A multimodal neural network with gradient blending improves predictions of survival and metastasis in sarcoma.

The objective of this study is to develop a multimodal neural network (MMNN) model that analyzes clinical variables and MRI images of a soft tissue sarcoma (STS) patient, to predict overall survival and risk of distant metastases. We compare the performance of this MMNN to models based on clinical variables alone, radiomics models, and an unimodal neural network. We include patients aged 18 or older with biopsy-proven STS who underwent primary resection between January 1st, 2005, and December 31st, 2020 with complete outcome data and a pre-treatment MRI with both a T1 post-contrast sequence and a T2 fat-sat sequence available. A total of 9380 MRI slices containing sarcomas from 287 patients are available. Our MMNN accepts the entire 3D sarcoma volume from T1 and T2 MRIs and clinical variables. Gradient blending allows the clinical and image sub-networks to optimally converge without overfitting. Heat maps were generated to visualize the salient image features. Our MMNN outperformed all other models in predicting overall survival and the risk of distant metastases. The C-Index of our MMNN for overall survival is 0.77 and the C-Index for risk of distant metastases is 0.70. The provided heat maps demonstrate areas of sarcomas deemed most salient for predictions. Our multimodal neural network with gradient blending improves predictions of overall survival and risk of distant metastases in patients with soft tissue sarcoma. Future work enabling accurate subtype-specific predictions will likely utilize similar end-to-end multimodal neural network architecture and require prospective curation of high-quality data, the inclusion of genomic data, and the involvement of multiple centers through federated learning.

Reconstruction of Internal Hemipelvectomy Defects After Oncologic Resection.

Internal hemipelvectomy is preferred to hindquarter amputation for pelvic tumor resection if a functional lower extremity can be obtained without compromising oncologic principles; multidisciplinary advances in orthopaedic and plastic surgery reconstruction have made this possible. The goals of skeletal reconstruction are restoration of pelvic and spinopelvic skeletal continuity, maintenance of limb length, and creation of a functional hip joint. The goals of soft-tissue reconstruction are stable coverage of skeletal, prosthetic, and neurovascular structures, elimination of dead space, and prevention of herniation. Pelvic resections are divided into four types: type I (ilium), type II (acetabulum), type III (ischiopubic rami), and type IV (sacrum). Type I and IV resections resulting in pelvic discontinuity are often reconstructed with vascularized bone flaps and instrumentation. Type II resections, which traditionally result in the greatest functional morbidity, are often reconstructed with hip transposition, allograft, prosthesis, and allograft-prosthetic composites. Type III resections require soft-tissue repair, sometimes with flaps and mesh, but generally no skeletal reconstruction. Extension of resection into the sacrum can result in additional skeletal instability, neurologic deficit, and soft-tissue insufficiency, necessitating a robust reconstructive strategy. Internal hemipelvectomy creates complex deficits that often require advanced multidisciplinary reconstructions to optimize outcomes and minimize complications.

Vegetation growth responses to climate change: A cross-scale analysis of biological memory and time lags using tree ring and satellite data.

Vegetation growth is affected by past growth rates and climate variability. However, the impacts of vegetation growth carryover (VGC; biotic) and lagged climatic effects (LCE; abiotic) on tree stem radial growth may be decoupled from photosynthetic capacity, as higher photosynthesis does not always translate into greater growth. To assess the interaction of tree-species level VGC and LCE with ecosystem-scale photosynthetic processes, we utilized tree-ring width (TRW) data for three tree species: Castanopsis eyrei (CE), Castanea henryi (CH, Chinese chinquapin), and Liquidambar formosana (LF, Chinese sweet gum), along with satellite-based data on canopy greenness (EVI, enhanced vegetation index), leaf area index (LAI), and gross primary productivity (GPP). We used vector autoregressive models, impulse response functions, and forecast error variance decomposition to analyze the duration, intensity, and drivers of VGC and of LCE response to precipitation, temperature, and sunshine duration. The results showed that at the tree-species level, VGC in TRW was strongest in the first year, with an average 77% reduction in response intensity by the fourth year. VGC and LCE exhibited species-specific patterns; compared to CE and CH (diffuse-porous species), LF (ring-porous species) exhibited stronger VGC but weaker LCE. For photosynthetic capacity at the ecosystem scale (EVI, LAI, and GPP), VGC and LCE occurred within 96 days. Our study demonstrates that VGC effects play a dominant role in vegetation function and productivity, and that vegetation responses to previous growth states are decoupled from climatic variability. Additionally, we discovered the possibility for tree-ring growth to be decoupled from canopy condition. Investigating VGC and LCE of multiple indicators of vegetation growth at multiple scales has the potential to improve the accuracy of terrestrial global change models.

