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Background: Clear cell sarcoma (CCS) and alveolar soft part sarcoma (ASPS) are rare, and standard systemic therapy is not established except for sunitinib in ASPS. It is known that CCS and ASPS have a common biological feature of melanoma and Xp11.2/TFE3 translocation renal cell carcinoma, and immune‐checkpoint inhibitors (ICIs) are effective in these tumors. The authors conducted a phase 2 trial to evaluate the efficacy and safety of nivolumab for CCS and ASPS. Methods: The number of patients expected to be enrolled was 15–25 and was determined based on the Bayesian design. The primary end point was the confirmed objective response rate (ORR) according to the central review and the secondary end points included ORR, progression‐free survival (PFS), overall survival (OS), and safety. Results: A total of 26 patients (CCS, 12; ASPS, 14) were enrolled. Efficacy and safety were analyzed on 25 and 26 patients, respectively. The minimum number of responses required for a positive conclusion regarding the efficacy was four. However, only one patient (4.0%) with ASPS had a partial response. Complete response, stable disease, progression disease, and not evaluable were 0%, 60%, 32%, and 4.0%, respectively. Adverse events of grade 3 or 4 occurred in 57.7% (15 of 26). The median PFS was 4.9 months (95% confidence interval [CI], 3.7–8.6 months) and the median OS was 15.8 months (95% CI, 8.2–not reached). Conclusions: The primary end point of the ORR was not met for CCS and ASPS on the central review. Further studies are needed to evaluate ICIs in patients with ASPS. This study evaluated the efficacy and safety of nivolumab monotherapy for patients with clear cell sarcoma and alveolar soft part sarcoma in a single‐arm phase 2 trial. The results showed no clinical efficacy among patients with clear cell sarcoma, whereas further investigation was considered necessary among patients with alveolar soft part sarcoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Sarcoma is difficult to treat because of its rarity. Ferroptosis is a new type of cell death mediated by ferrous iron. In the present study, we aimed to clarify the effect of ferroptosis in sarcoma. As compared with noncancer and carcinoma cell lines, ferroptosis is more sensitive in most of the sarcoma cell lines. Moreover, transferrin receptor 1 (TFRC) and SHANK-associated RH domain interactor (SHARPIN), both of which are oncogenic factors and related to poor overall survival, are highly expressed, particularly in synovial sarcoma cell lines. Furthermore, we discovered that SHARPIN is a positive regulator of ferroptosis through nuclear factor-kappa B (NF-κΒ) and protein arginine methyltransferase 5 (PRMT5)-mediated PGC1α reduction. In summary, we suggest that ferroptosis could be a therapeutic target in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression. Sarcoma is a rare type of cancer for which new therapeutic agents are required. Ferroptosis is a nonapoptotic cell death triggered by iron-mediated lipid peroxidation. We found that TFRC, an iron uptake protein, was expressed at higher levels in sarcoma cell lines than in noncancer and carcinoma cell lines. Glutathione peroxidase 4 (GPX4) protects cells against ferroptosis, and its inhibition using RAS-selective lethal 3 (RSL3) had an antitumor effect that was more pronounced in sarcoma cell lines, particularly synovial sarcoma cells, compared to non-sarcoma cells. Because NF-κB can provoke ferroptosis, we examined the role of SHARPIN, an activator of NF-κB, in sarcoma. We found that SHARPIN expression was significantly associated with reduced survival in cohorts of patients with cancer, including sarcoma. In addition, SHARPIN promoted the sensitivity of sarcoma cells to ferroptosis. Further analyses revealed that the PGC1α/NRF2/SLC7A11 axis and BNIP3L/NIX-mediated mitophagy are regulated through NF-κB and PRMT5 downstream of SHARPIN. Our findings suggest that ferroptosis could have a therapeutic effect in sarcoma, particularly in subpopulations with high TFRC and SHARPIN expression. [ABSTRACT FROM AUTHOR]

The efficacy of immune checkpoint inhibitors is limited in refractory solid tumors. T‐cell receptor gene‐modified T (TCR‐T)‐cell therapy has attracted attention as a new immunotherapy for refractory cold tumors. We first investigated the preclinical efficacy and mode of action of TCR‐T cells combined with the pullulan nanogel:long peptide antigen (LPA) vaccine in a mouse sarcoma model that is resistant to immune checkpoint inhibition. Without lymphodepletion, the pullulan nanogel:LPA vaccine markedly increased the number of TCR‐T cells in the draining lymph node and tumor tissue. This change was associated with enhanced CXCR3 expression in TCR‐T cells in the draining lymph node. In the phase 1 trial, autologous New York esophageal squamous cell carcinoma 1 (NY‐ESO‐1)‐specific TCR‐T cells were infused twice into HLA‐matched patients with NY‐ESO‐1+ soft tissue sarcoma (STS). The pullulan nanogel:LPA vaccine contains an epitope recognized by TCR‐T cells, and it was subcutaneously injected 1 day before and 7 days after the infusion of TCR‐T cells. Lymphodepletion was not performed. Three patients with refractory synovial sarcoma (SS) were treated. Two out of the three patients developed cytokine release syndrome (CRS) with low‐to‐moderate cytokine level elevation. We found obvious tumor shrinkage lasting for more than 2 years by tumor imaging and long‐term persistence of TCR‐T cells in one patient. In conclusion, NY‐ESO‐1‐specific TCR‐T‐cell therapy plus vaccination with the pullulan nanogel carrying an LPA containing the NY‐ESO‐1 epitope without lymphodepletion is feasible and can induce promising long‐lasting therapeutic effects in refractory SS (Registration ID: JMA‐IIA00346). [ABSTRACT FROM AUTHOR]

