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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.
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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.
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Neoplasias Ósseas , Osteogênese por Distração , Humanos , Osteogênese por Distração/métodos , Masculino , Feminino , Neoplasias Ósseas/cirurgia , Adulto , Estudos Prospectivos , Pessoa de Meia-Idade , Adolescente , Adulto Jovem , Osteossarcoma/cirurgia , Resultado do Tratamento , Criança , Procedimentos de Cirurgia Plástica/métodos , Suporte de Carga/fisiologia , Regeneração Óssea/efeitos dos fármacos , IdosoRESUMO
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.
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Transportador de Glucose Tipo 1 , Imunoterapia Adotiva , Receptores de Antígenos Quiméricos , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Modelos Animais de Doenças , Transportador de Glucose Tipo 1/genética , Transportador de Glucose Tipo 1/metabolismo , Imunoterapia Adotiva/métodos , Leucemia-Linfoma Linfoblástico de Células Precursoras/terapia , Leucemia-Linfoma Linfoblástico de Células Precursoras/genética , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Receptores de Antígenos Quiméricos/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/imunologiaRESUMO
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.
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Membros Artificiais , Neoplasias Ósseas , Retalhos de Tecido Biológico , Humanos , Fíbula/transplante , Retalhos de Tecido Biológico/patologia , Estudos Retrospectivos , Diáfises/cirurgia , Diáfises/patologia , Neoplasias Ósseas/cirurgia , Transplante Ósseo/métodos , Resultado do TratamentoRESUMO
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.
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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.
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Neoplasias Ósseas , Sarcoma de Ewing , Humanos , Criança , Sarcoma de Ewing/patologia , Neoplasias Ósseas/terapia , Etoposídeo , Ifosfamida , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Doxorrubicina , VincristinaRESUMO
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.
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Neoplasias Ósseas , Osteossarcoma , Adolescente , Criança , Antibacterianos , Extremidade Inferior , Osteossarcoma/cirurgia , Estudos Retrospectivos , Infecção da Ferida Cirúrgica , Resultado do Tratamento , HumanosRESUMO
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.
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Vesículas Extracelulares , Ácidos Graxos , Fígado Gorduroso , Fígado , Neoplasias Pancreáticas , Animais , Camundongos , Sistema Enzimático do Citocromo P-450/genética , Vesículas Extracelulares/metabolismo , Ácidos Graxos/metabolismo , Fígado Gorduroso/tratamento farmacológico , Fígado Gorduroso/etiologia , Fígado Gorduroso/metabolismo , Fígado Gorduroso/prevenção & controle , Fígado/metabolismo , Fígado/patologia , Fígado/fisiopatologia , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Microambiente Tumoral , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/metabolismo , Neoplasias Hepáticas/secundário , Humanos , Inflamação/metabolismo , Ácido Palmítico/metabolismo , Células de Kupffer , Fosforilação Oxidativa , Proteínas rab27 de Ligação ao GTP/deficiênciaRESUMO
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.
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Neoplasias Ósseas , Condrossarcoma , Telomerase , Humanos , Isocitrato Desidrogenase/genética , Condrossarcoma/genética , Mutação/genética , Metilação de DNA/genética , Neoplasias Ósseas/genética , Proteína Supressora de Tumor p53/genética , Telomerase/genéticaRESUMO
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).
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Tumor de Células Gigantes de Bainha Tendinosa , Qualidade de Vida , Humanos , Adulto , Estudos Prospectivos , Tumor de Células Gigantes de Bainha Tendinosa/cirurgia , Dor , Medidas de Resultados Relatados pelo PacienteRESUMO
Giant cell tumor of bone (GCTB) is a locally aggressive tumor that shows predilection for the metaphysis/epiphysis of long bones, with an incidence of 4-5% of primary bone tumors. GCTB shows two main populations of cells: mononuclear cells and non-neoplastic multi-nucleated giant cells, with or without fibrous background. On the other hand, giant-cell-poor GCTB are rare with only few reports in the literature. These cases offer a diagnostic challenge, given the absence of giant cells and such cases have consistently been shown to harbor the H3F3A gene mutation by sequencing. The H3.3 G34W mutation-specific monoclonal antibody has shown high specificity in the diagnosis of GCTB. Two cases of giant-cell-poor GCTB are presented in this study, in which giant cells were absent or sparse and the diagnosis of GCTB was confirmed by the expression of H3.3 G34W monoclonal antibody in the mononuclear cells by immunohistochemistry. Whether this represents a histologic variant of GCTB or partial involution of GCTB is not yet fully understood; however, an immune response, infectious/inflammatory reaction, and/or anti-tumor cytokine production have been purported to be factors inciting disease regression in GCTB.
