Systematic analysis of RNA-binding proteins identifies targetable therapeutic vulnerabilities in osteosarcoma.

Osteosarcoma is the most common primary malignant bone tumor with a strong tendency to metastasize, limiting the prognosis of affected patients. Genomic, epigenomic and transcriptomic analyses have demonstrated the exquisite molecular complexity of this tumor, but have not sufficiently defined the underlying mechanisms or identified promising therapeutic targets. To systematically explore RNA-protein interactions relevant to OS, we define the RNA interactomes together with the full proteome and the transcriptome of cells from five malignant bone tumors (four osteosarcomata and one malignant giant cell tumor of the bone) and from normal mesenchymal stem cells and osteoblasts. These analyses uncover both systematic changes of the RNA-binding activities of defined RNA-binding proteins common to all osteosarcomata and individual alterations that are observed in only a subset of tumors. Functional analyses reveal a particular vulnerability of these tumors to translation inhibition and a positive feedback loop involving the RBP IGF2BP3 and the transcription factor Myc which affects cellular translation and OS cell viability. Our results thus provide insight into potentially clinically relevant RNA-binding protein-dependent mechanisms of osteosarcoma.

Primary Multi-Systemic Metastases in Osteosarcoma: Presentation, Treatment, and Survival of 83 Patients of the Cooperative Osteosarcoma Study Group.

BACKGROUND: To evaluate patient and tumour characteristics, treatment, and their impact on survival in patients with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma. Precedure: Eighty-three consecutive patients who presented with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma were retrospectively reviewed. In cases of curative intent, the Cooperative Osteosarcoma Study Group recommended surgical removal of all detectable metastases in addition to complete resection of the primary tumour and chemotherapy. RESULTS: Eighty-three eligible patients (1.8%) were identified among a total of 4605 individuals with high-grade osteosarcoma. Nine (10.8%) of these achieved complete surgical remission, of whom seven later had recurrences. The median follow-up time was 12 (range, 1-165) months for all patients. Actuarial event-free survival after 1, 2, and 5 years was 9.6 ± 3.2%, 1.4 ± 1.4%, and 1.4 ± 1.4%, and overall survival was 54.0 ± 5.6%, 23.2 ± 4.9%, and 8.7 ± 3.3%. In univariate analyses, elevated alkaline phosphatase before chemotherapy, pleural effusion, distant bones as metastatic sites, and more than one bone metastasis were negative prognostic factors. Among treatment-related factors, the microscopically complete resection of the primary tumour, a good response to first-line chemotherapy, the macroscopically complete resection of all affected tumour sites, and local treatment (surgery ± radiotherapy) of all bone metastases were associated with better outcomes. Tumour progression under first-line treatment significantly correlated with shorter survival times. CONCLUSION: The outlook for patients with multi-systemic primary metastases from osteosarcoma remains very poor. The utmost importance of surgical resection of all tumour sites was confirmed. For unresectable bone metastases, radiotherapy might be considered. In the patient group studied, standard chemotherapy was often insufficiently effective. In the case of such advanced disease, alternative treatment options are urgently required.

Osteosarcoma Arising After Ewing Sarcoma or Vice Versa: A Report of 20 Affected Patients from the Cooperative Osteosarcoma Study Group (COSS).

BACKGROUND/AIM: Ewing sarcoma can arise in patients after osteosarcoma or vice versa. Our aim was to learn more about which patients develop these secondary tumors, which treatments may be effective, and which patients might survive. PATIENTS AND METHODS: The database of the Cooperative Osteosarcoma Study Group (1980-09/2022) was searched for all patients with an osteosarcoma (including undifferentiated pleomorphic sarcoma of the bone) who also suffered from Ewing sarcoma (incl. peripheral neuroectodermal tumor) at any time, previously or thereafter. The identified patients were then analyzed for patient, tumor, and treatment-related variables as well as their disease- and survival-status at the last follow-up. RESULTS: A total of 20 eligible patients [17 Ewing sarcoma prior to osteosarcoma, 3 vice versa; 10 males, 10 females; median age at 1st cancer 10.5 (2.4-20.6), at 2nd cancer 20.5 (9.9-42.4) years] were identified. None of the patients developed a 3rd cancer and none had a known tumor-predisposition syndrome. Sixteen/17 secondary osteosarcomas and no secondary Ewing sarcoma developed in sites that had previously been irradiated. Nineteen/20 (95%) patients received primary multi-agent chemotherapy for their 1st and 2nd cancers. Actuarial overall and event-free survival probabilities at five years after the diagnosis of the secondary cancer were 69% and 42%, respectively. CONCLUSION: Secondary osteosarcoma arising after Ewing sarcoma is almost exclusively associated with radiation. This is not the case vice versa. Either way, long-term survival is a realistic possibility with appropriate multidisciplinary treatment; thus, therapeutic negligence is clearly inadequate.

