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OBJECTIVES: The revised European Society of Musculoskeletal Radiology (ESSR) consensus guidelines on soft tissue tumor imaging represent an update of 2015 after technical advancements, further insights into specific entities, and revised World Health Organization (2020) and AJCC (2017) classifications. This second of three papers covers algorithms once histology is confirmed: (1) standardized whole-body staging, (2) special algorithms for non-malignant entities, and (3) multiplicity, genetic tumor syndromes, and pitfalls. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements that had undergone interdisciplinary revision were scored online by the level of agreement (0 to 10) during two iterative rounds, that could result in 'group consensus', 'group agreement', or 'lack of agreement'. RESULTS: The three sections contain 24 statements with comments. Group consensus was reached in 95.8% and group agreement in 4.2%. For whole-body staging, pulmonary MDCT should be performed in all high-grade sarcomas. Whole-body MRI is preferred for staging bone metastasis, with [18F]FDG-PET/CT as an alternative modality in PET-avid tumors. Patients with alveolar soft part sarcoma, clear cell sarcoma, and angiosarcoma should be screened for brain metastases. Special algorithms are recommended for entities such as rhabdomyosarcoma, extraskeletal Ewing sarcoma, myxoid liposarcoma, and neurofibromatosis type 1 associated malignant peripheral nerve sheath tumors. Satisfaction of search should be avoided in potential multiplicity. CONCLUSION: Standardized whole-body staging includes pulmonary MDCT in all high-grade sarcomas; entity-dependent modifications and specific algorithms are recommended for sarcomas and non-malignant soft tissue tumors. CLINICAL RELEVANCE STATEMENT: These updated ESSR soft tissue tumor imaging guidelines aim to provide support in decision-making, helping to avoid common pitfalls, by providing general and entity-specific algorithms, techniques, and reporting recommendations for whole-body staging in sarcoma and non-malignant soft tissue tumors. KEY POINTS: An early, accurate, diagnosis is crucial for the prognosis of patients with soft tissue tumors. These updated guidelines provide best practice expert consensus for standardized imaging algorithms, techniques, and reporting. Standardization can improve the comparability examinations and provide databases for large data analysis.
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Achilles tendinopathy is a disabling condition that affects more than 50% of runners. Pre-clinical studies in a large animal model of naturally-occurring tendinopathy similar to human Achilles tendinopathy has shown benefits of autologous bone marrow-derived mesenchymal stem cell (MSC) implantation. However, MSCs are advanced therapies medicinal products (ATMPs), with strict regulatory requirements. Guided by the regulator we carried out a first in man study to assess the safety and efficacy of autologous MSC injection in human patients with non-insertional Achilles tendinopathy. Ten patients, mean age 47 with mid-portion Achilles tendon pain and swelling for more than 6 months, underwent autologous cultured cell injections (median 12.2 × 106, range 5-19 × 106 cells) into their Achilles tendon. At 24 weeks follow-up, no serious adverse reactions or important medical events were observed. MOXFQ, EQ-5D-5L, and VISA-A scores improved clinically at 12 and 24 weeks. VAS pain improved increasingly at 6, 12 and 24 weeks. MOXFQ Pain and VISA-A Scores improved > 12 points from baseline to 24 weeks in 8 patients. Maximum anteroposterior tendon thickness as measured by greyscale US decreased by mean 0.8 mm at 24 weeks. This phase IIa study demonstrated the safety of autologous MSC injection for non-insertional Achilles tendinopathy and provides proof-of-concept of the technique in patients, all of whom had previously failed conservative treatments for chronic disease and leads the way for a larger randomised controlled trial.