Undifferentiated pleomorphic sarcoma (UPS) is a high-grade, aggressive soft tissue sarcoma (STS) with a poor prognosis, and no definitive or effective treatment is currently available for it. Pazopanib, an orally available multiple tyrosine kinase inhibitor, has been approved for the treatment of advanced STS. The present study documents the case of a 51-year-old man with advanced UPS with coamplification of platelet-derived growth factor receptor A (PDGFRA), vascular endothelial growth factor receptor 2 (VEGFR2) and stem cell factor receptor (KIT) genes. The patient exhibited a marked and sustained response to pazopanib. The patient presented with a retroperitoneal tumour with pancreatic head lymph node metastasis, and bone metastases in the second/fifth thoracic vertebrae and left femur. Based on the histological analysis of the retroperitoneal tumour and femoral mass, the patient was diagnosed with UPS. Palliative radiation therapy was administered to the left femur and second/fifth thoracic vertebrae to prevent fractures. After radiation therapy, the patient achieved a partial response after eight courses of doxorubicin. A comprehensive genomic profiling analysis (FoundationOne® CDx) revealed coamplification of PDGFRA, VEGFR2 and KIT genes. Hence, pazopanib was initiated as a second-line treatment. Notably, the retroperitoneal tumour shrank, and no new lesions developed for 3 years after the initiation of pazopanib treatment. This response suggests that the coamplification of PDGFRA, VEGFR2 and KIT may predict favourable outcomes in response to pazopanib. [ABSTRACT FROM AUTHOR]

Background: The high rate of aseptic loosening of cemented stems has led to their frequent use in endoprosthetic reconstruction. However, problems, such as stem breakage and stress shielding at the insertion site, remain. The Japanese Musculoskeletal Oncology Group (JMOG) has developed Kyocera Modular Limb Salvage System (KMLS) cementless stems with a unique tapered press-fit and short fixation design. This study aimed to clarify the short-term postoperative outcomes of this prosthesis and validate the stem design.Methods: One hundred cases of KMLS cementless stems (51 male patients; median age, 49 years; mean follow-up period, 35 months), with a minimum follow-up of 2 years, for the proximal femur (PF), distal femur (DF), and proximal tibia were prospectively registered for use. Prosthesis survival, complication rates, postoperative functional, and radiographical evaluation were analyzed. Complications or failures after insertion of the KMLS endoprostheses were classified into five types and functional results were analyzed according to the MSTS scoring system at postoperative 1 year. The diaphyseal interface and anchorage were graded by the ISOLS system at postoperative 2 years.Results: The overall prosthesis survival rates at 2 and 4 years were 88.2 and 79.6%, respectively. The prosthesis-specific survival rate excluding infection and tumor recurrence was 90.2 and 87.9%, respectively. Younger age (p = 0.045) and primary tumor (p = 0.057) were associated with poor prognosis of prosthesis-specific survival excluding infection and tumor recurrence. Complications were observed in 31 patients, 13 patients underwent revision surgery. The mean MSTS functional score at 1 year postoperatively was 68%. Early implant loosening was significantly more common in the DF (p = 0.006) and PF/DF straight stem (p = 0.038). The ISOLS radiographic evaluation at 2 years after surgery revealed good bone remodeling and anchorage in most cases (bone remodeling: 90% / excellent and good, anchorage: 97% / excellent and good).Conclusions: Tumor endoprosthesis long-term fixation to the diaphysis of the lower extremity remains challenging. The KMLS cementless stem with a unique tapered press fit design showed good short-term results in maintaining bone stock. To prevent early loosening, a curved stem should be used in PF and DF, but long-term follow-up is necessary. [ABSTRACT FROM AUTHOR]

Introduction. Few studies have described the characteristics and prognostic factors of patients with malignant peripheral nerve sheath tumour (MPNST). In this study, we retrospectively investigated the clinicopathological features, clinical outcomes, and prognostic factors of these patients. Patients and Methods. We recruited patients with MPNST who were treated at our institutions from 1991 to 2020. We collected and statistically analysed information on patient-, tumour-, and treatment-related factors. The median follow-up period was 61 months (range, 1–335.8 months). Results. A total of 60 patients (31 males, 29 females) with a median age of 55 years (range, 8–84 years) at initial diagnosis were included. The median tumour size was 7 cm (range, 1.6–30 cm) in the greatest dimension. The 5-year overall survival (OS) rate of all patients was 69.5%. Univariate analysis revealed that large-sized tumour, metastasis at diagnosis, and no surgery of the primary tumour were significantly associated with patients with worse OS. Multivariate analysis identified surgery of the primary tumour as an independent prognostic factor for improved OS. Among patients with localised disease at diagnosis who underwent surgery of the primary tumour at our institutions, the 5-year OS, local recurrence-free survival (LRFS), and metastasis-free survival (MFS) rates were 81.1%, 78.2%, and 70.3%, respectively. Univariate analysis revealed that positive surgical margin was significantly correlated with unfavourable OS and LRFS, and high grade was a poor prognostic indicator for MFS. Conclusion. Complete surgical resection with negative surgical margins is necessary for a successful MPNST treatment. Multidisciplinary management of MPNST with aggressive features is important for optimising patient outcomes. [ABSTRACT FROM AUTHOR]