Which Patients With Rhabdomyosarcoma Need Radiotherapy? Analysis of the Radiotherapy Strategies of the CWS-96 and CWS-2002P Studies and SoTiSaR Registry.

PURPOSE: To analyze and compare the indications, doses, and application methods of radiotherapy (RT) and their influence on prognosis of patients with localized rhabdomyosarcoma (RMS). METHODS: One thousand four hundred seventy patients with localized RMS 21 years and younger entered on CWS-96, CWS-2002P, and SoTiSaR were eligible for the analysis. The median follow-up was 6.5 years (IQR, 3.3-9.5). RESULTS: The 5-year event-free survival (EFS) and local control survival (LCS) for 910 (62%) irradiated versus nonirradiated patients were 71% versus 69% and 78% versus 73% (P = .03), respectively. Ninety-five percent of patients in IRS I (90% embryonal RMS [eRMS]) were nonirradiated (EFS, 87%). Irradiated patients with IRS II had improved LCS (91% v 80%; P = .01) and EFS (not significant). In IRS III, EFS and LCS were significantly better for RT patients: 71% versus 56% (P = 3.1e-06) and 76% versus 61% (P = 4.1e-07). Patients with tumors in the head and neck region (orbita, parameningeal, and nonparameningeal) and in other sites had significantly better EFS and LCS and in parameningeal also overall survival (OS). The efficacy of low RT doses of 32 Gy (hyperfractionated, accelerated RT [HART]) and 36 and 41.4 Gy (conventional fractionated RT [CFRT]) in the favorable groups and higher doses of 44.8 Gy (HART) and 50.4 and 55.4 Gy (CFRT) in the unfavorable groups was comparable. Proton RT was used predominantly in head/neck-parameningeal (HN-PM) tumors, with similar EFS and LCS to photon RT. CONCLUSION: RT can be omitted in patients with IRS I eRMS. RT improves LCS and EFS in IRS II and III. RT improves OS in patients with HN-PM, with proton RT comparable with photon RT. Doses of 32 Gy (HART) or 36 and 41.4 Gy (CFRT) had comparable efficacy in patients with favorable risk profiles and 44.8 Gy (HART) or 50.4 and 55.8 Gy (CFRT) in the unfavorable groups.

Solid pseudopapillary neoplasms of the pancreas in childhood and adolescence-an analysis of the German Registry for Rare Pediatric Tumors (STEP).

Solid pseudopapillary neoplasms (SPNs) are the most common entity among pediatric pancreatic tumors. Still, these are rare tumors with an annual incidence of 0.1-0.2/1,000,000, and little is known about their optimal treatment. This analysis aimed to increase knowledge about the occurrence and treatment strategies of SPN in childhood. Data regarding diagnostics, treatment, and outcome of children aged 0-18 years with SPN recorded in the German Registry for Rare Pediatric Tumors (STEP) were analyzed. Thirty-eight patients were identified with a median age of 14.5 years at diagnosis (range: 8-18) and a female preponderance (81.6%). The most frequent location of the tumor was the pancreatic tail. In histopathological and immunohistochemical examination, pseudopapillary, solid, and cystic lesions as well as expression of beta-catenin, progesterone receptors, and cyclin D1 were the most common findings. All patients underwent surgical resection. Most patients underwent open resection, predominantly tail resection for tumors in the tail region and pylorus-preserving pancreaticoduodenectomy for tumors in the head region. The main postoperative sequela was exogenous pancreatic insufficiency (23.7%), especially with SPN in the pancreatic head. No recurrence occurred during follow-up, although two patients underwent resection with microscopic residue. CONCLUSION: SPN of the pancreas in childhood are low-grade malignancies with usually favorable treatment outcomes. However, therapy can lead to relevant long-term sequelae. To prevent recurrence, complete surgical resection is recommended, sparing as much healthy pancreatic tissue as possible. Interdisciplinary collaboration between specialists is essential to optimize treatment. Molecular genetic analysis of these tumors could improve understanding of their genesis. WHAT IS KNOWN: • Solid pseudopapillary neoplasms (SPNs) of the pancreas are very rare tumors in childhood. • Little is known about tumorigenesis, and there are no specific guidelines for treatment and follow-up in pediatric patients. WHAT IS NEW: • Characteristics, treatment, and outcome were comprehensively assessed in a large cohort of pediatric patients with SPN. • We propose recommendations for diagnosis, treatment, and follow-up of children with SPN, based on our analysis and considering published experience.