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Tendón Calcáneo , Trasplante de Células Madre Mesenquimatosas , Células Madre Mesenquimatosas , Tendinopatía , Trasplante Autólogo , Humanos , Tendinopatía/terapia , Tendinopatía/patología , Tendón Calcáneo/patología , Masculino , Trasplante de Células Madre Mesenquimatosas/métodos , Trasplante de Células Madre Mesenquimatosas/efectos adversos , Persona de Mediana Edad , Femenino , Adulto , Células Madre Mesenquimatosas/citología , Resultado del TratamientoRESUMEN
ABSTRACT: Disruption of the intestinal microbiome is observed with acute graft-versus-host disease (GVHD) of the lower gastrointestinal (LGI) tract, and fecal microbiota transplantation (FMT) has successfully cured steroid-refractory cases. In this open-label, single-arm, pilot study, third-party, single-donor FMT was administered in combination with systemic corticosteroids to participants with high-risk acute LGI GVHD, with a focus on treatment-naïve cases. Participants were scheduled to receive 1 induction dose (15 capsules per day for 2 consecutive days), followed by 3 weekly maintenance doses, consisting of 15 capsules per dose. The primary end point of the study was feasibility, which would be achieved if ≥80% of participants able to swallow ≥40 of the 75 scheduled capsules. Ten participants (9 treatment-naïve; 1 steroid-refractory) were enrolled and treated. The study met the primary end point, with 9 of 10 participants completing all eligible doses. Organ-specific LGI complete response rate at day 28 was 70%. Initial clinical response was observed within 1 week for all responders, and clinical responses were durable without recurrent LGI GVHD in complete responders. Exploratory analyses suggest that alpha diversity increased after FMT. Although recipient microbiome composition never achieved a high degree of donor similarity, expansion of donor-derived species and increases in tryptophan metabolites and short-chain fatty acids were observed within the first 7 days after FMT. Investigation into the use of microbiome-targeted interventions earlier in the treatment paradigm for acute LGI GVHD is warranted. This trial was registered at www.ClinicalTrials.gov as #NCT04139577.
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Trasplante de Microbiota Fecal , Enfermedad Injerto contra Huésped , Humanos , Enfermedad Injerto contra Huésped/terapia , Enfermedad Injerto contra Huésped/etiología , Trasplante de Microbiota Fecal/métodos , Masculino , Femenino , Persona de Mediana Edad , Adulto , Microbioma Gastrointestinal , Anciano , Proyectos Piloto , Enfermedad Aguda , Resultado del TratamientoRESUMEN
OBJECTIVES: Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements, and reporting is therefore a prerequisite. Since the first European Society of Musculoskeletal Radiology (ESSR) consensus in 2015, technical achievements, further insights into specific entities, and the revised WHO-classification (2020) and AJCC staging system (2017) made an update necessary. The guidelines are intended to support radiologists in their decision-making and contribute to interdisciplinary tumor board discussions. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements were scored online by level of agreement (0 to 10) during two iterative rounds. Either "group consensus," "group agreement," or "lack of agreement" was achieved. RESULTS: Eight sections were defined that finally contained 145 statements with comments. Overall, group consensus was reached in 95.9%, and group agreement in 4.1%. This communication contains the first part consisting of the imaging algorithm for suspected soft tissue tumors, methods for local imaging, and the role of tumor centers. CONCLUSION: Ultrasound represents the initial triage imaging modality for accessible and small tumors. MRI is the modality of choice for the characterization and local staging of most soft tissue tumors. CT is indicated in special situations. In suspicious or likely malignant tumors, a specialist tumor center should be contacted for referral or teleradiologic second opinion. This should be done before performing a biopsy, without exception. CLINICAL RELEVANCE: The updated ESSR soft tissue tumor imaging guidelines aim to provide best practice expert consensus for standardized imaging, to support radiologists in their decision-making, and to improve examination comparability both in individual patients and in future studies on individualized strategies. KEY POINTS: ⢠Ultrasound remains the best initial triage imaging modality for accessible and small suspected soft tissue tumors. ⢠MRI is the modality of choice for the characterization and local staging of soft tissue tumors in most cases; CT is indicated in special situations. Suspicious or likely malignant tumors should undergo biopsy. ⢠In patients with large, indeterminate or suspicious tumors, a tumor reference center should be contacted for referral or teleradiologic second opinion; this must be done before a biopsy.