We elucidated clinicopathological characteristics of giant cell tumor of bone (GCTB) in Japan, and significant clinicopathological factors for predicting local recurrence. Clinicopathological profiles of 213 patients with GCTB (100 male, 113 female) involving extra‐craniofacial bones were retrieved. Pathological slides obtained at the initial surgery were reviewed. Fourteen pathological and five clinical features were statistically analyzed to disclose prognostic significance. Patient age ranged from 12–80 years (Average 38.7). Long bones were most frequently affected (86.4%), especially around the knee (62.9%). Histological features are basically similar to those previously reported. Within a follow‐up period (24–316 months, average 106.1 months), the local recurrence rate is 29.1%. Metastasis has occurred in 9 patients. Cox regression analysis of representative clinicopathological features shows that younger age, higher mitotic count, smaller zones of stromal hemorrhage, considerable vascular invasion and absence of ischemic necrosis are significant predictors for local recurrence. Initial operative method (curettage) is a significant risk factor in univariate analysis but not by multivariate analysis (P = 0.053). Denosumab administration increases risk but not significantly (P = 0.053). Histone 3.3 G34W immunopositivity is not significant for predicting local recurrence. [ABSTRACT FROM AUTHOR]

Background: A prospective cohort study was conducted to determine the incidence and risk factors of symptomatic venous thromboembolism (sVTE) during the perioperative period in patients with malignant bone and soft tissue tumors. Methods: Patients with newly diagnosed primary malignant bone and soft tissue tumors for whom definitive surgery was planned were consecutively registered among 27 tertiary hospitals specializing in musculoskeletal oncology. Clinicopathological information on each patient was collected prospectively, and careful follow-up was conducted for 6 months after surgery. The study endpoint was the occurrence of sVTE, including deep vein thrombosis (DVT) and pulmonary embolism (PE). Results: Eleven of 929 patients developed sVTE, including 8 patients with DVT, 2 with PE, and 1 with both, making the incidence of sVTE 1.18%. The median time until the development of sVTE after tumor resection was 11 days, ranging from − 7 to 95 days. Multiple logistic regression analyses revealed that ischemic heart disease as a comorbidity, maximum tumor diameter exceeding 8 cm, and elevated preoperative platelet count were independent risk factors for sVTE. Conclusions: The incidence of sVTE in this series of patients with bone and soft tissue sarcomas was 1.18%, which was relatively lower than in previous retrospective studies. We identified the risk factors for sVTE specific to patients with malignant bone and soft tissue tumors, and these included ischemic heart disease, tumor size, and elevation of the preoperative platelet count. [ABSTRACT FROM AUTHOR]

Background and Objectives. Osteoarticular extracorporeal irradiated autograft is an alternative operation technique to prosthetic devices or allografts for reconstruction after resection of bone malignancies. The aim of this study is to assess the complications, radiographic changes, and functional outcomes of osteoarticular ECIA. Methods. We retrospectively reviewed 33 patients who underwent osteoarticular ECIA after bone tumor resection from 1988 to 2014. We investigated complications, radiographic changes by the International Society of Limb Salvage graft evaluation criteria, and functional outcomes according to the Musculoskeletal Tumor Society scoring system. Results. Fifteen patients were reoperated upon due to infection (n = 9), protruding fixation implant (n = 4), or fracture of the grafted bone (n = 2). The average radiographic evaluation score was 66.4%, and the median functional score was 23 (77%). The radiographic score for the proximal humerus or proximal tibia was lower than that for the other locations. The functional score was not different among the autograft sites but was related to the radiographic score. Conclusion. Although osteoarticular ECIA is one of the reasonable surgical options for patients with tumors for which reliable prostheses are not available, we do not recommend osteoarticular ECIA as a routine procedure because of high complication rate. [ABSTRACT FROM AUTHOR]

Synovial sarcoma (SS) is considered to be a chemosensitive, soft tissue sarcoma. Therefore, neoadjuvant and/or adjuvant chemotherapy (N/AC) is used for the treatment of high-risk SS patients. However, the role of N/AC remains controversial. The present study aimed to review the clinical outcomes of surgically treated localized SS and investigate the effects of N/AC with long-term observation. The clinical outcomes of 54 patients with surgically treated localized SS were retrospectively analyzed. The median patient age was 42 years (range, 8–81 years), and the median follow-up period was 94 months for survivors (range, 7–220 months). A total of 38 patients (70%) received chemotherapy. Of these, 32 (59%) patients received neoadjuvant chemotherapy, 33 (61%) received adjuvant chemotherapy, and 27 (50%) received neoadjuvant and adjuvant chemotherapy. Fourteen patients (26%) received adjuvant radiotherapy. Three patients (6%) had local recurrence and 13 patients (24%) developed distant metastasis. The overall survival (OS) rates at 5 and 10 years were 87 and 84%, respectively. N/AC did not improve survival. In conclusion, we found satisfactory long-term OS among patients with a high utilization rate of N/AC. Further study should be necessary to evaluate which population of SS would benefit from N/AC. [ABSTRACT FROM AUTHOR]