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Neoplasias Ósseas , Tumor de Células Gigantes do Osso , Humanos , Histonas/genética , Tumor de Células Gigantes do Osso/diagnóstico por imagem , Tumor de Células Gigantes do Osso/genética , Anticorpos Monoclonais , Imuno-Histoquímica , Neoplasias Ósseas/diagnósticoRESUMO
Cathepsin proteases, activated in the lysosomes, are upregulated in many cancers. Intraoperative detection systems of microscopic residual tumor using cathepsin-mediated release of fluorescent nanoparticles may guide surgical excisions to improve local control. We sought to define the genetic and proteomic expression of cathepsins and their clinicopathological correlates in myxofibrosarcoma and undifferentiated pleomorphic sarcoma (UPS)-soft tissue sarcomas with high rates of positive resection margins and local recurrence-and to establish a cellular justification for cathepsin-dependent systems to identify residual cancer in the resection bed. Real-time quantitative polymerase chain reaction analysis of 58 fresh-frozen tumor specimens revealed that 56 (97%) had elevated mRNA expression of ≥1 cathepsin, including cathepsin-B (79%), cathepsin-K (59%), cathepsin-L (71%), and -S (71%). Immunohistochemical analysis of these fresh-frozen specimens revealed that 98% of tumors were positive for one or more of cathepsin-B (85%), cathepsin-K (50%), cathepsin-L (63%), and -S (10%). Strong cathepsin-K expression was associated with greater risks of local recurrence (hazard ratio, 3.78; p = 0.044) and disease-specific mortality (hazard ratio, 3.70; p = 0.025). Immunohistochemical analysis of 33 formalin-fixed paraffin-embedded block samples revealed that 97% were positive for cathepsin-B (88%), cathepsin-K (76%), cathepsin-L (52%), or -S (52%) at the tumor periphery; cathepsin-K positivity correlated with a radiographic tail-like sign (p = 0.004) and microscopic infiltrative growth (p = 0.020). We conclude that cathepsins are broadly overexpressed in myxofibrosarcoma and UPS, and cathepsin-K may be an immunohistochemical marker of local infiltration and poorer prognosis that could be used to guide precision surgery.
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Fibrossarcoma , Histiocitoma Fibroso Maligno , Sarcoma , Neoplasias de Tecidos Moles , Humanos , Adulto , Catepsinas/genética , Catepsinas/metabolismo , Peptídeo Hidrolases , Proteômica , Sarcoma/cirurgia , Sarcoma/patologia , Fibrossarcoma/genética , Fibrossarcoma/cirurgia , Fibrossarcoma/patologia , Neoplasias de Tecidos Moles/patologiaRESUMO
Osteosarcoma is the most common primary bone cancer, whose standard treatment includes pre-operative chemotherapy followed by resection. Chemotherapy response is used for prognosis and management of patients. Necrosis is routinely assessed after chemotherapy from histology slides on resection specimens, where necrosis ratio is defined as the ratio of necrotic tumor/overall tumor. Patients with necrosis ratio ≥90% are known to have a better outcome. Manual microscopic review of necrosis ratio from multiple glass slides is semiquantitative and can have intraobserver and interobserver variability. In this study, an objective and reproducible deep learning-based approach was proposed to estimate necrosis ratio with outcome prediction from scanned hematoxylin and eosin whole slide images (WSIs). To conduct the study, 103 osteosarcoma cases with 3134 WSIs were collected. Deep Multi-Magnification Network was trained to segment multiple tissue subtypes, including viable tumor and necrotic tumor at a pixel level and to calculate case-level necrosis ratio from multiple WSIs. Necrosis ratio estimated by the segmentation model highly correlates with necrosis ratio from pathology reports manually assessed by experts. Furthermore, patients were successfully stratified to predict overall survival with P = 2.4 × 10-6 and progression-free survival with P = 0.016. This study indicates that deep learning can support pathologists as an objective tool to analyze osteosarcoma from histology for assessing treatment response and predicting patient outcome.