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The Blood and Marrow Transplant Clinical Trials Network study 1101 (BMT CTN 1101; ClinicaTrials.gov identifier NCT01597778) was a multicenter phase III randomized trial comparing the clinical outcomes and quality of life (QoL) of patients with hematologic malignancies undergoing double umbilical cord blood transplantation (dUCBT) or HLA-haploidentical bone marrow transplantation (haplo-BMT) after reduced-intensity conditioning. At a 5-year follow-up, there were no significant differences in progression- free survival (PFS) or overall survival (OS) between the 2 cohorts. The impact of alternative donor source on QoL is unknown, however. English- and Spanish-speaking patients completed the Functional Assessment of Cancer Therapy-General (FACT-G), Short Form 36 (SF-36), EuroQoL-5 Dimensions EQ-5D, and Global QoL patient-reported outcome (PRO) assessments pretransplantation and at 12 and 24 months post-transplantation. We compared longitudinal QoL measures between the dUCBT and haplo-BMT cohorts and investigated the association of QoL and clinical outcomes using an inverse probability weighted-independent estimating equations method, accounting for missingness and baseline variables. We found no significant differences between the 2 cohorts in any of the QoL scores pretransplantation and at 12 and 24 months post-transplantation. Pretransplantation scores were the only significant predictors of post-transplantation QoL scores. Relapse and grade III-IV acute graft-versus-host disease (GVHD) were associated with significant declines in mean FACT-BMT and SF-36 Physical Component scores, and chronic GVHD was associated with a decline in mean EQ-5D utility scores. There were no significant associations between pretransplantation QoL scores and OS or PFS. Donor type did not impact post-transplantation QoL. Pretransplantation QoL scores and clinical events of GVHD and relapse were the only predictors of post-transplantation QoL. QoL was not associated with survival in either treatment arm. PROs may be valuable tools in pretransplantation risk assessment strategies to improve QoL outcomes.
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Trasplante de Médula Ósea , Enfermedad Injerto contra Huésped , Humanos , Trasplante de Médula Ósea/métodos , Médula Ósea , Sangre Fetal , Calidad de Vida , Recurrencia Local de Neoplasia , Enfermedad Injerto contra Huésped/epidemiología , Enfermedad CrónicaRESUMEN
BMT CTN 1101 was a Phase III randomized controlled trial comparing reduced-intensity conditioning followed by double unrelated umbilical cord blood transplantation (UCBT) versus HLA-haploidentical related donor bone marrow transplantation (haplo-BMT) for patients with high-risk hematologic malignancies. Here we report the results of a parallel cost-effectiveness analysis of these 2 hematopoietic stem cell transplantation (HCT) techniques. In this study, 368 patients were randomized to unrelated UCBT (n = 186) or haplo-BMT (n = 182). We estimated healthcare utilization and costs using propensity score-matched haplo-BMT recipients from the OptumLabs Data Warehouse for trial participants age <65 years and Medicare claims for participants age ≥65 years. Weibull models were used to estimate 20-year survival. EQ-5D surveys by trial participants were used to estimate quality-adjusted life-years (QALYs). At a 5-year follow-up, survival was 42% for haplo-BMT recipients versus 36% for UCBT recipients (P = .06). Over a 20-year time horizon, haplo-BMT is expected to be more effective (+.63 QALY) and more costly (+$118,953) for persons age <65 years. For those age ≥65 years, haplo-BMT is expected to be more effective and less costly. In one-way uncertainty analyses, for persons age <65, the cost per QALY result was most sensitive to life-years and health state utilities, whereas for those age ≥65, life- years were more influential than costs and health state utilities. Compared to UCBT, haplo-BMT was moderately more cost-effective for patients age <65 years and less costly and more effective for persons age ≥65 years. Haplo-BMT is a fair value choice for commercially insured patients with high-risk leukemia and lymphoma who require HCT. For Medicare enrollees, haplo-BMT is a preferred choice when considering costs and outcomes.
