Prognostic nutrition index as a predictive factor for overall survival in trabectedin-treated advanced soft tissue sarcoma.

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.

A phase 1 trial of NY-ESO-1-specific TCR-engineered T-cell therapy combined with a lymph node-targeting nanoparticulate peptide vaccine for the treatment of advanced soft tissue sarcoma.

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).

What Are the Complications, Function, and Survival of Tumor-devitalized Autografts Used in Patients With Limb-sparing Surgery for Bone and Soft Tissue Tumors? A Japanese Musculoskeletal Oncology Group Multi-institutional Study.

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.

Local surgery feasibility and safety after carbon ion radiotherapy for primary bone sarcomas.

BACKGROUND: It is known that several complications are caused by local surgery after radiotherapy. Clinical reports that describe the postoperative complications associated with surgery after carbon ion radiotherapy are sparse. This study aimed to elucidate local surgery feasibility after carbon ion radiotherapy specifically for primary bone sarcomas. METHODS: The medical, surgical, and irradiation records of patients who had local surgery at the area irradiated with carbon ion beams between 2004 and 2018 were reviewed retrospectively to evaluate the feasibility and indication of local surgery after CIRT. RESULTS: There were eight patients who had 10 local surgeries at the irradiated sites among the 42 carbon ion radiotherapy patients. There were seven males and one female with a median age of 50 years (range 26-73 years). The reasons for surgery were three for skin toxicity and associated infection, five for bone collapse, and associated implant failure, and two for tumor regrowth. All surgical fields included the area of more than 60 Gy (RBE) irradiated dose. All three surgical cases caused by skin toxicity and associated infection had Grade I wound complication after surgery according to the Clavien-Dindo Classification. CONCLUSION: Local surgery after CIRT appeared feasible in selected patients with primary bone sarcoma, especially for the patients with bone collapse and associated implant failure. However, infection and prescribed irradiation dose at the incision site must be carefully evaluated.

Giant cell tumor of bone - Analysis of 213 cases involving extra-craniofacial bones.

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.

A long-term follow-up study of extracorporeal irradiated autografts in limb salvage surgery for malignant bone and soft tissue tumors: A minimum follow-up of 10 years after surgery.

BACKGROUND AND OBJECTIVES: The aim of this study is to assess the survival, function, radiographic appearance, and modes of failure of extracorporeal irradiated (ECI) autografts in a long-term setting. METHODS: We retrospectively reviewed 87 patients who were treated for bone and soft tissue tumors using ECI autografts between 1988 and 2009. RESULTS: The 56 patients had a minimum follow-up of 10 years, and the median follow-up period was 16.5 years. The reimplantation procedures included 24 osteoarticular grafts, 16 intercalary grafts, 10 autograft-prosthetic composite grafts, and 6 hemicortical grafts. The 15-year graft and event-free survival rates were 76.8% and 47.9%, respectively. Infection and structural failure were the most common reasons for additional surgery. The time for additional surgery was significantly longer in patients with composite grafts (P < .01). The median Musculoskeletal Tumor Society score and the International Society of Limb Salvage score were 80% and 84%, respectively. CONCLUSIONS: ECI autografts are a durable option for reconstruction after resection of musculoskeletal tumors and provide good function over more than 15 years. Most graft failures occurred within 5 years of the index surgery. However, composite grafts showed a tendency to fail more than 10 years after the surgery.

Clinical outcomes of chondroblastoma treated using synthetic bone substitute: risk factors for developing radiographic joint degeneration.