Background/Purpose: The effects of chemical and physical interactions in the microen-vironment of solid tumors have not been fully elucidated.We hypothesized that acidosis, hypoxia, and elevated interstitial fluid pressure (eIFP) have additive effects on tumor cell biology and lead to more aggressive behavior during tumor progression.We investigated this phenomenon using three human osteosarcoma (OS) cell lines and a novel in vitro cell culture apparatus. Materials and Methods: U2OS, SaOS, and MG63 cell lines were cultured in media adjusted to various pH levels, oxygen tension (hypoxia 2% O2, normoxia 20% O2), and hydrostatic gage pressure (0 or 50 mmHg). Growth rate, apoptosis, cell cycle parameters, and expression of mRNA for proteins associated with invasiveness and tumor microen-vironment (CA IX, VEGF-A, HIF-1A, MMP-9, and TIMP-2) were analyzed. Levels of CA IX, HIF-1a, and MMP-9 were measured using immunofluorescence. The effect of pH on invasiveness was evaluated in a Matrigel chamber assay. Results: Within the acidic-hypoxic-pressurized conditions that simulate the microenvi-ronment at a tumor's center, invasive genes were upregulated, but the cell cycle was downregulated. The combined influence of acidosis, hypoxia, and IFP promoted invasive-ness and angiogenesis to a greater extent than did pH, pO2, or eIFP individually. Significant cell death after brief exposure to acidic conditions occurred in each cell line during accli-mation to acidic media, while prolonged exposure to acidic media resulted in reduced cell death. Furthermore, 48-h exposure to acidic conditions promoted tumor invasiveness in the Matrigel assay. Conclusion: Our findings demonstrate that tumor microenvironmental parameters - par-ticularly pH, pO2, and eIFP - additively influence tumor proliferation, invasion, metabolism, and viability to enhance cell survival and must be controlled in OS research. [ABSTRACT FROM AUTHOR]

Objective: Positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) has been used for the evaluation of soft-tissue tumors. However, the range of accumulation of 18F-FDG for malignant soft-tissue lesions overlaps with that of benign lesions. The aim of this study is to investigate the usefulness of delayed 18F-FDG PET imaging in the differentiation between malignant and benign soft-tissue tumors.Methods: Fifty-six patients with soft-tissue tumors underwent whole body 18F-FDG PET scan at 1 hour (early scan) and additional scan at 2 hours after injection (delayed scan). The standardized uptake value (SUV(max)) of the tumor was determined, and the retention index (RI) was defined as the ratio of the increase in SUV(max) between early and delayed scans to the SUV(max) in the early scan. Surgical resection with histopathologic analysis confirmed the diagnosis.Results: Histological examination proved 19 of 56 patients to have malignant soft-tissue tumors and the rest benign ones. In the scans of all 56 patients, there was a statistically significant difference in the SUV(max) between malignant and benign lesions in the early scan (5.50 +/- 5.32 and 3.10 +/- 2.64, respectively, p < 0.05) and in the delayed scan (5.95 +/- 6.40 and 3.23 +/- 3.20, respectively, p < 0.05). The mean RI was not significantly different between malignant and benign soft-tissue tumors (0.94 +/- 23.04 and -2.03 +/- 25.33, respectively).Conclusions: In the current patient population, no significant difference in the RI was found between malignant and benign soft-tissue lesions. Although the mean SUV(max) in the delayed scan for malignant soft-tissue tumors was significantly higher than that for benign ones, there was a marked overlap. The delayed 18F-FDG PET scan may have limited capability to differentiate malignant soft-tissue tumors from benign ones. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) with 2-deoxy-2-[18F]fiuoro-D-glucose (18F-FDG) has been used for the evaluation of soft-tissue tumors. However, the range of accumulation of18F-FDG for malignant soft-tissue lesions overlaps with that of benign lesions. The aim of this study is to investigate the usefulness of delayed18F-FDG PET imaging in the differentiation between malignant and benign soft-tissue tumors. Fifty-six patients with soft-tissue tumors underwent whole body18F-FDG PET scan at 1 hour (early scan) and additional scan at 2 hours after injection (delayed scan). The standardized uptake value (SUVmax) of the tumor was determined, and the retention index (RI) was defined as the ratio of the increase in SUVmax between early and delayed scans to the SUVmax in the early scan. Surgical resection with histopathologic analysis confirmed the diagnosis. Histological examination proved 19 of 56 patients to have malignant soft-tissue tumors and the rest benign ones. In the scans of all 56 patients, there was a statistically significant difference in the SUVmax between malignant and benign lesions in the early scan (5.50 ± 5.32 and 3.10 ± 2.64, respectively, p < 0.05) and in the delayed scan (5.95 ± 6.40 and 3.23 ± 3.20, respectively, p < 0.05). The mean RI was not significantly different between malignant and benign soft-tissue tumors (0.94 ± 23.04 and -2.03 ± 25.33, respectively). In the current patient population, no significant difference in the RI was found between malignant and benign soft-tissue lesions. Although the mean SUVmax in the delayed scan for malignant soft-tissue tumors was significantly higher than that for benign ones, there was a marked overlap. The delayed18F-FDG PET scan may have limited capability to differentiate malignant soft-tissue tumors from benign ones. [ABSTRACT FROM AUTHOR]

Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules and comprise a family of four members. At the mossy fiber terminals of hippocampus, nectin-1 and nectin-3 localize at the presynaptic and postsynaptic sides of synaptic junctions, respectively, and their trans-interactions play a role in formation of synapses in cooperation with N-cadherin. Nectins are associated with the actin cytoskeleton through afadin, a nectin- and actin-filament-binding protein. Five nectin-like molecules (Necls) which have domain structures similar to those of nectins have been identified and here we characterize Necl-1/TSLL1/SynCAM3, from now on referred to as Necl-1. Tissue distribution analysis showed that Necl-1 was specifically expressed in the neural tissue. Immunofluorescence and immunoelectron microscopy revealed that Necl-1 localized at the contact sites among axons, their terminals, and glia cell processes that cooperatively formed synapses, axon bundles and myelinated axons. Necl-1 showed Ca2+-independent homophilic cell-cell adhesion activity. It furthermore showed Ca2+-independent heterophilic cell-cell adhesion activity with Necl-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 from now on referred to as Necl-2, nectin-1 and nectin-3, but not with Necl-5 or nectin-2. The C-terminal cytoplasmic region of Necl-1 did not bind afadin but bound membrane-associated guanylate kinase subfamily members that contain the L27 domain, including Dlg3, Pals2 and CASK. These results indicate that Necl-1 is a neural-tissue-specific Ca2+-independent immunoglobulin-like cell-cell adhesion molecule which potentially has membrane-associated guanylate kinase subfamily member-binding activity and localizes at the non-junctional cell-cell contact sites. [ABSTRACT FROM AUTHOR]

Necl-5/Trage4/poliovirus receptor/CD155 has been shown to be the poliovirus receptor and to be up-regulated in rodent and human carcinoma. We have found previously that mouse Necl-5 regulates cell motility. We show here that mouse Necl-5 is furthermore involved in the regulation of cell proliferation. Studies using a specific antibody against Necl-5 and a dominant negative mutant of Necl-5 revealed that Necl-5 enhanced the serum-induced proliferation of NIH3T3, Swiss3T3, and mouse embryonic fibroblast cells. Necl-5 enhanced the serum-induced activation of the Ras-Raf-MEK-ERK signaling, up-regulated cyclins D2 and E, and down-regulated p27Kip1, eventually shortening the period of the G0/G1 phase of the cell cycle in NIH3T3 cells. Necl-5 similarly enhanced the platelet-derived growth factor-induced activation of the Ras-Raf-MEK-ERK signaling and shortened the period of the G0/G1 phase of the cell cycle in NIH3T3 cells. Neclo5 acted downstream of the platelet-derived growth factor receptor and upstream of Ras. Moreover, up-regulated Necl-5 was involved at least partly in the enhanced proliferation of transformed cells including NIH3T3 cells transformed by an oncogenic Ras or v-Src. These results indicate that Necl-5 plays roles not only in cell motility but also in cell proliferation. [ABSTRACT FROM AUTHOR]

Cell migration plays roles in invasion of transformed cells and scattering of embryonic mesenchymal cells into surrounding tissues. We have found that Ig-like Necl-5/Tage4 is up-regulated in NIH3T3 cells transformed by an oncogenic Ras (V12Ras-NIH3T3 cells) and heterophilically trans-interacts with a Ca2+-independent Ig-like cell adhesion molecule nectin-3, eventually enhancing their intercellular motility. We show here that Nec1-5 furthermore enhances cell migration in a nectin-3-independent manner. Studies using L fibroblasts expressing various mutants of Necl-5, NIH3T3 cells, and V12Ras-NIH3T3 cells have revealed that Necl-5 enhances serum, and platelet-derived growth factor-induced cell migration. The extracellular region of Necl-5 is necessary for directional cell migration, but not for random cell motility. The cytoplasmic region of Necl-5 is necessary for both directional and random cell movement. Necl-5 colocalizes with integrin αvβ3 at leading edges of migrating cells. Analyses using an inhibitor or an activator of integrin αvβ3 or a dominant negative mutant of Necl-5 have shown the functional association of Necl-5 with integrin αvβ3 in cell motility. Cdc42 and Rac small G proteins are activated by the action of Necl-5 and required for the serum-induced, Necl-5-enhanced cell motility. These results indicate that Necl-5 regulates serum, and platelet-derived growth factor-induced cell migration in an integrin-dependent, nectin-3-independent manner, when cells do not contact other cells. We furthermore show here that enhanced motility and metastasis of V12Ras-NIH3T3 cells are at least partly the result of up-regulated Necl-5. [ABSTRACT FROM AUTHOR]

Malignant transformation of cells causes disruption of cell-cell adhesion, enhancement of cell motility, and invasion into surrounding tissues. Nectins have both homophilic and heterophilic cell-cell adhesion activities and organize adherens junctions in cooperation with cadherins. We examined here whether Tage4, which was originally identified to be a gene overexpressed in colon carcinoma and has a domain structure similar to those of nectins, is involved in cell adhesion and/or migration. Tage4 heterophilically trans-interacted with nectin-3, but not homophilically with Tage4. Expression of Tage4 was markedly elevated in NIH3T3 cells transformed by an oncogenic Ki-Ras (V12Ras-NIH3T3 cells) as compared with that of wild-type NIH3T3 cells. trans-Interaction of Tage4 with nectin-3 enhanced motility of V12RasNIH3T3 cells. Tage4 did not bind afadin, a nectin- and actin filament-binding protein that connects nectins to the actin cytoskeleton and cadherins through catenins. Thus, Tage4 heterophilically trans-interacts with nectin-3 and regulates cell migration. Tage4 is tentatively re-named here nectin-like molecule-5 (necl-5) on the basis of its function and domain structure similar to those of nectins. [ABSTRACT FROM AUTHOR]

