Third-party fecal microbiota transplantation for high-risk treatment-naïve acute GVHD of the lower GI tract.

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.

Soft tissue tumor imaging in adults: European Society of Musculoskeletal Radiology-Guidelines 2023-overview, and primary local imaging: how and where?

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.

Health-Related Quality of Life in Double Umbilical Cord Blood versus Haploidentical Marrow Transplantation: A Quality of Life Analysis Report of BMT CTN 1101.

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.

Cost-Effectiveness of Unrelated Umbilical Cord Blood Transplantation versus HLA-Haploidentical Related Bone Marrow Transplantation: Evidence from BMT CTN 1101.

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.

The development of post-transplant cyclophosphamide: Half a century of translational team science.

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.

Extra-skeletal osteosarcoma: a review.

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.

Total Ankle Replacement Versus Arthrodesis for End-Stage Ankle Osteoarthritis: A Randomized Controlled Trial.

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.

Aberrant paracrine signalling for bone remodelling underlies the mutant histone-driven giant cell tumour of bone.

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.

Impact of Center Experience with Donor Type on Outcomes: A Secondary Analysis, Blood and Marrow Transplant Clinical Trials Network 1101Open for Accrual June 2012Open for Accrual June 2012.

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.

Differential diagnosis of hip pain in children referred to a specialist bone tumour service.

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.

Safety and efficacy of tisagenlecleucel in primary CNS lymphoma: a phase 1/2 clinical trial.

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.

Single-center experience using anakinra for steroid-refractory immune effector cell-associated neurotoxicity syndrome (ICANS).

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.

Peripheral and periosteal chondrosarcoma: MRI-pathological correlation in 58 cases.

OBJECTIVE: To determine whether MRI can distinguish atypical cartilaginous tumour/grade 1 peripheral/periosteal chondrosarcoma (ACT/Gd1 PP-CS) from high-grade peripheral/periosteal chondrosarcoma (HG-PP-CS) or dedifferentiated peripheral/periosteal chondrosarcoma (DD-PP-CS). MATERIALS AND METHODS: Retrospective review of patients diagnosed between January 2007 and December 2020 who had undergone resection of PP-CS. Data collected included age, sex, and skeletal location. Histological tumour grades based on surgical resection were classified as ACT/grade 1 PP-CS, HG-PP-CS, or DD-PP-CS. A variety of MRI features were reviewed independently by 2 musculoskeletal radiologists blinded to final diagnosis and compared between the 3 groups. For statistical analysis, HG-PP-CS and DD-PP-CS were combined. RESULTS: Fifty-eight patients fulfilled the inclusion criteria, 31 (53%) males and 27 (47%) females with a mean age at diagnosis of 46.1 years (range 11-83 years), 14 (24%) of whom had an underlying diagnosis of diaphyseal aclasis. Forty-one (70.7%) cases were peripheral and 17 (29.3%) periosteal, 38 (66%) involving the flat bones, 15 (26%) the major long bones, 3 (5%) the spine, and 2 (3%) the bones of the hands and feet. Final histology revealed 33 (57%) ACT/Gd1-PP-CS, 18 (31%) HG-PP-CS, and 7 (12%) DD-PP-CS. Periosteal tumours were 16 times more likely to be HG/DD-CS compared to peripheral tumours (p < 0.001). Intra-medullary tumour extension was predictive of HG/DD-CS (p = 0.004) for both tumour types, while cap thickness (p = 0.04) and a diffuse cap type (p = 0.03) were differentiating features of low-grade and high-grade peripheral CS. DISCUSSION: A variety of features can help differentiate low-grade from high-grade peripheral/periosteal CS, the most significant being origin from the bone surface.

Long-term survival with mixed chimerism in patients with AML and MDS transplanted after conditioning with targeted busulfan, fludarabine, and thymoglobulin.

We evaluated long-term outcome in 40 patients with MDS or AML, transplanted from related or unrelated donors following conditioning with targeted busulfan (Bu, over 4 days), fludarabine (Flu, 120 [n = 23] or 250 [n = 17] mg/m2) and thymoglobulin (THY). Compared to 95 patients conditioned with Bu/Cyclophosphamide (Cy) without THY, BuFluTHY-conditioned patients had lower rates of chronic graft-vs.-host disease (GVHD). Adjusted hazard ratios (HR) for BuFlu(120)THY and BuFlu(250)THY-conditioned patients were 1.60 (95% confidence interval (CI) 0.66-3.86) and 1.87 (0.68-5.11), respectively, for relapse; 0.77 (0.30-1.99) and 1.32 (0.54-3.23) for non-relapse mortality; 0.81 (0.42-1.57) and 1.38 (0.72-2.57) for overall mortality; and 0.78 (0.30-2.05) and 1.62 (0.63-4.41) for relapse or death (failure for relapse-free survival). At one year, 45% of BuFlu(120 or 250)THY-conditioned patients had mixed CD3+ chimerism compared to 0% with BuCy (p < 0.0001). None of 7 patients with long-term mixed chimerism had chronic GVHD; two relapsed, five remained stable mixed chimeras. THY is effective in reducing chronic GVHD, and long-term mixed T-cell chimerism can be compatible with relapse-free survival. However, Thy may also be associated with an increased risk of relapse and, dose-dependent, with non-relapse mortality.

Ossifying Fibroma of Non-odontogenic Origin: A Fibro-osseous Lesion in the Craniofacial Skeleton to be (Re-)considered.

In the cranio-facial skeleton, a heterogeneous group of well characterized fibro-osseous lesions can be distinguished. Whereas fibrous dysplasia can affect any skeletal bone, ossifying fibroma and cemento-osseous dysplasia exclusively develop in the cranio-facial region, with most subtypes restricted to the tooth bearing areas of the jaws. Herein we present a series of 20 fibro-osseous lesions that developed mostly in the frontal bone and in the mandible, presenting as expansile intramedullary tumors with a unique histologic appearance and an indolent clinical course. We provide evidence that these tumors are distinct from the categories included in the WHO classification and are therefore currently unclassifiable. The definition of cemento-ossifying fibroma as an odontogenic neoplasm developing only in close proximity to teeth should be re-considered and incorporate also extragnathic lesions as shown here.