Augmenting CAR T Cell Functions with LIGHT.

Chimeric antigen receptor (CAR) T-cell therapy has resulted in remarkable clinical success in the treatment of B-cell malignancies. However, its clinical efficacy in solid tumors is limited, primarily by target antigen heterogeneity. To overcome antigen heterogeneity, we developed CAR T cells that overexpress LIGHT, a ligand of both LTßR on cancer cells and HVEM on immune cells. LIGHT-expressing CAR T cells displayed both antigen-directed cytotoxicity mediated by the CAR and antigen-independent killing mediated through the interaction of LIGHT with LTßR on cancer cells. Moreover, CAR T cells expressing LIGHT had immunostimulatory properties that improved the cells' proliferation and cytolytic profile. These data indicate that LIGHT-expressing CAR T cells may provide a way to eliminate antigen-negative tumor cells to prevent antigen-negative disease relapse.

Distraction Osteogenesis Reconstruction Following Resection of Bone Sarcomas: Surgical, Functional, and Oncological Outcomes from a Prospective Trial Analysis.

BACKGROUND: While sustainable long-term function has been established for biological reconstruction with distraction osteogenesis (DO) following osseous resections, there is a paucity of published data informing surgeons and patients on important milestones in the reconstructive process. The objectives of this study were to determine when to expect complete bone healing and full weight-bearing as well as to quantify the influence of chemotherapy on the osseous regeneration process. METHODS: Prospectively, pathological and clinical data were collected for 30 consecutive patients who underwent primary or secondary DO-based reconstruction following osseous resection from 2018 to 2021. Serial radiographs indicated the times to cortex formation and full union. An unpaired t test was used to compare the time required for full bone remodeling of segments transported with and without concurrent chemotherapy. RESULTS: The average resection length was 13.6 cm (range, 4 to 22 cm). Patients underwent an average of 6.1 procedures (range, 1 to 14 procedures). Half (50%) of all procedures were planned, while half were unplanned procedures. All patients achieved full, independent weight-bearing at a median of 12 months (interquartile range [IQR], 9 to 16 months). For the 34 segments transported concurrently with chemotherapy, the mean bone healing index (BHI) was 2.3 ± 0.7, and the mean BHI was 1.2 ± 0.4 for the 25 segments without chemotherapy at any point during their transport (p < 0.0001). CONCLUSIONS: All 30 patients achieved full bone healing and independent weight-bearing at a median of 1 year postoperatively and continued to show functional improvement afterward. Surgeons and patients can expect bone healing to be nearly twice as fast for segments transported after completion of systemic chemotherapy compared with segments transported concurrently with adjuvant chemotherapy. LEVEL OF EVIDENCE: Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.

GLUT1 overexpression enhances CAR T cell metabolic fitness and anti-tumor efficacy.

