Transfer of Cell-Surface Antigens by Scavenger Receptor CD36 Promotes Thymic Regulatory T Cell Receptor Repertoire Development and Allo-tolerance.

The development of T cell tolerance in the thymus requires the presentation of host proteins by multiple antigen-presenting cell (APC) types. However, the importance of transferring host antigens from transcription factor AIRE-dependent medullary thymic epithelial cells (mTECs) to bone marrow (BM) APCs is unknown. We report that antigen was primarily transferred from mTECs to CD8α+ dendritic cells (DCs) and showed that CD36, a scavenger receptor selectively expressed on CD8α+ DCs, mediated the transfer of cell-surface, but not cytoplasmic, antigens. The absence of CD8α+ DCs or CD36 altered thymic T cell selection, as evidenced by TCR repertoire analysis and the loss of allo-tolerance in murine allogeneic BM transplantation (allo-BMT) studies. Decreases in these DCs and CD36 expression in peripheral blood of human allo-BMT patients correlated with graft-versus-host disease. Our findings suggest that CD36 facilitates transfer of mTEC-derived cell-surface antigen on CD8α+ DCs to promote tolerance to host antigens during homeostasis and allo-BMT.

S100A9 upregulated by IFNGR signaling blockade functions as a novel GVHD suppressor without compromising GVL in mice.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curative treatment for both malignant and nonmalignant hematologic disorders. However, graft-versus-host disease (GVHD) and malignant relapse limit its therapeutic success. We previously demonstrated that the blockade of interferon-gamma receptor (IFNGR) signaling in donor T cells resulted in a reduction in GVHD while preserving graft-versus-leukemia (GVL) effects. However, the underlying molecular mechanisms remain inconclusive. In this study, we found that S100A9 is a novel GVHD suppressor upregulated when IFNGR is blocked in T cells. Both Ifngr1-/- and S100a9-overexpressing T cells significantly reduced GVHD without compromising GVL, altering donor T-cell trafficking to GVHD target organs in our mouse model of allo-HSCT. In addition, in vivo administration of recombinant murine S100A9 proteins prolongs the overall survival of recipient mice. Furthermore, in vivo administration of anti-human IFNGRα neutralizing antibody (αhGR-Nab) significantly upregulates the expression of S100A9 in human T cells and improved GVHD in our mouse model of xenogeneic human peripheral blood mononuclear cell transplantation. Consistent with S100a9-overexpressing T cells in our allo-HSCT model, αhGR-Nab reduced human T-cell trafficking to the GVHD target organs. Taken together, S100A9, a downstream molecule suppressed by IFNGR signaling, functions as a novel GVHD suppressor without compromising GVL.

A "Prime and Expand" strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy.

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 ("Expand" step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting "Prime and Expand" ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the "Prime and Expand" strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.

CAR-modified memory-like NK cells exhibit potent responses to NK-resistant lymphomas.

Natural killer (NK) cells are a promising cellular immunotherapy for cancer. Cytokine-induced memory-like (ML) NK cells differentiate after activation with interleukin-12 (IL-12), IL-15, and IL-18, exhibit potent antitumor responses, and safely induce complete remissions in patients with leukemia. However, many cancers are not fully recognized via NK cell receptors. Chimeric antigen receptors (CARs) have been used to enhance tumor-specific recognition by effector lymphocytes. We hypothesized that ML differentiation and CAR engineering would result in complementary improvements in NK cell responses against NK-resistant cancers. To test this idea, peripheral blood ML NK cells were modified to express an anti-CD19 CAR (19-CAR-ML), which displayed significantly increased interferon γ production, degranulation, and specific killing against NK-resistant lymphoma lines and primary targets compared with nonspecific control CAR-ML NK cells or conventional CAR NK cells. The 19-CAR and ML responses were synergistic and CAR specific and required immunoreceptor tyrosine-based activation motif signaling. Furthermore, 19-CAR-ML NK cells generated from lymphoma patients exhibited improved responses against their autologous lymphomas. 19-CAR-ML NK cells controlled lymphoma burden in vivo and improved survival in human xenograft models. Thus, CAR engineering of ML NK cells enhanced responses against resistant cancers and warrants further investigation, with the potential to broaden ML NK cell recognition against a variety of NK cell-resistant tumors.