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Neoplasias Ósseas , Aprendizado Profundo , Osteossarcoma , Humanos , Neoplasias Ósseas/tratamento farmacológico , Neoplasias Ósseas/patologia , Prognóstico , Necrose/patologia , Osteossarcoma/tratamento farmacológico , Osteossarcoma/patologiaRESUMO
BACKGROUND: The double-blind, randomized, placebo-controlled phase 3 study of orally administered PLX3397 in patients with pigmented villonodular synovitis or giant cell tumor of the tendon sheath (ENLIVEN) showed that pexidartinib provides a robust objective tumor response in adults with tenosynovial giant cell tumors (TGCT) not amenable to improvement with surgery. Based on these results, in 2019, pexidartinib received accelerated approval in the United States in this population as a breakthrough therapy under an orphan drug designation. However, the ability of pexidartinib to relieve pain in ENLIVEN was not fully detailed, and the relationship between pain relief and objective tumor response was not described. QUESTIONS/PURPOSES: (1) What level of pain relief was achieved by pexidartinib treatment in ENLIVEN? (2) How was pain relief related to objective tumor responses? (3) How durable was pain relief? METHODS: The current study included planned primary and exploratory assessments of patient-assessed worst pain at the site of the tumor in the ENLIVEN trial. ENLIVEN was a phase 3 randomized, placebo-controlled clinical trial in which adults with TGCT not amenable to improvement with surgery received pexidartinib or placebo for 24 weeks, after which eligible patients could receive open-label pexidartinib. Of 174 patients assessed for eligibility, 121 were randomized (50% [60] to placebo, 50% [61] to pexidartinib), and 120 were given either placebo or pexidartinib (59 received placebo and 61 received pexidartinib) and were included in an intent-to-treat analysis. Fifty-nine percent (71 of 120) of the overall treated population was female, and 88% (106 of 120) were White. Mean age was 45 ± 13 years. Tumors were mostly in the lower extremities (92% [110 of 120]), most commonly in the knee (61% [73 of 120]) and ankle (18% [21 of 120]). As a secondary outcome, patients scored worst pain at the site of the tumor in the past 24 hours on an 11-point numeric rating scale (NRS). The primary definition of a pain response was a decrease of at least 30% in the weekly mean worst-pain NRS score and increase of less than 30% in narcotic analgesic use between baseline and week 25. Planned exploratory assessments of pain included the frequency of a pain response using alternative thresholds, including a decrease in worst-pain NRS score of 50% or more and a decrease of at least 2 points (minimum clinically important difference [MCID]), the magnitude of pain reduction between baseline and week 25, correlation between worst-pain NRS score and tumor shrinkage by RECIST 1.1 criteria, and the durability of the pain response during the open-label extension. Pain responses during the randomized portion of the trial were compared according to intention-to-treat analysis, with a one-sided threshold of p < 0.025 to reduce the risk of false-positive results. Pain assessment was complete for 59% (35 of 59) of patients in the placebo group and 54% (33 of 61) of patients in the pexidartinib group. Demographic and disease characteristics did not differ between the two treatment groups. RESULTS: A difference in the primary assessment of a pain response was not detected between pexidartinib and placebo (response percentage 31% [19 of 61] [95% CI 21% to 44%] versus 15% [9 of 59] [95% CI 8% to 27%]; one-sided p = 0.03). In the exploratory analyses, pexidartinib provided a modest improvement in pain (response percentage 26% [16 of 61] [95% CI 17% to 38%] versus 10% [6 of 59] [95% CI 5% to 20%]; one-sided p = 0.02 using the 50% threshold and 31% [19 of 61] [95% CI 21% to 44%] versus 14% [8 of 59] [95% CI 7% to 25%]; one-sided p = 0.02 using the MCID threshold). The least-squares mean change in the weekly mean worst-pain NRS score between baseline and week 25 was larger in patients treated with pexidartinib than placebo (-2.5 [95% CI -3.0 to -1.9] versus -0.3 [95% CI -0.9 to 0.3]; p < 0.001), although the mean difference between the two groups (-2.2 [95% CI -3.0 to -1.4]) was just over the MCID. Improvement in the weekly mean worst-pain NRS score correlated with the reduction in tumor size (r = 0.44; p < 0.001) and tumor volume score (r = 0.61; p < 0.001). For patients in the open-label extension, the change in the worst-pain NRS score from baseline was similar to the change at the end of the randomized portion and just above the MCID (mean -2.7 ± 2.2 after 25 weeks and -3.3 ± 1.7 after 50 weeks of receiving pexidartinib). CONCLUSION: Based on the current study, a modest reduction in pain, just larger than the MCID, may be an added benefit of pexidartinib in these patients, although the findings are insufficient to justify the routine use of pexidartinib for pain relief. LEVEL OF EVIDENCE: Level II, therapeutic study.