Solitary pulmonary metastases at first recurrence of osteosarcoma: Presentation, treatment, and survival of 219 patients of the Cooperative Osteosarcoma Study Group.

BACKGROUND: To evaluate patient and tumour characteristics, treatment and their impact on survival in patients with a solitary pulmonary metastasis at first relapse of high-grade osteosarcoma. PROCEDURE: Two-hundred and nineteen consecutive patients who had achieved a complete surgical remission and then developed a solitary pulmonary metastasis at first recurrence of high-grade osteosarcoma were retrospectively reviewed. RESULTS: Two hundred and three (94.9%) of 214 patients achieved a second complete remission. After a median time from initial diagnosis of osteosarcoma to first relapse of 2.3 years (range, 0.3-18.8 years), actuarial post-relapse overall survival after 2 and 5 years was 72.0% and 51.2%. Post-relapse event-free survival was 39.1% and 31.1%. Median follow-up time was 3.2 years (range, 0.1-29.4 years). A longer time until first relapse and diagnosis due to imaging were positive prognostic factors in uni- and multivariate analyses, as were a second complete surgical remission and, in regard to death, the absence of a subsequent relapse. The use of salvage chemotherapy and radiotherapy were not associated with patient outcomes, nor was the surgical approach (thoracoscopy vs. thoracotomy) nor the exploration (uni- vs. bilateral). CONCLUSION: Approximately half of the patients who experience a solitary pulmonary relapse at first recurrence of osteosarcoma remain alive 5 years after this first relapse. Only one third will remain disease-free. A complete surgical resection of the lesion is essential for long-term survival while relapse chemotherapy does not seem to improve survival. Innovative therapies are required to improve outcomes.

Clinical outcome of pediatric medulloblastoma patients with Li-Fraumeni syndrome.

BACKGROUND: The prognosis for Li-Fraumeni syndrome (LFS) patients with medulloblastoma (MB) is poor. Comprehensive clinical data for this patient group is lacking, challenging the development of novel therapeutic strategies. Here, we present clinical and molecular data on a retrospective cohort of pediatric LFS MB patients. METHODS: In this multinational, multicenter retrospective cohort study, LFS patients under 21 years with MB and class 5 or class 4 constitutional TP53 variants were included. TP53 mutation status, methylation subgroup, treatment, progression free- (PFS) and overall survival (OS), recurrence patterns, and incidence of subsequent neoplasms were evaluated. RESULTS: The study evaluated 47 LFS individuals diagnosed with MB, mainly classified as DNA methylation subgroup "SHH_3" (86%). The majority (74%) of constitutional TP53 variants represented missense variants. The 2- and 5-year (y-) PFS were 36% and 20%, and 2- and 5y-OS were 53% and 23%, respectively. Patients who received postoperative radiotherapy (RT) (2y-PFS: 44%, 2y-OS: 60%) or chemotherapy before RT (2y-PFS: 32%, 2y-OS: 48%) had significantly better clinical outcome then patients who were not treated with RT (2y-PFS: 0%, 2y-OS: 25%). Patients treated according to protocols including high-intensity chemotherapy and patients who received only maintenance-type chemotherapy showed similar outcomes (2y-PFS: 42% and 35%, 2y-OS: 68% and 53%, respectively). CONCLUSIONS: LFS MB patients have a dismal prognosis. In the presented cohort use of RT significantly increased survival rates, whereas chemotherapy intensity did not influence their clinical outcome. Prospective collection of clinical data and development of novel treatments are required to improve the outcome of LFS MB patients.