Multi-modality imaging characteristics of costochondral fractures, a highly specific rib fracture for child abuse.

BACKGROUND: Rib fractures in young children are strongly associated with nonaccidental trauma (NAT). Costochondral junction (CCJ) fractures are unique with most being identified in the healing phase on radiographs. NAT-associated CCJ fractures, therefore, may be underdiagnosed. Improved diagnoses of CCJ fractures may lead to better identification of NAT. OBJECTIVE: To document the association of CCJ fractures with NAT, and improve CCJ fracture recognition by documenting the imaging features with multiple radiologic modalities. MATERIALS AND METHODS: Children, ages 0-4 years, with CCJ fractures on radiologic reports were identified over a 10-year period. All available radiographic skeletal surveys, chest radiographs, computed tomography (CT), magnetic resonance imaging (MRI) and ultrasound (US) studies were reviewed. We chose CT as the radiologic gold standard. Imaging patterns of the primary fracture and healing changes were documented. The diagnosis of NAT by the child protective team was documented. RESULTS: One hundred and nine CCJ fractures were found in 22 patients, 21 of whom were diagnosed with NAT (95.5%). Radiographic skeletal survey identified 34.6% of CCJ fractures (P < 0.0001) with a sensitivity of 32.5% and specificity of 99.2%. MRI identified 50.0% of CCJ fractures with a sensitivity of 42.9% and specificity of 98.1%. CONCLUSION: CCJ fractures are highly specific for NAT. As sensitivity is low for radiographic skeletal survey in CCJ fracture diagnosis compared with CT, CT may have a role in confirming a clinical suspicion of NAT.

Osteomyelitis of the ribs in children: a rare and potentially challenging diagnosis.

BACKGROUND: Rib osteomyelitis is rare in children and can mimic other pathologies. Imaging has a major role in the diagnosing rib osteomyelitis. OBJECTIVE: To evaluate clinical presentation and imaging findings in children with rib osteomyelitis. MATERIALS AND METHODS: We performed a retrospective (2009-2018) study on children with rib osteomyelitis verified by either positive culture or pathology. We excluded children with multifocal osteomyelitis or empyema necessitans. We reviewed medical charts for clinical, laboratory and pathology data, and treatment. All imaging modalities for rib abnormalities were evaluated for presence and location of osteomyelitis and abscess. We calculated descriptive statistics to compare patient demographics, clinical presentation and imaging findings. RESULTS: The study group included 10 children (6 boys, 4 girls), with an average age of 7.3 years (range, 3 months to 15.9 years). The most common clinical presentations were fever (n=8) and pain (n=5). Eight children had elevated inflammatory indices (leukocytosis, erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]). Localized chest wall swelling was found initially in six children and later in two more children. Rib osteomyelitis was suspected on presentation in only two children. All children had chest radiographs. Rib lytic changes were found on only one chest radiograph, in two of the four ultrasound studies, and in four of eight CTs. Bone marrow signal abnormalities were seen in all eight MRIs. In nine children the osteomyelitis involved the costochondral junction. Six children had an associated abscess. Staphylococcus aureus was cultured in eight children. Osteomyelitis was diagnosed based on pathology in one child with negative cultures. CONCLUSION: While rib osteomyelitis is rare, imaging findings of lytic changes at the costochondral junction combined with a history of fever, elevated inflammatory markers or localized soft-tissue swelling in the chest should raise suspicion for this disease.

Accuracy of ultrasound in the diagnosis of classic metaphyseal lesions using radiographs as the gold standard.