The tumor microenvironment presents many obstacles to effective chimeric antigen receptor (CAR) T cell therapy, including glucose competition from tumor and myeloid cells. Using mouse models of acute lymphoblastic leukemia (ALL), renal cell carcinoma (RCC), and glioblastoma (GBM), we show that enforced expression of the glucose transporter GLUT1 enhances anti-tumor efficacy and promotes favorable CAR-T cell phenotypes for two clinically relevant CAR designs, 19-28z and IL13Rα2-BBz. In the NALM6 ALL model, 19-28z-GLUT1 promotes T stem cell-like memory formation and prolongs survival. RNA sequencing of these CAR-T cells reveals that the overexpression of GLUT1, but not GLUT3, enriches for genes involved in glycolysis, mitochondrial respiration, and memory precursor phenotypes. Extending these data, 19-28z-GLUT1 CAR-T cells improve tumor control and response to rechallenge in an RCC patient-derived xenograft model. Furthermore, IL13Rα2-BBz CAR-T cells overexpressing GLUT1 prolong the survival of mice bearing orthotopic GBMs and exhibit decreased exhaustion markers. This novel engineering approach can offer a competitive advantage to CAR-T cells in harsh tumor environments where glucose is limiting.

Chromoplexy Is a Frequent Early Clonal Event in EWSR1-Rearranged Round Cell Sarcomas That Can Be Detected Using Clinically Validated Targeted Sequencing Panels.

Chromoplexy is a phenomenon defined by large-scale chromosomal chained rearrangements. A previous study observed chromoplectic events in a subset of Ewing sarcomas (ES), which was linked to an increased relapse rate. Chromoplexy analysis could potentially facilitate patient risk stratification, particularly if it could be detected with clinically applied targeted next-generation sequencing (NGS) panels. Using DELLY, a structural variant (SV) calling algorithm that is part of the MSK-IMPACT pipeline, we characterized the spectrum of SVs in EWSR1-fused round cell sarcomas, including 173 ES and 104 desmoplastic small round cell tumors (DSRCT), to detect chromoplexy and evaluate its association with clinical and genomic features. Chromoplectic events were detected in 31% of the ES cases and 19% of the DSRCT cases. EWSR1 involvement accounted for 76% to 93% of these events, being rearranged with diverse noncanonical gene partners across the genome, involving mainly translocations but also intrachromosomal deletions and inversions. A major breakpoint cluster was located on EWSR1 exons 8-13. In a subset of cases, the SVs disrupted adjacent loci, forming deletion bridges. Longitudinal sequencing and breakpoint allele fraction analysis showed that chromoplexy is an early event that remains detectable throughout disease progression and likely develops simultaneously with the driver fusion. The presence of chromoplexy was validated in an external ES patient cohort with whole exome sequencing. Chromoplexy was significantly more likely to be present in cases that were metastatic at presentation. Together, this study identifies chromoplexy as a frequent genomic alteration in diverse EWSR1-rearranged tumors that can be captured by targeted NGS panels. SIGNIFICANCE: Chromoplexy is detectable using targeted NGS in a substantial portion of EWSR1-rearranged round cell sarcomas as an early and persistent clonal event, expanding the genomic complexity of fusion-associated sarcomas.

Tandem Reconstruction of the Femoral Diaphysis Using an Intercalary Prosthesis and a Fibular Free Flap.