Simple Summary: Retroperitoneal sarcomas are difficult malignancies to treat because complete surgical resection is the only effective treatment option, but it is difficult to secure sufficient surgical margins. It is essential for developing a treatment strategy to assess tumor aggressiveness and predict prognosis for patients. However, the aggressiveness of retroperitoneal sarcomas before treatment cannot be fully evaluated. In patients with resectable soft tissue sarcomas or several carcinomas, SUV evaluated with FDG-PET has been reported to be a valuable prognostic parameter. However, the correlation between SUVmax on FDG-PET and the prognosis of several histological subtypes in retroperitoneal sarcoma, including dedifferentiated liposarcoma, well-differentiated liposarcoma, and leiomyosarcoma, remains uncertain. This study revealed that SUVmax calculated with FDG-PET was useful as a prognostic factor in retroperitoneal sarcoma, especially in dedifferentiated liposarcoma and Grade2 retroperitoneal sarcoma. Background: Retroperitoneal sarcomas are rare neoplasms that occur in the retroperitoneum. Complete surgical resection is the only effective treatment option. The prediction of prognosis by histological diagnosis has not yet been established. The purpose of this study was to identify the usefulness of [18-F] fluorodeoxyglucose (FDG) positron emission tomography (PET) imaging for validating the prognosis of retroperitoneal sarcoma (RPS) established by histological diagnosis. Methods: We retrospectively reviewed 201 patients with RPS treated at the Osaka International Cancer Institute between 2010 and 2021. We extracted the clinical data, including standardized uptake values (SUVs), evaluated with FDG-PET, and statistically analyzed the data. Results: The median age of patients was 64 years (range, 31–85 years). A total of 101 (50.2%) patients were men, and 100 (49.8%) were women. Surgical resection was performed in 155 (77.1%) patients. On histological analysis, 75 (37.3%), 52 (25.9%), and 29 (14.4%) patients were diagnosed with dedifferentiated liposarcoma, well-differentiated liposarcoma, and leiomyosarcoma, respectively. The median survival time for patients with high maximum SUV (SUVmax) (≥4) or low SUVmax (<4) was 275.8 months and 79.5 months, respectively. Furthermore, among the patients with dedifferentiated liposarcoma, the overall survival rate for patients with high SUVmax (≥4) was significantly lower than that of those with low SUVmax (<4). Conclusions: The present study demonstrated that SUVmax calculated with FDG-PET was useful as a prognostic factor in RPS, especially in dedifferentiated liposarcoma and Grade2 RPS. To devise a treatment strategy for RPS, SUVmax during FDG-PET scan may be considered for clinical assessment. [ABSTRACT FROM AUTHOR]

Abstract: Background context: Localized amyloid deposits result in a mass, that is, so-called amyloidoma; it has been reported in every anatomic site, although systemic amyloid deposition is much more common. However, primary lumbar epidural amyloidoma without bony involvement is extremely rare. To the best of our knowledge, only one case has been reported previously. Purpose: To report and review the clinical presentations, imaging studies, and treatment of epidural and paravertebral amyloidoma. Study design: A case report and review of the literature. Methods: Lumbar epidural and paravertebral amyloidoma in a 75-year-old man with neurologic compromise is presented. Laminectomy with mass resection was performed. Results: After surgery, almost complete neurologic improvement was observed. Histologically, definite diagnosis was obtained only after the specific staining of tissue. No sign of local recurrence was evident 1 year after surgery. Conclusions: Primary amyloidoma, although rare, should be included in the differential diagnosis of epidural mass of the spine. Diagnosis before surgery is difficult as there were no characteristic findings in clinical and imaging studies. Special histologic technique and stains are useful to make a definite diagnosis. [Copyright &y& Elsevier]

Nectins are Ca[sup 2+]-independent immunoglobulin-like cell-cell adhesion molecules that play roles in organization of a variety of cell-cell junctions in cooperation with or independently of cadherins. Four nectins have been identified. Five nectin-like molecules, which have domain structures similar to those of nectins, have been identified, and we characterized here nectin-like molecule-2 (Necl-2)/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1. Necl-2 showed Ca[sup 2+]-independent homophilic cell-cell adhesion activity. It furthermore showed Ca[sup 2+]-independent heterophilic cell-cell adhesion activity with Nec;l-1/TSLL1/SynCAM3 and nectin-3. Necl-2 was widely expressed in rat tissues examined. Necl-2 localized at the basolateral plasma membrane in epithelial cells of the mouse gall bladder, but not at specialized cell-cell junctions, such as tight junctions, adherens junctions, and desmosomes. Nectins bind afadin, whereas Necl-2 did not bind afadin but bound Pals2, a membrane-associated guanylate kinase family member known to bind Lin-7, implicated in the proper localization of the Let-23 protein in Caenorhabditis elegans, the homologue of mammalian epidermal growth factor receptor. These results indicate the unique localization of Necl-2 and its possible involvement in localization of a transmembrane protein(s) through Pals2. [ABSTRACT FROM AUTHOR]

Abstract: The cytogenetic hallmark of myxoid type and round cell type liposarcoma consists of reciprocal translocation of t(12;16)(q13;p11) and t(12;22)(q13;q12), which results in fusion of TLS/FUS and CHOP, and EWS and CHOP, respectively. Nine structural variations of the TLS/FUS–CHOP chimeric transcript have been reported, however, only two types of EWS–CHOP have been described. We describe here a case of myxoid liposarcoma containing a novel EWS–CHOP chimeric transcript and identified the breakpoint occurring in intron 13 of EWS. Reverse transcription-polymerase chain reaction and direct sequence showed that exon 13 of EWS was in-frame fused to exon 2 of CHOP. Genomic analysis revealed that the breaks were located in intron 13 of EWS and intron 1 of CHOP. [Copyright &y& Elsevier]