BACKGROUND: Chondroblastoma (CB) is a rare locally aggressive bone tumor that commonly occurs in the epiphysis or apophysis of long bones. Although surgical treatment of CB carries potential risk for physeal or articular cartilage damage, risk factors for joint degeneration have not been well described. In addition, we have mainly used synthetic bone substitute (SBS) to fill the bone defect after intralesional curettage as treatment for CB. This study thus aimed to evaluate the incidence of and risk factors for adjacent-joint radiographic degeneration after SBS treatment for CB. METHODS: We retrospectively reviewed 48 patients treated for CB at our institutions between 1996 and 2017. Clinical data, radiographic images, treatments, and local recurrence were analyzed. RESULTS: We identified 40 patients [29 males and 11 females with a mean age of 19 years (range, 8-35 years)] who received SBS to fill the defect after curettage with a minimum follow-up of 1 year. The mean follow-up period was 71 months (range, 13-239 months). A total of 8 patients (20%) developed local recurrence. Radiographic analysis showed that 5 patients (16.7%) developed radiographic joint degeneration. Joint degeneration was significantly associated with the affected joint (p = 0.004). CONCLUSIONS: Curettage and SBS filling had been found to be a reasonable treatment method for CB, which commonly occurs in the epiphysis or apophysis. Radiographic joint degeneration was not uncommon after CB treatment, especially in the talus and proximal humerus.

Prognostic implication of adjuvant/neoadjuvant chemotherapy consisting of doxorubicin and ifosfamide in patients with extraskeletal osteosarcoma.

BACKGROUND: Extraskeletal osteosarcoma (ESOS) is an extremely rare soft tissue sarcoma. Their prognosis remains poor. Our purposes were to identify the effective chemotherapeutic regimen for ESOS. METHODS: We retrospectively reviewed 16 patients with ESOS treated at the Osaka University Orthopaedic Oncology Group between 1992 and 2012. We extracted the clinical data on patients. Kaplan-Meier method and the log-rank test were used for survival analyses. RESULTS: Median age of the patients was 61.5 years (range 25-79 years). Wide local excision was performed for 11 patients and 9 patients were treated combined with chemotherapy. The 5-year disease-specific survival (DSS) rate was 53.9%. The 5-year DSS rates for patients treated with adjuvant/neoadjuvant chemotherapy or not were 66.7% or 25%, respectively (p = 0.0215). Furthermore, the 5-year DSS rates for patients treated with adjuvant/neoadjuvant chemotherapy consisting of doxorubicin and ifosfamide and those treated with other regimens were 100% or 40%, respectively (p = 0.0327). CONCLUSION: The present study demonstrated that adjuvant/neoadjuvant chemotherapy, especially consisting of doxorubicin and ifosfamide, was potentially efficacious for ESOS. Further prospective study using this multimodality treatment approach to patients with ESOS should be strongly warranted.

Survival analysis of elderly patients with osteosarcoma.

BACKGROUND: Few studies have described the characteristics and prognostic factors of elderly patients with osteosarcoma. We retrospectively investigated clinico-pathological features and prognostic factors in osteosarcoma patients > 40 years old. METHODS: Patients with high-grade osteosarcoma > 40 years old who were treated at our institutions from 2000 to 2016 were recruited for this study. Information on patient, tumour, and treatment-related factors was collected and statistically analyzed. The median follow-up was 26.5 months (range, 5-139 months) for all patients. RESULTS: Fifty patients (30 males and 20 females) were included. The median age at diagnosis was 59.5 years (range, 41-81 years). The primary lesions were found in the limbs in 32 patients, trunk in 12, and craniofacial bones in six. Primary and secondary osteosarcoma occurred in 41 and 9 patients, respectively. Eight patients exhibited initial distant metastasis. Definitive surgery and chemotherapy were performed in 39 patients each. The rate of good responders after neoadjuvant chemotherapy was 38%. The five year overall survival (OS) rates for all patients and those without distant metastasis at diagnosis were 44.5% and 51.1%, respectively. Multivariate analysis showed that definitive surgery was the only significant prognostic factor in non-metastatic patients. The five year OS and disease-free survival (DFS) rates for non-metastatic patients who received definitive surgery were 64.3% and 60%, respectively. Among these patients, neoadjuvant and/or adjuvant chemotherapy significantly improved both OS and DFS. CONCLUSIONS: Complete surgical resection and intensive chemotherapy should be performed for osteosarcoma patients > 40 years old despite distinct clinicopathological characteristics from those of younger patients.

Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis.

PURPOSE: An epithelioid sarcoma is a rare histological subtype of a soft tissue sarcoma with a high local recurrence rate, which frequently shows lymph node metastasis. However, because of the rarity of this tumor, the impact of nodal metastasis and its appropriate management remain unclear. The present study investigated the clinical outcomes of patients with epithelioid sarcomas, with a focus on lymph node metastasis. METHODS: We retrospectively evaluated the clinical outcomes of 27 patients with epithelioid sarcomas treated between 1985 and 2015. The log-rank test was used to assess the prognostic variables. RESULTS: The overall local recurrence rate was 33%, and the estimated overall 5-year survival rate was 62%. Hand and foot locations were associated with favorable overall survival. During the follow-up period, new nodal metastasis was noted in 14 patients (52%). The incidence of local recurrence was higher in patients with new nodal metastasis than in patients who did not develop nodal metastasis. The development of new nodal metastasis had a tendency to worsen survival; however, this association was not statistically significant. Lymphadenectomy did not affect overall survival. CONCLUSIONS: Peripheral tumor location is associated with a better prognosis. The development of new nodal metastasis tends to be associated with poor prognosis; however, among patients with nodal metastasis, resection of the metastatic lesions has a low impact on survival.

Treatment outcomes of Japanese patients with Ewing sarcoma: differences between skeletal and extraskeletal Ewing sarcoma.

OBJECTIVE: The incidence of Ewing sarcoma is lower in non-Caucasian populations, compared with Caucasian populations, for unknown reasons. Most studies from western countries have reported improvement in outcomes following multi-agent chemotherapy, with no difference in outcome between skeletal and extraskeletal Ewing sarcoma. However, there are few studies of Ewing sarcoma in non-Caucasian populations, with especially few comparing outcomes between skeletal and extraskeletal Ewing sarcoma. Thus, the purpose of this study is to determine whether the outcomes and prognostic factors of Ewing sarcoma in the Japanese population are similar to those in Caucasian populations and to determine whether skeletal and extraskeletal Ewing sarcoma have similar outcomes in Japanese patients. METHODS: We retrospectively evaluated the outcomes of 74 Japanese patients with Ewing sarcoma treated between 1981 and 2011 from the Osaka University Orthopaedic Oncology Group. RESULTS: Extraskeletal Ewing sarcoma, tumors in the extremities, localized disease at presentation and diagnosis after 2000 were significantly associated with a favorable outcome. Among patients with localized disease at presentation, a significantly better outcome was observed for those with extraskeletal Ewing sarcoma, those who underwent a VDC/IE based or VAIA chemotherapy protocol, and those who were diagnosed after 2000. In the multivariable analyses, extraskeletal Ewing sarcoma was an independent predictor of increased overall survival among all patients and the subset of patients with localized disease. CONCLUSIONS: The outcome of patients with Ewing sarcoma in Japan has improved in the last decade. The outcomes and prognostic factors are similar for Japanese and Caucasian patients, though in this series of Japanese patients, a better prognosis was observed for patients with extraskeletal rather than skeletal Ewing sarcoma.

Comparison of clinical and functional outcome between surgical treatment and carbon ion radiotherapy for pelvic chondrosarcoma.

BACKGROUND: As there are no reports of studies in patients with pelvic chondrosarcoma treated with carbon ion radiotherapy (CIRT), the aim of this study was to evaluate the applicability of CIRT for patients with chondrosarcoma of the pelvis. METHODS: The medical records of 31 patients with chondrosarcoma of the pelvis treated either by surgical resection or by CIRT between 1983 and 2014 were reviewed. There were 22 males and 9 females with a median age of 43 years (range 16-77 years). The median duration of follow-up was 66 months (range 5-289 months). Twenty-four patients underwent surgery, and 7 patients received CIRT (70.4 GyE in 16 fractions over 4 weeks). RESULTS: The overall local recurrence rate was 32 %, and the estimated overall 5- and 10-year survival rates were 72 and 57 %, respectively. The mean Musculoskeletal Tumor Society functional score was 59 %. The treatment procedures (surgery or CIRT) did not affect overall survival (P = 0.347). However, the patients who underwent surgery had impaired function compared with those who received CIRT (P = 0.03). CONCLUSION: Although more patients need to be monitored to assess the clinical and functional outcomes of CIRT for patients with chondrosarcoma of the pelvis, this treatment might offer an acceptable alternative.

Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi-institutional study.

BACKGROUND: In this era of individualized cancer treatment, data that could be applied to predicting the survival of patients with osteosarcoma are still limited because of the rarity of the disease and the difficulty in accumulating a sufficient number of patients. Therefore, a multi-institutional collaboration was implemented to develop and externally validate nomograms that would predict metastasis-free survival (MFS) and overall survival (OAS) for patients with nonmetastatic osteosarcoma. METHODS: This study retrospectively examined 1070 patients treated with neoadjuvant chemotherapy and surgery for nonmetastatic osteosarcoma. Data from Japanese patients (n = 557) were used to develop multivariate nomograms based on Cox regression. Six clinical and pathologic variables were built into nomograms estimating the probability of MFS and OAS 3 and 5 years after diagnosis. The model was internally validated for discrimination and calibration with bootstrap resampling and was externally validated with an independent patient cohort from Korea (n = 513). RESULTS: A patient's age, tumor site, and histologic response were found to have a stronger influence on MFS and OAS in the model than sex, tumor size, or pathologic fracture. The nomograms and calibration plots based on these results well predicted the probability of MFS (concordance index, 0.631) and OAS (concordance index, 0.679). The concordance indices for external validation were 0.682 for MFS and 0.665 for OAS. CONCLUSIONS: The nomograms were externally validated and verified to be useful for the prediction of MFS and OAS and for the assessment of the postoperative prognosis. They can be used for counseling patients and for establishing appropriate surveillance strategies after surgery.

Phase I and pharmacokinetic study of trabectedin, a DNA minor groove binder, administered as a 24-h continuous infusion in Japanese patients with soft tissue sarcoma.

BACKGROUND: Trabectedin is a novel anticancer agent used to treat soft tissue sarcoma (STS). This phase I study of trabectedin was performed to determine the recommended dose for phase II studies in Japanese patients with STS. METHODS: Patients who had STS refractory to, or who could not tolerate, anthracycline-based chemotherapy were enrolled. The starting dose of trabectedin was 0.9 mg/m(2), given as a 24-h continuous infusion every 21 days. The dose was escalated to 1.2 mg/m(2) and then to 1.5 mg/m(2), using a "3 + 3" cohort expansion design. Plasma samples were collected for pharmacokinetic analysis. RESULTS: Fifteen patients received 1 of 3 dose levels of trabectedin. Dose-limiting toxicity occurred in two of three patients at 1.5 mg/m(2): 1 had a grade 3 increase in creatine phosphokinase and grade 3 anorexia, and the other had grade 4 platelet count decreased. Frequent grade 3 or 4 adverse events (AEs) included elevations of alanine aminotransferase and aspartate aminotransferase and decrease in neutrophil count. The frequency and severity of AEs were clearly greater at 1.5 mg/m(2) than at the lower doses. Pharmacokinetic analysis showed that the area under the concentration-time curve at a dose of 1.2 mg/m(2) was adequate to produce antitumor activity. A partial response was obtained in three patients with translocation-related sarcomas (1 each with myxoid liposarcoma, synovial sarcoma, and extraskeletal Ewing sarcoma). CONCLUSIONS: The recommended dose of trabectedin for phase II studies is 1.2 mg/m(2) in Japanese patients with STS. Trabectedin may be especially effective against translocation-related sarcomas.

A case of pelvic EWSR1-PATZ1 fusion sarcoma treated with carbon ion radiotherapy.