BACKGROUND: Femoral diaphyseal reconstructions with metal prostheses have mediocre results because of high mechanical forces that result in eventual implant failure. Biological alternatives require prolonged restrictions on weight-bearing and have high rates of infection, nonunion, and fracture. A novel method of utilizing a vascularized fibula in combination with an intercalary prosthesis was developed to complement the immediate stability of the prosthesis with the long-term biological fixation of a vascularized fibular graft. METHODS: A prospectively maintained database was retrospectively reviewed to identify patients who underwent reconstruction of an oncological intercalary femoral defect using an intercalary prosthesis and an inline fibular free flap (FFF). They were compared with patients who underwent femoral reconstruction using an intercalary allograft and an FFF. RESULTS: Femoral reconstruction with an intercalary metal prosthesis and an FFF was performed in 8 patients, and reconstruction with an allograft and an FFF was performed in 16 patients. The mean follow-up was 5.3 years and 8.5 years, respectively (p = 0.02). In the bioprosthetic group, radiographic union of the fibula occurred in 7 (88%) of 8 patients, whereas in the allograft group, 13 (81%) of 16 patients had allograft union (p = 1.00) and all 16 patients had fibular union (p = 0.33). The mean time to fibular union in the bioprosthetic group was 9.0 months, whereas in the allograft group, the mean time to allograft union was 15.3 months (p = 0.03) and the mean time to fibular union was 12.5 months (p = 0.42). Unrestricted weight-bearing occurred at a mean of 3.7 months in the prosthesis group and 16.5 months in the allograft group (p < 0.01). Complications were observed in 2 (25%) of 8 patients in the prosthesis group and in 13 (81%) of 16 patients in the allograft group (p = 0.02). Neither chemotherapy nor radiation affected fibular or allograft union rates. Musculoskeletal Tumor Society scores did not differ significantly between the groups (mean, 26 versus 28; p = 0.10). CONCLUSIONS: Bioprosthetic intercalary femoral reconstruction with a metal prosthesis and an FFF resulted in earlier weight-bearing, a shorter time to union, fewer operations needed for union, and lower complication rates than reconstruction with an allograft and an FFF. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Horizontal viewsheds of large herbivores as a function of woodland structure.

There is great potential for the use of terrestrial laser scanning (TLS) to quantify aspects of habitat structure in the study of animal ecology and behaviour. Viewsheds-the area visible from a given position-influence an animal's perception of risk and ability to respond to potential danger. The management and conservation of large herbivores and their habitats can benefit greatly from understanding how vegetation structure shapes viewsheds and influences animal activity patterns and foraging behaviour. This study aimed to identify how woodland understory structure influenced horizontal viewsheds at deer eye height. Mobile TLS was used in August 2020 to quantify horizontal visibility-in the form of Viewshed Coefficients (VC)-and understory leaf area index (LAI) of 71 circular sample plots (15-m radius) across 10 woodland sites in North Wales (UK) where fallow deer (Dama dama) are present. The plots were also surveyed in summer for woody plant size structure, stem density and bramble (Rubus fruticosus agg.). Eight plots were re-scanned twice in winter to compare seasonal VC values and assess scan consistency. Sample plots with higher densities of small stems had significantly reduced VC 1 m from the ground. Other stem size classes, mean percentage bramble cover and understory LAI did not significantly affect VC. There was no difference in VC between summer and winter scans, or between repeated winter scans. The density of small stems influenced viewsheds at deer eye height and may alter behavioural responses to perceived risk. This study demonstrates how TLS technology can be applied to address questions in large herbivore ecology and conservation.

Breast Cancer Macrophage Heterogeneity and Self-renewal are Determined by Spatial Localization.

Tumor-infiltrating macrophages support critical steps in tumor progression, and their accumulation in the tumor microenvironment (TME) is associated with adverse outcomes and therapeutic resistance across human cancers. In the TME, macrophages adopt diverse phenotypic alterations, giving rise to heterogeneous immune activation states and induction of cell cycle. While the transcriptional profiles of these activation states are well-annotated across human cancers, the underlying signals that regulate macrophage heterogeneity and accumulation remain incompletely understood. Here, we leveraged a novel ex vivo organotypic TME (oTME) model of breast cancer, in vivo murine models, and human samples to map the determinants of functional heterogeneity of TME macrophages. We identified a subset of F4/80highSca-1+ self-renewing macrophages maintained by type-I interferon (IFN) signaling and requiring physical contact with cancer-associated fibroblasts. We discovered that the contact-dependent self-renewal of TME macrophages is mediated via Notch4, and its inhibition abrogated tumor growth of breast and ovarian carcinomas in vivo, as well as lung dissemination in a PDX model of triple-negative breast cancer (TNBC). Through spatial multi-omic profiling of protein markers and transcriptomes, we found that the localization of macrophages further dictates functionally distinct but reversible phenotypes, regardless of their ontogeny. Whereas immune-stimulatory macrophages (CD11C+CD86+) populated the tumor epithelial nests, the stroma-associated macrophages (SAMs) were proliferative, immunosuppressive (Sca-1+CD206+PD-L1+), resistant to CSF-1R depletion, and associated with worse patient outcomes. Notably, following cessation of CSF-1R depletion, macrophages rebounded primarily to the SAM phenotype, which was associated with accelerated growth of mammary tumors. Our work reveals the spatial determinants of macrophage heterogeneity in breast cancer and highlights the disruption of macrophage self-renewal as a potential new therapeutic strategy.