Primary osteosarcoma of the ribs: A report from the Cooperative Osteosarcoma Study Group.

PURPOSE: Primary rib osteosarcoma has not been investigated extensively, and clinical characteristics and optimal therapeutic strategies have not been defined. The authors used the database of the Cooperative Osteosarcoma Study Group (COSS) to analyze this tumor-site in depth. METHODS: The COSS database was searched for treatment-naive, high-grade osteosarcomas of the rib. Affected patients were analyzed for demographic and tumor-related factors, treatments, and outcomes. RESULTS: A total of 44 patients (23 males, 21 females; median age, 23 years [range, 6-59]) were identified. Primary metastases were detected in six of 44 (14%) patients. Surgery was performed in 40 of 44 (91%) patients and rendered 35 of 44 (80%) patients macroscopically disease-free. Chemotherapy was known to have been administered in 43 of 44 (98%) patients and radiotherapy in seven of 42 (17%) (no data for two patients). A good response to chemotherapy was only noted in five (33%) of those 15 evaluable patients who had received any preoperative chemotherapy. After a median follow-up of 2.49 (0.22-40.35) years for all patients and 6.61 (0.25-40.35) years for 26 survivors (21 of these in first complete remission), 5-year actuarial overall and event-free survival were 53.0% (8.5%) and 42.2% (8.1%), respectively. Incomplete tumor surgery was the most notable negative prognostic factor. Osteoblastic histology and a poor response to chemotherapy may have contributed. CONCLUSION: This large series provides evidence that patients with costal primaries are older than the average osteosarcoma patient, but appear to share the similar tumor biology and-if treated according to standard protocols-prognostic factors with tumors of other sites. Early, preoperative diagnosis and permanent, definitive local control remain major challenges and should contribute to improved outcomes.

Establishment, Maintenance, and Performance of the Cooperative Osteosarcoma Study Group (COSS).

INTRODUCTION: Osteosarcoma treatment has benefitted greatly from collaborative research. This paper describes the history and accomplishments of the Cooperative Osteosarcoma Study Group (COSS), mainly dedicated to clinical questions, as well as remaining challenges. MATERIALS AND METHODS: Narrative review of over four decades of uninterrupted collaboration within the multi-national German-Austrian-Swiss COSS group. RESULTS: Since its very first prospective osteosarcoma trial starting in 1977, COSS has continuously been able to provide high-level evidence on various tumor- and treatment-related questions. This includes both the cohort of patients enrolled into prospective trials as well as those patients excluded from them for various reasons, followed in a prospective registry. Well over one hundred disease-related publications attest to the group's impact on the field. Despite these accomplishments, challenging problems remain. DISCUSSION: Collaborative research within a multi-national study group resulted in better definitions of important aspects of the most common bone tumor, osteosarcoma, and its treatments. Important challenges continue to persist.

Osteosarcomas in older adults: A report from the Cooperative Osteosarcoma Study Group.