EWSR1-PATZ1 fusion sarcoma is a type of round-cell sarcoma with EWSR1-non-EST fusion that was newly categorized in the 2020 World Health Organization classification of soft tissue and bone tumors. In general, local disease is managed via surgical resection; however, at present, there is no standard therapy for locally advanced or metastatic disease. Here, we report our experience with a middle-aged male patient with pelvic EWSR1-PATZ1 fusion sarcoma who was treated with carbon ion radiotherapy and maintained stable disease for 13 months. The patient's clinical course suggests that carbon ion radiotherapy may be effective in patients with locally advanced EWSR1-PATZ1 fusion sarcoma.

Lorlatinib for the Treatment of Inflammatory Myofibroblastic Tumor after Allogeneic Hematopoietic Stem Cell Transplantation: A Case Report.

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.

Constrained total hip megaprosthesis for primary periacetabular tumors.

BACKGROUND: Limb-salvage reconstruction for periacetabular malignant tumors is one of the most challenging problems in orthopaedic oncology. Reconstructive options include resection arthroplasty, endoprosthesis, allograft, recycled autobone graft, arthrodesis, and pseudarthrosis. However, no standard procedure exists because of rarity and clinical variability of the disease. We previously developed a megaprosthetic system with a constrained total hip mechanism (C-THA). QUESTIONS/PURPOSES: We evaluated (1) survival of patients and C-THA; (2) postoperative function; and (3) complications. METHODS: We retrospectively reviewed 25 patients with primary periacetabular tumors treated using C-THA between 1985 and 2009. There were 18 male and seven female patients with a median age of 44 years (range, 16-72 years). They included 11 chondrosarcomas, eight osteosarcomas, two giant cell tumors of bone (one locally aggressive benign, one malignant), and others in four. Surgical margin was wide in 18 patients, marginal in five, and intralesional in two. The minimum postoperative followup for survivors was 32 months (median, 163 months; range, 32-285 months). RESULTS: The 10-year overall survival rate of all patients was 47%. C-THA implants survived in 19 of 25 patients at last followup. Twenty-one patients acquired ambulatory activity. There were seven local recurrences, resulting in hemipelvectomy in one patient. Postoperative complications included deep infection in eight of the 25 patients, dislocation in four, and aseptic loosening in two, necessitating five revision surgeries and three implant removals. CONCLUSIONS: Our observations suggest C-THA using an acetabular reconstruction cup is a useful reconstructive option after resection of periacetabular malignant tumors despite frequent postoperative complications. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

SHARPIN Enhances Ferroptosis in Synovial Sarcoma Cells via NF-κB- and PRMT5-Mediated PGC1α Reduction.

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.

Secondary leiomyosarcoma of the nasal cavity in a treated patient with possible hereditary retinoblastoma with germline reciprocal translocation of RB1 and DMXL1 and somatic TP53 mutation: A case report.

Retinoblastoma is a common primary intraocular malignant tumor that affects infants and young children. Radiation therapy for hereditary retinoblastoma increases the risk of secondary malignancy. The present report discusses the case of a retinoblastoma survivor who developed secondary leiomyosarcoma 42 years after receiving radiation therapy. The retinoblastoma of the patient was unilateral, and the patient had no family history of the disease. RNA and DNA panel sequencing of the leiomyosarcoma tissue was performed to elucidate the molecular mechanism of this secondary malignancy. The RNA panel sequencing detected a germline reciprocal translocation of RB1 and DMXL1, leading to a diagnosis of possible hereditary retinoblastoma. Furthermore, it detected a somatic fusion gene (RAD51-KNL1). The DNA panel sequencing identified various germline or somatic variants, including a somatic splice acceptor site mutation of TP53. We hypothesized that the molecular mechanism of the secondary malignancy of this patient was the combination of a germline reciprocal translocation of RB1 and DMXL1 and the accumulation of various somatic mutations containing the splice acceptor site mutation of TP53, which ultimately led to the development of a secondary leiomyosarcoma. Further prospective investigations are necessary to fully understand the role of reciprocal translocation of RB1 and DMXL1 or other mutations in the tumorigenesis of second malignancies in patients with hereditary retinoblastoma.