Predicting the spatial expansion of an animal population with presence-only data.

Predictive models can improve the efficiency of wildlife management by guiding actions at the local, landscape and regional scales. In recent decades, a vast range of modelling techniques have been developed to predict species distributions and patterns of population spread. However, data limitations often constrain the precision and biological realism of models, which make them less useful for supporting decision-making. Complex models can also be challenging to evaluate, and the results are often difficult to interpret for wildlife management practitioners. There is therefore a need to develop techniques that are appropriately robust, but also accessible to a range of end users. We developed a hybrid species distribution model that utilises commonly available presence-only distribution data and minimal demographic information to predict the spread of roe deer (Capreolus caprelous) in Great Britain. We take a novel approach to representing the environment in the model by constraining the size of habitat patches to the home-range area of an individual. Population dynamics are then simplified to a set of generic rules describing patch occupancy. The model is constructed and evaluated using data from a populated region (England and Scotland) and applied to predict regional-scale patterns of spread in a novel region (Wales). It is used to forecast the relative timing of colonisation events and identify important areas for targeted surveillance and management. The study demonstrates the utility of presence-only data for predicting the spread of animal species and describes a method of reducing model complexity while retaining important environmental detail and biological realism. Our modelling approach provides a much-needed opportunity for users without specialist expertise in computer coding to leverage limited data and make robust, easily interpretable predictions of spread to inform proactive population management.

Circular wood use can accelerate global decarbonisation but requires cross-sectoral coordination.

Predominantly linear use of wood curtails the potential climate-change mitigation contribution of forestry value-chains. Using lifecycle assessment, we show that more cascading and especially circular uses of wood can provide immediate and sustained mitigation by reducing demand for virgin wood, which increases forest carbon sequestration and storage, and benefits from substitution for fossil-fuel derived products, reducing net greenhouse gas emissions. By United Kingdom example, the circular approach of recycling medium-density fibreboard delivers 75% more cumulative climate-change mitigation by 2050, compared with business-as-usual. Early mitigation achieved by circular and cascading wood use complements lagged mitigation achieved by afforestation; and in combination these measures could cumulatively mitigate 258.8 million tonnes CO2e by 2050. Despite the clear benefits of implementing circular economy principles, we identify many functional barriers impeding the structural reorganisation needed for such complex system change, and propose enablers to transform the forestry value-chain into an effective societal change system and lead to coherent action.

Long-Term Outcomes in Patients With Localized Ewing Sarcoma Treated With Interval-Compressed Chemotherapy on Children's Oncology Group Study AEWS0031.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Long-term outcomes from Children's Oncology Group study AEWS0031 were assessed to determine whether the survival advantage of interval-compressed chemotherapy (ICC) was maintained over 10 years in patients with localized Ewing sarcoma (ES). AEWS0031 enrolled 568 eligible patients. Patients were randomly assigned to receive vincristine-doxorubicin-cyclophosphamide and ifosfamide-etoposide alternating once every 3 weeks (standard timing chemotherapy [STC]) versus once every 2 weeks (ICC). For this updated report, one patient was excluded because of uncertainty of original diagnosis. The 10-year event-free survival (EFS) was 70% with ICC compared with 61% with STC (P = .03), and 10-year overall survival (OS) was 76% with ICC compared with 69% with STC (P = .04). There was no difference in the 10-year cumulative incidence of second malignant neoplasms (SMNs; PC [see Data Supplement, online only] = .5). A test for interaction demonstrated that ICC provided greater risk reduction for patients with tumor volume ≥200 mL than for patients with tumors <200 mL, but no evidence for a significant interaction in other subgroups defined by age, primary site, and histologic response. With longer-term follow-up, ICC for localized ES is associated with superior EFS and OS without an increased risk for SMN compared with STC. ICC is associated with improved outcomes even in adverse-risk patient groups.