BACKGROUND: Diagnosis of classic metaphyseal lesions (CMLs) in children suspected for child abuse can be challenging. Ultrasound (US) can potentially help diagnose CMLs. However, its accuracy is unknown. OBJECTIVE: To evaluate the accuracy of US in the diagnosis of CMLs using skeletal survey reports as the gold standard. MATERIALS AND METHODS: US of the metaphysis was performed in three patient groups age <1 year. Informed consent was obtained for patients scheduled for renal US (Group 1) and for patients scheduled for skeletal surveys for possible child abuse (Group 2). Targeted US was also performed in selected patients to evaluate for possible CML suspected on radiographs (Group 3). In Groups 1 and 2, US was performed of both distal femurs, and of either the right or left proximal and distal tibia. Two radiologists (Rad1 and Rad2) independently reviewed the US studies, blinded to history and other imaging. US sensitivity and specificity were calculated using the following gold standards: CML definitely seen on skeletal survey (positive), CML definitely not seen on skeletal survey or part of renal US group (negative). Cases where the skeletal survey was indeterminate for CML were excluded. Kappa statistics were used to evaluate interobserver variability. RESULTS: Two hundred forty-one metaphyseal sites were evaluated by US in 63 children (mean age: 5 months; 33 males); 34 had skeletal surveys and 29 had renal US. Kappa for the presence of CML was 0.70 with 95.7% agreement. US sensitivity was 55.0% and 63.2% and the specificity was 97.7% and 96.7% for Rad1 and Rad2, respectively. CONCLUSION: US has low sensitivity and high specificity in CML diagnosis. Thus, negative US does not exclude CML, but when the radiographs are equivocal, positive US can help substantiate the diagnosis.

Azacitidine Mitigates Graft-versus-Host Disease via Differential Effects on the Proliferation of T Effectors and Natural Regulatory T Cells In Vivo.

Azacitidine (AzaC) mitigates graft-versus-host disease (GvHD) in both murine preclinical transplant models and in human clinical trials while maintaining a robust graft-versus-leukemia effect. Previous studies have failed to investigate the role of natural regulatory T cells (nTregs) on the mitigation of GvHD by AzaC, instead focusing on the generation of suppressive Tregs (CD4+CD25+FOXP3+) through the in vivo conversion of alloreactive donor T effectors (Teffs; CD4+CD25-FOXP3-) and the direct antiproliferative effects of AzaC on allogeneic T cells. Using B6.Foxp3DTR/GFP mice in which Tregs can be specifically ablated through administration of diphtheria toxin, we demonstrate that natural Tregs are required in the donor graft for AzaC to optimally protect against GvHD and that nTregs, unlike Teffs (CD3+FOXP3-), are resistant to the antiproliferative effects of AzaC. Gene expression analysis identified the potent cell cycle inhibitor, p21, was significantly upregulated in Teffs but not nTregs after treatment with AzaC. Furthermore, we demonstrate that Teffs deficient in p21 are less sensitive to the antiproliferative effects of AzaC. These results demonstrate that nTregs are essential for AzaC to fully protect against GvHD and have important clinical implications for future clinical trials testing AzaC as a novel method of GvHD prophylaxis in man.

Diagnosis of Primary Ciliary Dyskinesia. An Official American Thoracic Society Clinical Practice Guideline.

BACKGROUND: This document presents the American Thoracic Society clinical practice guidelines for the diagnosis of primary ciliary dyskinesia (PCD). TARGET AUDIENCE: Clinicians investigating adult and pediatric patients for possible PCD. METHODS: Systematic reviews and, when appropriate, meta-analyses were conducted to summarize all available evidence pertinent to our clinical questions. Evidence was assessed using the GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach for diagnosis and discussed by a multidisciplinary panel with expertise in PCD. Predetermined conflict-of-interest management strategies were applied, and recommendations were formulated, written, and graded exclusively by the nonconflicted panelists. Three conflicted individuals were also prohibited from writing, editing, or providing feedback on the relevant sections of the manuscript. RESULTS: After considering diagnostic test accuracy, confidence in the estimates for each diagnostic test, relative importance of test results studied, desirable and undesirable direct consequences of each diagnostic test, downstream consequences of each diagnostic test result, patient values and preferences, costs, feasibility, acceptability, and implications for health equity, the panel made recommendations for or against the use of specific diagnostic tests as compared with using the current reference standard (transmission electron microscopy and/or genetic testing) for the diagnosis of PCD. CONCLUSIONS: The panel formulated and provided a rationale for the direction as well as for the strength of each recommendation to establish the diagnosis of PCD.

