or DFA. Conclusions and Clinical Importance Enteropathogens were commonly detected in dogs frequenting dog parks, and infection with Giardia correlated with fecal consistency. PCR detection of Giardia had limited diagnostic utility, and detection of Giardia cysts by microscopic technique can vary among laboratories.