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Trasplante de Células Madre de Sangre del Cordón Umbilical , Trasplante de Células Madre Hematopoyéticas , Anciano , Estados Unidos , Humanos , Trasplante de Médula Ósea/métodos , Análisis Costo-Beneficio , Medicare , Trasplante de Células Madre Hematopoyéticas/métodosRESUMEN
Close HLA matching of donors and recipients has been the dogma for successful allogeneic blood or marrow transplantation (alloBMT), to limit the complications of graft-versus-host disease (GVHD). However, many patients in need, especially those within certain ethnic groups such as those of African-Americans and Hispanics, remain unable to find a match even with the increased availability of unrelated donors. Over half a century ago, investigators at Johns Hopkins found that cyclophosphamide's immunosuppressive properties made it the ideal replacement for total body irradiation in alloBMT conditioning regimens. They also found it to be the best chemotherapeutic for preventing GVHD in animal models, but its cytotoxic properties scared them from using it clinically in the high doses successful in animal models. Subsequent work showed that cyclophosphamide spared hematopoietic and other stem cells including memory lymphocytes, prompting re-examination at high doses for GVHD prophylaxis. Animal and extensive human studies demonstrated that high-dose post-transplantation cyclophosphamide (PTCy) effectively and safely limited GVHD such that mismatched transplants are now considered standard-of-care worldwide. The beneficial effects of PTCy on GVHD appears to be independent of donor type, graft source, or conditioning regimen intensity.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Animales , Humanos , Investigación Interdisciplinaria , Ciclofosfamida/uso terapéutico , Trasplante de Médula Ósea/efectos adversos , Trasplante de Células Madre Hematopoyéticas/efectos adversos , Enfermedad Injerto contra Huésped/etiología , Enfermedad Injerto contra Huésped/prevención & control , Donante no Emparentado , Acondicionamiento Pretrasplante/efectos adversosRESUMEN
Extra-skeletal osteosarcoma is a rare malignant soft tissue sarcoma which can cause a diagnostic challenge due to its non-specific presentation and soft tissue mineralisation, thus potentially mimicking conditions such as myositis ossificans. This review will outline the demographics, clinical presentation, key imaging features, differential diagnosis, management and outcomes of extra-skeletal osteosarcoma and serve as a reference to radiologists and other clinicians involved in the care of patients with soft tissue tumours and tumour-like lesions.
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Neoplasias Óseas , Miositis Osificante , Osteosarcoma , Neoplasias de los Tejidos Blandos , Humanos , Imagen por Resonancia Magnética , Osteosarcoma/diagnóstico por imagen , Osteosarcoma/terapia , Neoplasias de los Tejidos Blandos/patología , Miositis Osificante/diagnóstico por imagen , Miositis Osificante/patología , Diagnóstico Diferencial , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/terapiaRESUMEN
BACKGROUND: End-stage ankle osteoarthritis causes severe pain and disability. There are no randomized trials comparing the 2 main surgical treatments: total ankle replacement (TAR) and ankle fusion (AF). OBJECTIVE: To determine which treatment is superior in terms of clinical scores and adverse events. DESIGN: A multicenter, parallel-group, open-label randomized trial. (ISRCTN registry number: 60672307). SETTING: 17 National Health Service trusts across the United Kingdom. PATIENTS: Patients with end-stage ankle osteoarthritis, aged 50 to 85 years, and suitable for either procedure. INTERVENTION: Patients were randomly assigned to TAR or AF surgical treatment. MEASUREMENTS: The primary outcome was change in Manchester-Oxford Foot Questionnaire walking/standing (MOXFQ-W/S) domain scores between baseline and 52 weeks after surgery. No blinding was possible. RESULTS: Between 6 March 2015 and 10 January 2019, a total of 303 patients were randomly assigned; mean age was 68 years, and 71% were men. Twenty-one patients withdrew before surgery, and 281 clinical scores were analyzed. At 52 weeks, the mean MOXFQ-W/S scores improved for both groups. The adjusted difference in the change in MOXFQ-W/S scores from baseline was -5.6 (95% CI, -12.5 to 1.4), showing that TAR improved more than AF, but the difference was not considered clinically or statistically significant. The number of adverse events was similar between groups (109 vs. 104), but there were more wound healing issues in the TAR group and more thromboembolic events and nonunion in the AF group. The symptomatic nonunion rate for AF was 7%. A post hoc analysis suggested superiority of fixed-bearing TAR over AF (-11.1 [CI, -19.3 to -2.9]). LIMITATION: Only 52-week data; pragmatic design creates heterogeneity of implants and surgical techniques. CONCLUSION: Both TAR and AF improve MOXFQ-W/S and had similar clinical scores and number of harms. Total ankle replacement had greater wound healing complications and nerve injuries, whereas AF had greater thromboembolism and nonunion, with a symptomatic nonunion rate of 7%. PRIMARY FUNDING SOURCE: National Institute for Health and Care Research Heath Technology Assessment Programme.