Diagnosis of pediatric colonic volvulus with abdominal radiography: how good are we?

BACKGROUND: Colonic volvulus is rare in children and associated with colonic dysmotility. Diagnosis of colonic volvulus on radiographs in these patients can be challenging. The purpose of the study was to identify the accuracy of abdominal radiographs and findings suggestive of colonic volvulus. MATERIALS AND METHODS: A retrospective (2003- 2014) study of all children with colonic volvulus proven surgically or endoscopically reviewed their medical charts for underlying disease and clinical presentation as well as their original radiograph reports. Two pediatric radiologists (reader 1 and reader 2) independently reviewed the radiographs. The kappa test was used to evaluate interobserver variability. RESULTS: There were 19 cases of colonic volvulus in 18 patients (11 males) a mean age 14 years. Cecal volvulus was the most common finding at 14/19 cases (74%). Sixteen of 18 (89%) patients had neurological impairment and 10 of 18 (56%) had intestinal dysmotility. The most common presentation was abdominal distension (14/19 [74%]) and pain (11/19 [58%]). Colonic volvulus was diagnosed in only 7/16 (44%) of the abdominal radiographs. The specific finding of a coffee-bean sign was retrospectively observed only by reader 2 in two cases. Absence of rectal gas and focal colonic loop dilation were the most common findings by the readers (average 73.5% and 87%, respectively) with Kappa values of 0.3 and 0.38, respectively. CONCLUSION: Diagnosis of colonic volvulus in children can be challenging. Radiologists should be alerted to the possibility of colonic volvulus when there is focal colonic loop distention or absent rectal gas.

Can ultrasound be used as the primary imaging in children with suspected Crohn disease?

BACKGROUND: There is growing literature on the use of ultrasound (US) for evaluation of Crohn disease in adults, but few studies have been conducted on children. Several studies demonstrated high accuracy of US in the diagnosis of Crohn disease. Using US as the primary screening imaging modality for Crohn disease can reduce health care costs, the need for sedation and ionizing radiation exposure. OBJECTIVE: The aim of our study is to determine if US can be used for screening evaluation of pediatric Crohn disease. MATERIALS AND METHODS: A prospective cohort study of pediatric patients undergoing MR enterography (MRE) for suspected or known history of Crohn disease was performed, with gray-scale and Doppler US of the terminal ileum done immediately before or after MRE. US images were interpreted by two radiologists (Reader 1 and Reader 2) not involved in image acquisition, in blinded and randomized fashion. US findings of Crohn disease including bowel wall thickening, wall stratification, increased vascularity on Doppler, lymphadenopathy, fat infiltration and extraintestinal complications were evaluated. MRE findings of terminal ileitis were considered the reference standard. Demographic data, body mass index (BMI), symptoms, and laboratory, endoscopic and histopathological data were obtained from electronic medical records. RESULTS: Forty-one patients (mean age: 13.7 years: 4.6-18.9 years) were evaluated. Mean BMI was 21.2 (range: 13-40.2); 10 patients (24.3%) were either overweight or obese. Final diagnoses were Crohn disease (n=24), ulcerative colitis (n=4) and normal/non-inflammatory bowel disease-related diagnoses (n=13). US demonstrated sensitivity of 67% and 78% and specificity of 78% and 83%, by Reader 1 and Reader 2, respectively. MRE sensitivity and specificity were 75% and 100%, respectively, compared to final clinicopathological diagnosis. Interobserver agreement between Reader 1 and Reader 2 was good (0.6< kappa <0.8). CONCLUSION: In screening for Crohn disease in children, US has limited sensitivity for detecting terminal ileitis.