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Tumor de Células Gigantes de Bainha Tendinosa , Adulto , Humanos , Feminino , Pessoa de Meia-Idade , Resultado do Tratamento , Aminopiridinas , Dor , Método Duplo-CegoRESUMO
Metastatic disease of the periacetabular region is a common problem in orthopaedic oncology, associated with severe pain, decreased mobility, and substantial decline of the quality of life. Conservative management includes optimisation of pain management, activity modification, and radiation therapy. However, patients with destructive lesions affecting the weight-bearing portion of the acetabulum often require reconstructive surgery to decrease pain and restore mobility. The goal of surgery is to provide an immediately stable and durable construct, allowing immediate postoperative weight-bearing and maintaining functional independence for the remaining lifetime of the patient. A variety of surgical techniques have been reported, most of which are based upon cemented total hip arthroplasty, but also include porous tantalum implants and percutaneous cementoplasty. This review discusses the various reconstructive concepts and options, including their respective indications and outcome. A reconstructive algorithm incorporating different techniques and strategies based upon location and quality of remaining bone is also presented.
Assuntos
Artroplastia de Quadril , Neoplasias Ósseas , Humanos , Acetábulo/cirurgia , Acetábulo/patologia , Artroplastia de Quadril/métodos , Qualidade de Vida , Neoplasias Ósseas/cirurgia , Dor/etiologia , Dor/patologia , Dor/cirurgiaRESUMO
Among mesenchymal tumors, MAML2 gene rearrangements have been described in a subset of composite hemangioendothelioma and myxoinflammatory fibroblastic sarcoma (MIFS). However, we have recently encountered MAML2-related fusions in a group of seven undifferentiated malignant epithelioid neoplasms that do not fit well to any established pathologic entities. The patients included five males and two female, aged 41-71 years old (median 65 years). The tumors involved the deep soft tissue of extremities (hip, knee, arm, hand), abdominal wall, and the retroperitoneum. Microscopically, the tumors consisted of solid sheets of atypical epithelioid to histiocytoid cells with abundant cytoplasm. Prominent mitotic activity and necrosis were present in 4 cases. In 3 cases, the cells displayed hyperchromatic nuclei or conspicuous macronucleoli, and were admixed with background histiocytoid cells and a lymphoplasmacytic infiltrate. By immunohistochemistry (IHC), the neoplastic cells had a nonspecific phenotype. On targeted RNA sequencing, MAML2 was the 3' partner and fused to YAP1 (4 cases), ARHGAP42 (2 cases), and ENDOD1 (1 case). Two cases with YAP1::MAML2 harbored concurrent RAF kinase fusions (RBMS3::RAF1 and AGK::BRAF, respectively). In 2 cases with targeted DNA sequencing, mutations in TP53, RB1 and PTEN were detected in 1 case, and PDGFRB mutations, CCNE1 amplifications and CDKN2A/2B deletion were detected in another case, which showed strong and diffuse PDGFRB expression by IHC. Of the 4 cases with detailed clinical history (median follow-up period 8 months), three developed distant metastatic disease (one of which died of disease); one case remained free of disease 3 years following surgical excision. In conclusion, we describe a heterogeneous series of MAML2-rearranged undifferentiated malignant epithelioid neoplasms, a subset of which may overlap with a recently described MIFS variant with YAP1::MAML2 fusions, further expanding the clinicopathologic spectrum of mesenchymal neoplasms with recurrent MAML2 gene rearrangements.