Reconstruction of oncologic upper extremity defects with fibula free flaps has high union rates and excellent functional outcomes.

BACKGROUND: Limb salvage has better functional outcomes than amputation in the upper extremity. This can however be challenging after bony tumor resections. METHODS: This is a retrospective case series of patients who underwent humerus, ulna, or radius reconstruction with a fibula free flap. Data were collected on demographics, oncologic history, surgical details, and complications. Functional outcome measures included the patient's ability to perform activities of daily living (ADL), presence of pain, and musculoskeletal tumor society (MSTS) score. RESULTS: Over a 25-year period, 38 reconstructions were performed. The flap success rate was 97.5%. Bony union was obtained in 19 of 19 (100%) forearm reconstructions and in 15 of 19 (79%) humerus reconstructions (p = 0.10). All 19 forearm reconstruction patients and 18/19 humerus reconstruction patients were able to perform ADLs with no pain or only occasional pain. The MSTS scores were not significantly different between the humerus and forearm cohorts (27.1 vs. 27.3, p = 0.68). Functional outcomes were significantly better in limbs that achieved union (p < 0.001). Recipient and donor site complications occurred in 10 (26.3%) and 5 (13%) patients, respectively. CONCLUSIONS: Oncologic upper-extremity reconstruction with fibula free flaps has excellent functional outcomes. Bone union is a predictor of superior limb function.

Operative Treatment and Outcomes of Pediatric Patients with an Extremity Bone Tumor: A Secondary Analysis of the PARITY Trial Data.

BACKGROUND: Osteosarcoma and Ewing sarcoma are the 2 most common primary bone sarcomas, occurring predominantly in pediatric patients, with the incidence of osteosarcoma correlating with periods of peak bone-growth velocity. Although survival outcomes have plateaued over the past several decades, ongoing treatment advances have improved function, decreased infection rates, and improved other clinical outcomes in patients with bone tumors. Recently, the Prophylactic Antibiotic Regimens in Tumor Surgery (PARITY) trial addressed the serious problem of surgical site infection (SSI) and the lack of consensus regarding the appropriate prophylactic postoperative antibiotic regimen. The objective of the present secondary analysis of the PARITY trial was to characterize the modern treatment and surgical and oncologic outcomes of pediatric patients with bone tumors at 1 year postoperatively. METHODS: The PARITY trial included patients ≥12 years old with a bone tumor or soft-tissue sarcoma that was invading the femur or tibia, necessitating osseous resection and endoprosthetic reconstruction. This pediatric subanalysis of the PARITY trial data included all PARITY patients ≤18 years old. As in the main PARITY study, patients were randomized to either a 5-day or 1-day course of postoperative antibiotic prophylaxis. The primary outcome measure was the development of an SSI within 1 year, and secondary outcomes included antibiotic-related adverse events, unplanned additional operations, local recurrence, metastasis, and death. RESULTS: A total of 151 patients were included. An adjudicated SSI occurred in 27 patients (17.9%). There was no difference in the rate of any SSI between the 5-day and 1-day antibiotic groups (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.4 to 1.9; p = 0.82). Antibiotic-related complications occurred in 13 patients (8.6%), with no difference noted between groups (HR, 0.46; 95% CI, 0.2 to 1.4; p = 0.18). A total of 45 patients (29.8%) required a return to the operating room within the first postoperative year, which corresponded with a 68.8% reoperation-free rate of survival at 1 year when accounting for competing risks. The most common reason for reoperation was infection (29 of 45; 64.4%). A total of 7 patients (4.6%) required subsequent amputation of the operative extremity, and an additional 6 patients (4.0%) required implant revision within 12 months. A total of 36 patients (23.8%) developed metastases, and 6 patients (4.0%) developed a local recurrence during the first postoperative year. A total of 11 patients (7.3%) died during the study period. There were no significant differences in oncologic outcomes between the 5-day and 1-day antibiotic groups (HR, 0.97; 95% CI, 0.5-1.8; p = 0.92). CONCLUSIONS: There were no significant differences in surgical or oncologic outcomes between pediatric patients who underwent a 1-day versus 5-day antibiotic regimen following endoprosthetic reconstruction in the PARITY trial. Surgeons should be aware of and counsel patients and caregivers regarding the 30% rate of reoperation and the risks of infection (17.9%), death (7.3%), amputation (4.6%), and implant revision (4%) within the first postoperative year. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Tumour extracellular vesicles and particles induce liver metabolic dysfunction.