[(18)F]FHBG PET/CT Imaging of CD34-TK75 Transduced Donor T Cells in Relapsed Allogeneic Stem Cell Transplant Patients: Safety and Feasibility.

Described herein is a first-in-man attempt to both genetically modify T cells with an imagable suicide gene and track these transduced donor T cells in allogeneic stem cell transplantation recipients using noninvasive positron emission tomography/computerized tomography (PET/CT) imaging. A suicide gene encoding a human CD34-Herpes Simplex Virus-1-thymidine kinase (CD34-TK75) fusion enabled enrichment of retrovirally transduced T cells (TdT), control of graft-versus-host disease and imaging of TdT migration and expansion in vivo in mice and man. Analysis confirmed that CD34-TK75-enriched TdT contained no replication competent γ-retrovirus, were sensitive to ganciclovir, and displayed characteristic retroviral insertion sites (by targeted sequencing). Affinity-purified CD34-TK75(+)-selected donor T cells (1.0-13 × 10(5))/kg were infused into eight patients who relapsed after allogeneic stem cell transplantation. Six patients also were administered 9-[4-((18)F)fluoro-3-hydroxymethyl-butyl]guanine ([(18)F]FHBG) to specifically track the genetically modified donor T cells by PET/CT at several time points after infusion. All patients were assessed for graft-versus-host disease, response to ganciclovir, circulating TdT cells (using both quantitative polymerase chain reaction and [(18)F]FHBG PET/CT imaging), TdT cell clonal expansion, and immune response to the TdT. This phase 1 trial demonstrated that genetically modified T cells and [(18)F]FHBG can be safely infused in patients with relapsed hematologic malignancies after allogeneic stem cell transplantation.

Clinical features of childhood primary ciliary dyskinesia by genotype and ultrastructural phenotype.

RATIONALE: The relationship between clinical phenotype of childhood primary ciliary dyskinesia (PCD) and ultrastructural defects and genotype is poorly defined. OBJECTIVES: To delineate clinical features of childhood PCD and their associations with ultrastructural defects and genotype. METHODS: A total of 118 participants younger than 19 years old with PCD were evaluated prospectively at six centers in North America using standardized procedures for diagnostic testing, spirometry, chest computed tomography, respiratory cultures, and clinical phenotyping. MEASUREMENTS AND MAIN RESULTS: Clinical features included neonatal respiratory distress (82%), chronic cough (99%), and chronic nasal congestion (97%). There were no differences in clinical features or respiratory pathogens in subjects with outer dynein arm (ODA) defects (ODA alone; n = 54) and ODA plus inner dynein arm (IDA) defects (ODA + IDA; n = 18) versus subjects with IDA and central apparatus defects with microtubular disorganization (IDA/CA/MTD; n = 40). Median FEV1 was worse in the IDA/CA/MTD group (72% predicted) versus the combined ODA groups (92% predicted; P = 0.003). Median body mass index was lower in the IDA/CA/MTD group (46th percentile) versus the ODA groups (70th percentile; P = 0.003). For all 118 subjects, median number of lobes with bronchiectasis was three and alveolar consolidation was two. However, the 5- to 11-year-old IDA/CA/MTD group had more lobes of bronchiectasis (median, 5; P = 0.0008) and consolidation (median, 3; P = 0.0001) compared with the ODA groups (median, 3 and 2, respectively). Similar findings were observed when limited to participants with biallelic mutations. CONCLUSIONS: Lung disease was heterogeneous across all ultrastructural and genotype groups, but worse in those with IDA/CA/MTD ultrastructural defects, most of whom had biallelic mutations in CCDC39 or CCDC40.

Testicular microlithiasis in children and associated testicular cancer.