Inflammatory myofibroblastic tumors (IMTs) are rare sarcomas composed of myofibroblastic and fibroblastic cells, accompanied by inflammatory cell infiltration. Many IMTs exhibit clonal rearrangement of anaplastic lymphoma kinase (ALK). We herein report a 56-year-old woman with uterine IMT harboring a thrombospondin-1::ALK fusion that developed after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Laboratory data before systemic therapy indicated increased interleukin-6 and severe leukocytosis. The patient was treated with lorlatinib; however, the response duration was approximately two months. Similar case reports need to be compiled and evaluated to elucidate the efficacy of lorlatinib in post-allo-HSCT IMT with ALK rearrangement.

Background: Trabectedin binds covalently to the DNA minor groove and causes DNA to bend toward the main groove, then trabectedin regulates the transcription of the involved genes in cell proliferation or acts on the mononuclear phagocyte system in tumors, which contributes to its antitumor effects. Several clinical trials confirmed the efficacy of trabectedin for patients with advanced soft tissue sarcoma (STS) although clinically useful biomarkers remained unidentified. This study aimed to identify prognostic factors of trabectedin treatment, especially focusing on the systemic inflammatory, immune response, and nutritional status., Methods: This study included 44 patients with advanced STS treated with trabectedin from January 2018 to August 2022. We evaluated the associations of clinical factors that influence the efficacy of trabectedin treatment with progression-free survival (PFS) and overall survival (OS), focusing on systemic inflammatory, immune response, and nutritional status represented by the absolute lymphocyte count (ALC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), systemic inflammation response index (SIRI), prognostic nutrition index (PNI), and C-reactive protein (CRP) using the Kaplan-Meier method and the log-rank test., Results: ALC, LMR, PNI, NLR, PLR, and SIRI demonstrated no association with PFS. Patients with CRP of ≥0.3 had a significantly shorter PFS than those with CRP of <0.3 (median PFS: 863 vs. 105 days, P = 0.045). PNI of ≥44 (median: 757 days vs. 232 days, P = 0.021) and CRP of <0.3 (median: 877 days vs. 297 days, P = 0.043) were significantly good prognostic factors in terms of OS., Conclusions: The study results indicate pretreatment PNI and CRP levels as prognostic factors for trabectedin treatment in advanced STS., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: To determine, for patients with advanced or recurrent synovial sarcoma (SS) not suitable for surgical resection and resistant to anthracycline, the safety and efficacy of the infusion of autologous T lymphocytes expressing NY-ESO-1 antigen-specific T-cell receptor (TCR) gene and siRNA to inhibit the expression of endogenous TCR (product code: TBI-1301)., Patients and Methods: Eligible Japanese patients (HLA-A*02:01 or *02:06, NY-ESO-1-positive tumor expression) received cyclophosphamide 750 mg/m2 on days -3 and -2 (induction period) followed by a single dose of 5×109 (±30%) TBI-1301 cells as a divided infusion on days 0 and 1 (treatment period). Primary endpoints were safety-related (phase I) and efficacy-related [objective response rate (ORR) by RECIST v1.1/immune-related RECIST (irRECIST); phase II]. Safety- and efficacy-related secondary endpoints were considered in both phase I/II parts., Results: For the full analysis set (N = 8; phase I, n = 3; phase II, n = 5), the ORR was 50.0% (95% confidence interval, 15.7-84.3) with best overall partial response in four of eight patients according to RECIST v1.1/irRECIST. All patients experienced adverse events and seven of eight patients (87.5%) had adverse drug reactions, but no deaths were attributed to adverse events. Cytokine release syndrome occurred in four of eight patients (50.0%), but all cases recovered with prespecified treatment. Immune effector cell-associated neurotoxicity syndrome, replication-competent retrovirus, and lymphocyte clonality were absent., Conclusions: Adoptive immunotherapy with TBI-1301 to selectively target NY-ESO-1-positive tumor cells appears to be a promising strategy for the treatment of advanced or recurrent SS with acceptable toxicity., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: Tumor-devitalized autografts treated with deep freezing, pasteurization, and irradiation are biological reconstruction methods after tumor excision for aggressive or malignant bone or soft tissue tumors that involve a major long bone. Tumor-devitalized autografts do not require a bone bank, they carry no risk of viral or bacterial disease transmission, they are associated with a smaller immunologic response, and they have a better shape and size match to the site in which they are implanted. However, they are associated with disadvantages as well; it is not possible to assess margins and tumor necrosis, the devitalized bone is not normal and has limited healing potential, and the biomechanical strength is decreased owing to processing and tumor-related bone loss. Because this technique is not used in many countries, there are few reports on the results of this procedure such as complications, graft survival, and limb function., Questions/purposes: (1) What was the rate of complications such as fracture, nonunion, infection, or recurrence in a tumor-devitalized autograft treated with deep freezing, pasteurization, and irradiation, and what factors were associated with the complication? (2) What were the 5-year and 10-year grafted bone survival (free from graft bone removal) of the three methods used to devitalize a tumor-containing autograft, and what factors were associated with grafted bone survival? (3) What was the proportion of patients with union of the tumor-devitalized autograft and what factors were associated with union