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Artroplastia de Reemplazo de Tobillo , Osteoartritis , Masculino , Humanos , Anciano , Femenino , Artroplastia de Reemplazo de Tobillo/efectos adversos , Artroplastia de Reemplazo de Tobillo/métodos , Articulación del Tobillo/cirugía , Tobillo/cirugía , Medicina Estatal , Resultado del Tratamiento , Artrodesis/efectos adversos , Artrodesis/métodosRESUMEN
Oncohistones represent compelling evidence for a causative role of epigenetic perturbations in cancer. Giant cell tumours of bone (GCTs) are characterised by a mutated histone H3.3 as the sole genetic driver present in bone-forming osteoprogenitor cells but absent from abnormally large bone-resorbing osteoclasts which represent the hallmark of these neoplasms. While these striking features imply a pathogenic interaction between mesenchymal and myelomonocytic lineages during GCT development, the underlying mechanisms remain unknown. We show that the changes in the transcriptome and epigenome in the mesenchymal cells caused by the H3.3-G34W mutation contribute to increase osteoclast recruitment in part via reduced expression of the TGFß-like soluble factor, SCUBE3. Transcriptional changes in SCUBE3 are associated with altered histone marks and H3.3G34W enrichment at its enhancer regions. In turn, osteoclasts secrete unregulated amounts of SEMA4D which enhances proliferation of mutated osteoprogenitors arresting their maturation. These findings provide a mechanism by which GCTs undergo differentiation in response to denosumab, a drug that depletes the tumour of osteoclasts. In contrast, hTERT alterations, commonly found in malignant GCT, result in the histone-mutated neoplastic cells being independent of osteoclasts for their proliferation, predicting unresponsiveness to denosumab. We provide a mechanism for the initiation of GCT, the basis of which is dysfunctional cross-talk between bone-forming and bone-resorbing cells. The findings highlight the role of tumour/microenvironment bidirectional interactions in tumorigenesis and how this is exploited in the treatment of GCT.
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Neoplasias Óseas , Tumor Óseo de Células Gigantes , Humanos , Tumor Óseo de Células Gigantes/genética , Tumor Óseo de Células Gigantes/tratamiento farmacológico , Tumor Óseo de Células Gigantes/patología , Histonas/genética , Histonas/metabolismo , Denosumab/metabolismo , Denosumab/uso terapéutico , Neoplasias Óseas/genética , Neoplasias Óseas/tratamiento farmacológico , Neoplasias Óseas/metabolismo , Osteoclastos/metabolismo , Remodelación Ósea/genética , Microambiente Tumoral , Proteínas de Unión al Calcio/metabolismoRESUMEN
We previously reported the results of Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 1101, a randomized comparison of hematopoietic cell transplantation (HCT) performed with double umbilical cord blood units (dUCB) or with haploidentical bone marrow (haplo-BMT) with post-transplantation cyclophosphamide (PTCy) in the nonmyeloablative setting. Those results showed similar progression-free survival in the 2 treatment groups but lower nonrelapse mortality and better overall survival in the haplo-BM arm. In this secondary analysis, we sought to investigate whether transplantation center's previous experience with haplo-BM and/or dUCB HCT had an impact on outcomes. All patients randomized in BMT CTN 1101 were included. Center experience was assigned based on the number of transplantations with each platform performed in the year before initiation of the study according to the Center for International Blood and Marrow Transplant Research. Centers were then classified as a dUCB center (>10 dUCB HCTs; n = 117 patients, 10 centers), a haplo-BM center (>10 haplo-BM HCTs and ≤10 dUCB HCTs; n = 110 patients, 2 centers), or other center (≤10 haplo and ≤10 dUCB HCTs; n = 140 patients, 21 centers). After adjusting for age, Karnofsky Performance Status, and Disease Risk Index, we found that haplo-BM centers had lower overall mortality with this donor type compared with dUCB centers (hazard ratio [HR], 2.56; 95% confidence interval [CI], 1.44 to 4.56). In contrast, there were no differences in overall mortality between haplo-BM and dUCB in centers that were experienced with dUCB HCT (HR, 1.02; 95% CI, .59 to 1.79) or had limited to no experience with either dUCB or haplo-BM HCT (HR, 1.36; 95% CI, .83 to 2.21). The higher risk of treatment failure and overall mortality in dUCB HCT in haplo BM-experienced centers was driven by a significantly higher risk of relapse (HR, 1.78; 95% CI, 1.07 to 2.97). With the exception of worse outcomes among dUCB HCT recipients in haplo-BM centers, transplantation center experience in the year before initiation of BMT CTN 1101 had a limited impact on the outcomes of this randomized clinical trial.