PURPOSE: To evaluate the prevalence of testicular microlithiasis (TM) in children who have undergone scrotal ultrasonography (US) and their association with testicular tumors. MATERIALS AND METHODS: This HIPAA-compliant study with waiver of informed consent was approved by the institutional review board. From 2003 to 2012, all patients with scrotal US and report mentioning calcifications or microlithiasis and all patients with testicular tumors from pathology database were identified. US studies were evaluated for the type of TM (classic ≥5 microliths or limited <5 microliths in a single view) and change in follow-up studies if available. Medical charts were reviewed for US indication, underlying medical conditions, and pathologic abnormalities, when available. Fisher exact test was used to analyze the association of testicular tumors and TM. RESULTS: A total of 3370 boys had scrotal US, 83 (2%) of whom had TM or microcalcifications in the report. TM was usually bilateral (n = 62, 75%) and classic (n = 59, 71%) type.TM was significantly less common in those younger than 2 years of age than in older age groups (0.1% vs 3.1%, P < .0001). The most common indication for US was scrotal pain (40 of 83 patients, 48%), and the most common associated medical condition was cryptorchidism (nine of 83 patients, 11%). Testicular tumor was significantly more likely in boys with TM (12% vs 0.3%, P < .01). Five (83%) of six patients with premalignant or benign tumors had a premalignant condition (cryptochydism in two and Peutz-Jeghers syndrome in three). Four patients with TM had malignant testicular tumors, all diagnosed after the age of 16 years. CONCLUSION: TM has a prevalence of 2% in boys who undergo scrotal US. It is most commonly bilateral, classic type, and stable at follow-up studies. There is a significant association of TM and testicular tumors. Malignant tumors were seen only in adolescent boys.

IFNγR signaling mediates alloreactive T-cell trafficking and GVHD.

The clinical goal of allogeneic hematopoietic stem cell transplantation (allo-HSCT) is to minimize GVHD while maintaining GvL. Here, we show that interferon γ receptor-deficient (IFNγR(-/-)) allogeneic Tconv, which possess normal alloreactivity and cytotoxicity, induce significantly less GVHD than wild-type (WT) Tconv. This effect is mediated by altered trafficking of IFNγR(-/-) Tconv to GVHD target organs, especially the gastrointestinal (GI) tract. We show that the chemokine receptor CXCR3 is induced via IFNγR-mediated signaling and partially contributes to the trafficking of WT Tconv to GVHD target organs. Indeed, CXCR3(-/-) Tconv recapitulate the reduced GVHD potential of IFNγR(-/-) Tconv in a minor-mismatched GVHD model. Most importantly, IFNγR(-/-) (and CXCR3(-/-)) Tconv mediate a robust and beneficial GvL effect. In addition, we show that IFNγR(-/-) regulatory T cells (Tregs) are fully suppressive in vitro although defective in suppressor function in vivo and that WT Tregs suppress GVHD in vivo only when allogeneic Tconv produce interferon γ (IFNγ), suggesting that the IFNγR signaling pathway is the major mechanism for both Tregs and Tconv to migrate to GVHD target organs. Finally, pharmacologic inhibition of IFNγR signaling with inhibitors of JAK1/JAK2, which are mediators of IFNγR signaling, results in the decreased expression of CXCR3 and reduced GVHD and improved survival after allo-HSCT and this effect is mediated by altered trafficking of Tconv to GVHD target organs.

ACR Appropriateness Criteria® Urinary Tract Infection-Child: 2023 Update.

Urinary tract infection (UTI) is a frequent infection in childhood. The diagnosis is usually made by history and physical examination and confirmed by urine analysis. Cystitis is infection or inflammation confined to the bladder, whereas pyelonephritis is infection or inflammation of kidneys. Pyelonephritis can cause renal scarring, which is the most severe long-term sequela of UTI and can lead to accelerated nephrosclerosis, leading to hypertension and chronic renal failure. The role of imaging is to guide treatment by identifying patients who are at high risk to develop recurrent UTIs or renal scarring. This document provides initial imaging guidelines for children presenting with first febrile UTI with appropriate response to medical management, atypical or recurrent febrile UTI, and follow-up imaging for children with established vesicoureteral reflux. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

ACR Appropriateness Criteria® Soft Tissue Vascular Anomalies: Vascular Malformations and Infantile Vascular Tumors (Non-CNS)-Child.