of the graft-host bone junction? (4) What was the limb function after the tumor-devitalized autograft, and what factors were related to favorable limb function?, Methods: This was a retrospective, multicenter, observational study that included data from 26 tertiary sarcoma centers affiliated with the Japanese Musculoskeletal Oncology Group. From January 1993 to December 2018, 494 patients with benign or malignant tumors of the long bones were treated with tumor-devitalized autografts (using deep freezing, pasteurization, or irradiation techniques). Patients who were treated with intercalary or composite (an osteoarticular autograft with a total joint arthroplasty) tumor-devitalized autografts and followed for at least 2 years were considered eligible for inclusion. Accordingly, 7% (37 of 494) of the patients were excluded because they died within 2 years; in 19% (96), an osteoarticular graft was used, and another 10% (51) were lost to follow-up or had incomplete datasets. We did not collect information on those who died or were lost to follow-up. Considering this, 63% of the patients (310 of 494) were included in the analysis. The median follow-up was 92 months (range 24 to 348 months), the median age was 27 years (range 4 to 84), and 48% (148 of 310) were female; freezing was performed for 47% (147) of patients, pasteurization for 29% (89), and irradiation for 24% (74). The primary endpoints of this study were the cumulative incidence rate of complications and the cumulative survival of grafted bone, assessed by the Kaplan-Meier method. We used the classification of complications and graft failures proposed by the International Society of Limb Salvage. Factors relating to complications and grafted autograft removal were analyzed. The secondary endpoints were the proportion of bony union and better limb function, evaluated by the Musculoskeletal Tumor Society score. Factors relating to bony union and limb function were also analyzed. Data were investigated in each center by a record review and transferred to Kanazawa University., Results: The cumulative incidence rate of any complication was 42% at 5 years and 51% at 10 years. The most frequent complications were nonunion in 36 patients and infection in 34 patients. Long resection (≥ 15 cm) was associated with an increased risk of any complication based on the multivariate analyses (RR 1.8 [95% CI 1.3 to 2.5]; p < 0.01). There was no difference in the rate of complications among the three devitalizing methods. The cumulative graft survival rates were 87% at 5 years and 81% at 10 years. After controlling for potential confounding variables including sex, resection length, reconstruction type, procedure type, and chemotherapy, we found that long resection (≥ 15 cm) and composite reconstruction were associated with an increased risk of grafted autograft removal (RR 2.5 [95% CI 1.4 to 4.5]; p < 0.01 and RR 2.3 [95% CI 1.3 to 4.1]; p < 0.01). The pedicle freezing procedure showed better graft survival than the extracorporeal devitalizing procedures (94% versus 85% in 5 years; RR 3.1 [95% CI 1.1 to 9.0]; p = 0.03). No difference was observed in graft survival among the three devitalizing methods. Further, 78% (156 of 200 patients) of patients in the intercalary group and 87% (39 of 45 patients) of those in the composite group achieved primary union within 2 years. Male sex and the use of nonvascularized grafts were associated with an increased risk of nonunion (RR 2.8 [95% CI 1.3 to 6.1]; p < 0.01 and 0.28 [95% CI 0.1 to 1.0]; p = 0.04, respectively) in the intercalary group after controlling for confounding variables, including sex, site, chemotherapy, resection length, graft type, operation time, and fixation type. The median Musculoskeletal Tumor Society score was 83% (range 12% to 100%). After controlling for confounding variables including age, site, resection length, event occurrence, and graft removal, age younger than 40 years (RR 2.0 [95% CI 1.1 to 3.7]; p = 0.03), tibia (RR 6.9 [95% CI 2.7 to 17.5]; p < 0.01), femur (RR 4.8 [95% CI 1.9 to 11.7]; p < 0.01), no event (RR 2.2 [95% CI 1.1 to 4.5]; p = 0.03), and no graft removal (RR 2.9 [95% CI 1.2 to 7.3]; p = 0.03) were associated with an increased limb function. The composite graft was associated with decreased limb function (RR 0.4 [95% CI 0.2 to 0.7]; p < 0.01)., Conclusion: This multicenter study revealed that frozen, irradiated, and pasteurized tumor-bearing autografts had similar rates of complications and graft survival and all resulted in similar limb function. The recurrence rate was 10%; however, no tumor recurred with the devitalized autograft. The pedicle freezing procedure reduces the osteotomy site, which may contribute to better graft survival. Furthermore, tumor-devitalized autografts had reasonable survival and favorable limb function, which are comparable to findings reported for bone allografts. Overall, tumor-devitalized autografts are a useful option for biological reconstruction and are suitable for osteoblastic tumors or osteolytic tumors without severe loss of mechanical bone strength. Tumor-devitalized autografts could be considered when obtaining allografts is difficult and when a patient is unwilling to have a tumor prosthesis and allograft for various reasons such as cost or socioreligious reasons., Level of Evidence: Level III, therapeutic study., Competing Interests: Each author certifies that there are no funding or commercial associations (consultancies, stock ownership, equity interest, patent/licensing arrangements, etc.) that might pose a conflict of interest in connection with the submitted article related to the author or any immediate family members. All ICMJE Conflict of Interest Forms for authors and Clinical Orthopaedics and Related Research® editors and board members are on file with the publication and can be viewed on request., (Copyright © 2023 by the Association of Bone and Joint Surgeons.)