Cancer alters the function of multiple organs beyond those targeted by metastasis1,2. Here we show that inflammation, fatty liver and dysregulated metabolism are hallmarks of systemically affected livers in mouse models and in patients with extrahepatic metastasis. We identified tumour-derived extracellular vesicles and particles (EVPs) as crucial mediators of cancer-induced hepatic reprogramming, which could be reversed by reducing tumour EVP secretion via depletion of Rab27a. All EVP subpopulations, exosomes and principally exomeres, could dysregulate hepatic function. The fatty acid cargo of tumour EVPs-particularly palmitic acid-induced secretion of tumour necrosis factor (TNF) by Kupffer cells, generating a pro-inflammatory microenvironment, suppressing fatty acid metabolism and oxidative phosphorylation, and promoting fatty liver formation. Notably, Kupffer cell ablation or TNF blockade markedly decreased tumour-induced fatty liver generation. Tumour implantation or pre-treatment with tumour EVPs diminished cytochrome P450 gene expression and attenuated drug metabolism in a TNF-dependent manner. We also observed fatty liver and decreased cytochrome P450 expression at diagnosis in tumour-free livers of patients with pancreatic cancer who later developed extrahepatic metastasis, highlighting the clinical relevance of our findings. Notably, tumour EVP education enhanced side effects of chemotherapy, including bone marrow suppression and cardiotoxicity, suggesting that metabolic reprogramming of the liver by tumour-derived EVPs may limit chemotherapy tolerance in patients with cancer. Our results reveal how tumour-derived EVPs dysregulate hepatic function and their targetable potential, alongside TNF inhibition, for preventing fatty liver formation and enhancing the efficacy of chemotherapy.

Tenosynovial Giant Cell Tumor Observational Platform Project (TOPP) Registry: A 2-Year Analysis of Patient-Reported Outcomes and Treatment Strategies.