Soft tissue vascular anomalies may be composed of arterial, venous, and/or lymphatic elements, and diagnosed prenatally or later in childhood or adulthood. They are divided into categories of vascular malformations and vascular tumors. Vascular malformations are further divided into low-flow and fast-flow lesions. A low-flow lesion is most common, with a prevalence of 70%. Vascular tumors may behave in a benign, locally aggressive, borderline, or malignant manner. Infantile hemangioma is a vascular tumor that presents in the neonatal period and then regresses. The presence or multiple skin lesions in an infant can signal underlying visceral vascular anomalies, and complex anomalies may be associated with overgrowth syndromes. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Anti-myeloma efficacy of CAR-iNKT is enhanced with a long-acting IL-7, rhIL-7-hyFc.

Multiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. B-cell maturation antigen (BCMA) is the lead protein target for chimeric antigen receptor (CAR) therapy because of its high expression in most MM, with limited expression in other cell types, resulting in favorable on-target, off tumor toxicity. The response rate to autologous BCMA CAR-T therapy is high; however, it is not curative and is associated with risks of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome. Outcomes in patients treated with BCMA CAR-T cells (CAR-Ts) may improve with allogeneic CAR T-cell therapy, which offer higher cell fitness and reduced time to treatment. However, to prevent the risk of graft-versus-host disease (GVHD), allogenic BCMA CAR-Ts require genetic deletion of the T-cell receptor (TCR), which has potential for unexpected functional or phenotype changes. Invariant natural killer T cells (iNKTs) have an invariant TCR that does not cause GVHD and, as a result, can be used in an allogeneic setting without the need for TCR gene editing. We demonstrate significant anti-myeloma activity of BCMA CAR-iNKTs in a xenograft mouse model of myeloma. We found that a long-acting interleukin-7 (IL-7), rhIL-7-hyFc, significantly prolonged survival and reduced tumor burden in BCMA CAR-iNKT-treated mice in both primary and re-challenge settings. Furthermore, in CRS in vitro assays, CAR-iNKTs induced less IL-6 than CAR-Ts, suggesting a reduced likelihood of CAR-iNKT therapy to induce CRS in patients. These data suggest that BCMA CAR-iNKTs are potentially a safer, effective alternative to BCMA CAR-Ts and that BCMA CAR-iNKT efficacy is further potentiated with rhIL-7-hyFc.

An "off-the-shelf" CD2 universal CAR-T therapy for T-cell malignancies.

T-cell malignancies are associated with frequent relapse and high morbidity, which is partly due to the lack of effective or targeted treatment options. To broaden the use of CAR-T cells in pan T-cell malignancies, we developed an allogeneic "universal" CD2-targeting CAR-T cell (UCART2), in which the CD2 antigen is deleted to prevent fratricide, and the T-cell receptor is removed to prevent GvHD. UCART2 demonstrated efficacy against T-ALL and CTCL and prolonged the survival of tumor-engrafted NSG mice in vivo. To evaluate the impact of CD2 on CAR-T function, we generated CD19 CAR-T cells (UCART19) with or without CD2 deletion, single-cell secretome analysis revealed that CD2 deletion in UCART19 reduced frequencies of the effector cytokines (Granzyme-B and IFN-γ). We also observed that UCART19ΔCD2 had reduced anti-tumor efficacy compared to UCART19 in a CD19+NALM6 xenograft model. Of note is that the reduced efficacy resulting from CD2 deletion was reversed when combined with rhIL-7-hyFc, a long-acting recombinant human interleukin-7. Treatment with rhIL-7-hyFc prolonged UCART2 persistence and increased survival in both the tumor re-challenge model and primary patient T-ALL model in vivo. Together, these data suggest that allogeneic fratricide-resistant UCART2, in combination with rhIL-7-hyFc, could be a suitable approach for treating T-cell malignancies.