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Trasplante de Células Madre Hematopoyéticas , Acondicionamiento Pretrasplante , Médula Ósea , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Recurrencia Local de Neoplasia , Acondicionamiento Pretrasplante/métodos , Trasplante Haploidéntico/métodosRESUMEN
OBJECTIVE: To determine the differential diagnosis of bone lesions causing hip pain in children and the association between radiographic features of aggression and MRI appearances with final diagnosis. METHODS: Retrospective review of children with hip pain referred to a specialist musculoskeletal oncology service between September 2018 and December 2020. Patient demographics, lesion location, the radiographic and MRI features, and the final diagnosis, which was made either by image-guided biopsy, surgical curettage or based on typical imaging features were recorded. Statistical analysis examined the association between the Lodwick-Madewell score (determined from available radiographs) and MRI findings with final diagnosis. RESULTS: Fifty-nine patients were included, 40 males and 19 females with mean age 10.9 years, (range 3-16 years). Final diagnoses were based on histology in 24 (40.7%) cases and imaging in 35 (59.3%) cases. Eighteen lesions (30.5%) were classed as non-neoplastic, 31 (52.5%) as benign and 10 (16.9%) as malignant, of which four were primary bone sarcomas. There was a significant association between the Lodwick-Madewell score and final diagnosis (p < 0.001). On MRI, bone marrow oedema, presence of a focal lesion, bone expansion and the presence of an extraosseous mass were all significantly associated with final diagnostic classification. CONCLUSION: The differential diagnosis of hip pain in children presenting to a bone tumour service is wide. Most cases are due to benign or non-neoplastic conditions, with only 10 out of 59 children having a malignant lesion. Radiography complemented by MRI plays a major role in differentiating non-neoplastic, benign neoplastic and malignant lesions and in determining the requirement for needle biopsy. ADVANCES IN KNOWLEDGE: This is the first study to consider how imaging features relate to diagnosis in suspected paediatric hip tumours. Use of this information can help in determining which cases should undergo needle biopsy.
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Neoplasias Óseas , Adolescente , Artralgia/diagnóstico por imagen , Artralgia/etiología , Neoplasias Óseas/complicaciones , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/patología , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Biopsia Guiada por Imagen , Imagen por Resonancia Magnética/métodos , Masculino , Dolor/etiología , Estudios RetrospectivosRESUMEN
CD19-directed chimerical antigen receptor T-cell (CAR-T) products have gained US Food and Drug Administration approval for systemic large B-cell lymphoma. Because of concerns about potential immune cell-associated neurotoxicity syndrome (ICANS), patients with primary central nervous system (CNS) lymphoma (PCNSL) were excluded from all pivotal CAR-T studies. We conducted a phase 1/2 clinical trial of tisagenlecleucel in a highly refractory patients with PCNSL and significant unmet medical need. Here, we present results of 12 relapsed patients with PCNSL who were treated with tisagenlecleucel and followed for a median time of 12.2 months (range, 3.64-23.5). Grade 1 cytokine release syndrome was observed in 7/12 patients (58.3%), low-grade ICANS in 5/12 (41.6%) patients, and only 1 patient experienced grade 3 ICANS. Seven of 12 patients (58.3%) demonstrated response, including a complete response in 6/12 patients (50%). There were no treatment-related deaths. Three patients had ongoing complete remission at data cutoff. Tisagenlecleucel expanded in the peripheral blood and trafficked to the CNS. Exploratory analysis identified T-cell, CAR T, and macrophage gene signatures in cerebrospinal fluid following infusion when compared with baseline. Overall, tisagenlecleucel was well tolerated and resulted in a sustained remission in 3/7 (42.9%) of initial responders. These data suggest that tisagenlecleucel is safe and effective in this highly refractory patient population. This trial was registered at www.clinicaltrials.gov as #NCT02445248.