Assuntos
Fibrossarcoma , Neoplasias de Tecidos Moles , Masculino , Humanos , Feminino , Receptor beta de Fator de Crescimento Derivado de Plaquetas/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Fibrossarcoma/genética , Rearranjo Gênico , Fatores de Transcrição/genética , Neoplasias de Tecidos Moles/genética , Transativadores/genéticaRESUMO
Tenosynovial giant cell tumors (TGCTs) are rare, locally aggressive, mesenchymal neoplasms, most often arising from the synovium of joints, bursae, or tendon sheaths. Surgical resection is the first-line treatment, but recurrence is common, with resulting impairments in patients' mobility and quality of life. Developing and optimizing the role of systemic pharmacologic therapies in TGCT management requires an understanding of the underlying disease mechanisms. The colony-stimulating factor 1 receptor (CSF1R) has emerged as having an important role in the neoplastic processes underlying TGCT. Lesions appear to contain CSF1-expressing neoplastic cells derived from the synovial lining surrounded by non-neoplastic macrophages that express the CSF1R, with lesion growth stimulated by both autocrine effects causing proliferation of the neoplastic cells themselves and by paracrine effects resulting in recruitment of CSF1 R-bearing macrophages. Other signaling pathways with evidence for involvement in TGCT pathogenesis include programmed death ligand-1, matrix metalloproteinases, and the Casitas B-cell lymphoma family of ubiquitin ligases. While growing understanding of the pathways leading to TGCT has resulted in the development of both regulatory approved and investigational therapies, more detail on underlying disease mechanisms still needs to be elucidated in order to improve the choice of individualized therapies and to enhance treatment outcomes.
Assuntos
Tumor de Células Gigantes de Bainha Tendinosa , Fator Estimulador de Colônias de Macrófagos , Humanos , Fator Estimulador de Colônias de Macrófagos/genética , Qualidade de Vida , Tumor de Células Gigantes de Bainha Tendinosa/genética , Tumor de Células Gigantes de Bainha Tendinosa/metabolismo , Tumor de Células Gigantes de Bainha Tendinosa/patologia , Processos NeoplásicosRESUMO
Tenosynovial giant cell tumor (TGCT) is a rare neoplasm of the joint synovium that has a wide clinical spectrum including pain and stiffness in the affected joint, joint swelling, periarticular erosions, and cartilage loss, which can severely impact quality of life. The mainstay treatment for TGCT has been surgery involving partial or total synovectomy using arthroscopic or open techniques. However, surgical resection alone is associated with high recurrence rates, particularly in diffuse-TGCT (D-TGCT) cases. The 3 cases presented here summarize a combination approach (surgery+pexidartinib [tyrosine kinase inhibitor]) in patients with previously unresectable or inoperable D-TGCT. Case 1-Hip. A 29-year-old male was treated with pexidartinib prior to surgery, resulting in tumor reduction. A left total hip arthroplasty (THA) was then performed with a lack of recurrence in 12 months postoperative, and the patient currently on pexidartinib treatment. Case 2-Foot. A 35-year-old female, nearly a decade following a left foot mass resection, was treated with pexidartinib following disease recurrence. A decrease in soft tissue lesions at the midfoot and decreased marrow enhancement at the first metatarsal head were seen within 4-5 months of pexidartinib treatment; the patient is currently on pexidartinib (400 mg/day) with improved symptom control. Case 3-Knee. A 55-year-old male patient received pexidartinib pre- and postoperatively. A reduction in swelling and the size of the popliteal cyst was significant and maintained, with the synovial disease growing when pexidartinib was discontinued. Surgery and adjuvant therapy eliminated the disease as of the last follow-up visit (11 months postoperative). These cases provide a unique perspective based on tumor location, type/timing of treatment strategy, and patient outcomes. Optimal treatment strategies for this debilitating disease may entail utilizing a combination approach (surgery+systemic treatment) to reduce surgical morbidity and the risk of postoperative disease recurrence.