BACKGROUND: The Tenosynovial giant cell tumor Observational Platform Project (TOPP) registry is an international prospective study that -previously described the impact of diffuse-type tenosynovial giant cell tumour (D-TGCT) on patient-reported outcomes (PROs) from a baseline snapshot. This analysis describes the impact of D-TGCT at 2-year follow-up based on treatment strategies. MATERIAL AND METHODS: TOPP was conducted at 12 sites (EU: 10; US: 2). Captured PRO measurements assessed at baseline, 1-year, and 2-year follow-ups were Brief Pain Inventory (BPI), Pain Interference, BPI Pain Severity, Worst Pain, EQ-5D-5L, Worst Stiffness, and -Patient-Reported Outcomes Measurement Information System. Treatment interventions were no current/planned treatment (Off-Treatment) and systemic treatment/surgery (On-Treatment). RESULTS: A total of 176 patients (mean age: 43.5 years) were included in the full analysis set. For patients without active treatment strategy -(Off-Treatment) at baseline (n = 79), BPI Pain Interference (1.00 vs. 2.86) and BPI Pain Severity scores (1.50 vs. 3.00) were numerically favorable in patients remaining Off-Treatment compared with those who switched to an active treatment strategy at year 1. From 1-year to 2-year -follow-ups, patients who remained Off-Treatment had better BPI Pain Interference (0.57 vs. 2.57) and Worst Pain (2.0 vs. 4.5) scores compared with patients who switched to an alternative treatment strategy. In addition, EQ-5D VAS scores (80.0 vs. 65.0) were higher in patients who remained -Off-Treatment between 1-year and 2-year follow-ups compared with patients who changed treatment strategy. For patients receiving systemic treatment at baseline, numerically favorable scores were seen in patients remaining on systemic therapy at 1-year follow-up: BPI Pain Interference (2.79 vs. 5.93), BPI Pain Severity (3.63 vs. 6.38), Worst Pain (4.5 vs. 7.5), and Worst Stiffness (4.0 vs. 7.5). From 1-year to 2-year follow-up, EQ-5D VAS scores (77.5 vs. 65.0) were higher in patients who changed from systemic treatment to a different treatment strategy. CONCLUSION: These findings highlight the impact D-TGCT has on patient quality of life, and how treatment strategies may be influenced by these outcome measures. (ClinicalTrials.gov number: NCT02948088).

Distinct IDH1/2-associated Methylation Profile and Enrichment of TP53 and TERT Mutations Distinguish Dedifferentiated Chondrosarcoma from Conventional Chondrosarcoma.

Dedifferentiated chondrosarcoma (DDCS) is a rare high-grade chondrosarcoma characterized by a well-differentiated chondrosarcoma (WDCS) component that abruptly transitions to a high-grade, noncartilaginous sarcomatous component. To date, the molecular pathogenesis of DDCS and its distinction from conventional chondrosarcoma remain poorly understood. By targeted sequencing, we examined the mutational and copy-number profiles of 18 DDCS, including macrodissected WDCS components, compared with 55 clinically sequenced conventional chondrosarcomas. In conjunction with publicly available external data, we analyzed the methylation and expression profiles of 34 DDCS and 94 conventional chondrosarcomas. Isocitrate dehydrogenase 1/isocitrate dehydrogenase 2 (IDH1/IDH2) mutations were present in 36% conventional chondrosarcomas and 71% DDCS. Compared with conventional chondrosarcomas, DDCS had higher frequencies of TP53 and TERT promoter mutations and CDKN2A/B copy-number losses. Paired analysis of macrodissected WDCS and the high-grade components revealed TERT promoter mutations as early events. Despite phenotypic similarities, the percentage of genome with copy-number alterations in DDCS was significantly lower than that in other high-grade sarcomas. Differential methylation analysis revealed reduction of IDH1/IDH2-associated global hypermethylation characteristically seen in conventional chondrosarcoma and a distinct methylation profile in DDCS. The WDCS and high-grade components in DDCS showed similar methylation profiles. These CpG sites were associated with upregulated expression of genes involved in G2-M checkpoints and E2F targets. Genomic profiling revealed enrichment of TP53, TERT promoter, and CDKN2A/B alterations in DDCS. Integrated methylation and gene expression analysis revealed distinct IDH1/IDH2-associated methylation and transcriptional profiles as early events in DDCS, which may underlie the pathogenesis of dedifferentiation in chondrosarcomas. Significance: DDCS is a rare, high-grade chondrosarcoma with a dismal prognosis. About 50%-80% of DDCS harbor IDH1/IDH2 mutations. We uncover a significant alteration of IDH-associated methylation profile in DDCS, which we propose is key to the progression to dedifferentiation. In this context, the potential effect of the use of IDH inhibitors is unclear but important to address, as clinical trials of selective IDH1 inhibitors showed worse outcome in DDCS.