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Neoplasias del Sistema Nervioso Central , Inmunoterapia Adoptiva , Linfoma , Receptores de Antígenos de Linfocitos T , Antígenos CD19/uso terapéutico , Neoplasias del Sistema Nervioso Central/terapia , Humanos , Inmunoterapia Adoptiva/efectos adversos , Linfoma/terapia , Receptores de Antígenos de Linfocitos T/uso terapéutico , Receptores Quiméricos de Antígenos/uso terapéuticoRESUMEN
In addition to remarkable antitumor activity, chimeric antigen receptor (CAR) T-cell therapy is associated with acute toxicities such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS). Current treatment guidelines for CRS and ICANS include use of tocilizumab, a monoclonal antibody that blocks the interleukin (IL)-6 receptor, and corticosteroids. In patients with refractory CRS, use of several other agents as third-line therapy (including siltuximab, ruxolitinib, anakinra, dasatinib, and cyclophosphamide) has been reported on an anecdotal basis. At our institution, anakinra has become the standard treatment for the management of steroid-refractory ICANS with or without CRS, based on recent animal data demonstrating the role of IL-1 in the pathogenesis of ICANS/CRS. Here, we retrospectively analyzed clinical and laboratory parameters, including serum cytokines, in 14 patients at our center treated with anakinra for steroid-refractory ICANS with or without CRS after standard treatment with tisagenlecleucel (Kymriah) or axicabtagene ciloleucel (Yescarta) CD19-targeting CAR T. We observed statistically significant and rapid reductions in fever, inflammatory cytokines, and biomarkers associated with ICANS/CRS after anakinra treatment. With three daily subcutaneous doses, anakinra did not have a clear, clinically dramatic effect on neurotoxicity, and its use did not result in rapid tapering of corticosteroids; although neutropenia and thrombocytopenia were common at the time of anakinra dosing, there were no clear delays in hematopoietic recovery or infections that were directly attributable to anakinra. Anakinra may be useful adjunct to steroids and tocilizumab in the management of CRS and/or steroid-refractory ICANs resulting from CAR T-cell therapies, but prospective studies are needed to determine its efficacy in these settings.
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Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Receptores Quiméricos de Antígenos/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Proteína Antagonista del Receptor de Interleucina 1/farmacología , Masculino , Persona de Mediana EdadAsunto(s)
Edema , Muslo , Anciano , Edema/diagnóstico por imagen , Femenino , Humanos , Dolor , Muslo/diagnóstico por imagenRESUMEN
OBJECTIVE: To determine the additional benefit of MRI for children with flatfoot deformity assessed with weight-bearing radiographs in a specialist paediatric orthopaedic unit. METHODS AND MATERIALS: Patient cohort was obtained by searching the Radiology Information System for children referred for investigation of flatfoot. All patients with flatfoot on weight-bearing radiographs who had undergone MRI were included. Radiographs were classified by a consultant musculoskeletal radiologist as showing no underlying abnormality, talo-calcaneal coalition, calcaneonavicular coalition, accessory navicular or other abnormality. MRI studies were classified similarly by a different consultant musculoskeletal radiologist blinded to the radiographic findings. RESULTS: 33 males and 24 females were included (mean age 12.5 years; range 3-18 years). 24 had bilateral abnormality, so 81 feet were assessed. Radiographs showed no specific abnormality (n = 51), talocalcaneal coalition (n = 6), calcaneonavicular coalition (n = 3), os naviculare (n = 12) or other abnormality (n = 9). MRI showed no specific abnormality (n = 40), talocalcaneal coalition (n = 10), calcaneonavicular coalition (n = 5), os naviculare (n = 12) or other abnormality (n = 14). Assuming MRI as the diagnostic gold-standard, additional relevant diagnostic information was identified in 19 (23.5%) cases, while in the 51 cases for which radiographs provided no specific diagnosis MRI confirmed no underlying abnormality in 31 (60.8%). CONCLUSION: MRI is a valuable adjunct to weight-bearing radiography for investigating paediatric flatfoot deformity. ADVANCES IN KNOWLEDGE: MRI is of value in the assessment of paediatric flatfoot, additional diagnostic information to radiography being identified in 23.5% cases, while in 60.8% of cases for which radiographs provided no specific diagnosis MRI confirmed no underlying abnormality.