INTRODUCTION: Osteosarcoma is typically a disease of the young, but may affect any age. Little is known about the disease in older patients beyond retirement age. We aim to describe the characteristics, treatment, and outcomes of older adult patients registered with our cooperative group. MATERIALS AND METHODS: The database of the Cooperative Osteosarcoma Study Group (COSS) was searched for osteosarcoma patients diagnosed from 1980 to 2020 who were aged 65 years or older at diagnosis. Affected individuals were analyzed for presenting factors, treatments employed, and outcomes. RESULTS: Fifty-five eligible patients were detected (median age 68 [range: 65-84] years; male:female = 25:30). Among these patients, 15/55 (27%) tumors were secondary malignancies, 41/55 (75%) were high-grade central, 4/55 (7%) surface, and 10/55 (18%) extraosseous malignancies, and all but three high-grade. Primary metastases were present in 15/55 (27%) patients. Surgery was reported for 46/55 (84%) patients, radiotherapy for 6/54 (11%, 1 unknown), chemotherapy for 42/50 (84%, 5 unknown). A complete surgical remission was achieved in 31/55 (56%). There were two toxic deaths. With a median follow-up of 1.7 (range: 0.1-18.0) years for all 55 patients and 2.2 (0.1-12.4) years for 24 survivors, event-free and overall survival at 2/5 years were 39.6% (standard error: 6.8%) / 24.5% (6.5%) and 62.0% (7.1%) / 32.7% (7.5%), respectively. Tumor site, metastatic status, surgery, and a complete surgical remission were prognostic for event-free and/or overall survival. DISCUSSION: Osteosarcomas can occur in older individuals. It is more often secondary, axially located, or extraosseous than in younger patients. However, the same treatment principles seem to apply, and selected patients may be cured. Multi-center cooperation is encouraged, thereby gathering expertise for such a rare disease presentation.

Ultra-Late Osteosarcoma Recurrences: An Analysis of 17 Cooperative Osteosarcoma Study Group Patients with a First Recurrence Detected More Than 10 Years After Primary Tumor Diagnosis.

Purpose: Osteosarcoma is a typical malignancy of childhood and adolescence. Recurrences usually occur early, but rarely may arise after decades of remission. Little is known about these very late events and we set out to fill this knowledge gap. Methods: The database of the Cooperative Osteosarcoma Study Group (COSS) was searched for patients with a first recurrence of a high-grade central osteosarcoma occurring >10 years after diagnosis of the primary disease. Identified patients were analyzed for demographic, tumor-, and treatment-related factors as well as outcomes. Results: Among a total of 1,178 10-year relapse-free survivors, 17 affected patients were identified. Only five of these had a documented good response to initial chemotherapy. No presenting factor was identified to predict these very late events. Prognosis was generally very poor despite intensive multimodal therapy. Inoperability of the recurrences seems to have constituted a major limiting factor. Conclusion: Osteosarcoma patients should be followed for potential recurrences for well >10 years from initial diagnosis. Only through such an extended truly long-term follow-up and a structured transition of young patients can these be detected while they are still operable and, hence, potentially curable.

Osteosarcoma pre-diagnosed as another tumor: a report from the Cooperative Osteosarcoma Study Group (COSS).

PURPOSE: The course of osteosarcoma patients primarily treated as such has been well described. Little, however, is known about patients who were primarily treated assuming a different tumor diagnosis. METHODS: The database of the Cooperative Osteosarcoma Study Group COSS was searched (4.435 primary high-grade central osteosarcomas registered prior to 01/01/21). A different tumor entity had to have been assumed for at least one month after the initial diagnostic procedure before the correct diagnosis of osteosarcoma was finally made. Identified patients were analyzed for demographic, tumor-, and treatment-related factors as well as for survival outcomes. RESULTS: 37 patients were identified. They were a median of 19.7 (2.7-60.4) years old at first presentation and were more likely to be females than males (23:14). Bone cysts (n = 8), giant cell tumor of bone (n = 6), and osteoblastoma (n = 6) were the most frequent of 29/37 (78%) benign, chondrosarcoma and its variants (n = 6) the most frequent of 8/37 (22%) malignant original diagnoses. Tumors affected the extremities in 23 (62%), the trunk in 11 (30%), and the craniofacial bones in 3 (8%). Only one patient received systemic treatment while assuming the different diagnosis (1/37, 3%). The median time until the correct diagnosis of osteosarcoma was made was 8 months (range: 1 month-14.1 years). At that time, 6/37 (16%) presented with metastatic disease. All patients went on to receive chemotherapy, 17/37 (46%) neo-adjuvantly. Histologic response was only evaluated in 13/17 (76%) patients and was good (< 10% viable tumor) in only 4/13 (31%) patients. In 31/37 (84%) patients, a surgically complete resection of all macroscopically identified tumor manifestations could be achieved. Five-year overall and event-free survival rates at 5 years were 50.2% (standard error: 8.6%) and 42.6% (8.5%), respectively. CONCLUSION: Osteosarcoma may initially be misdiagnosed and hence subjected to inappropriate treatment including misguided surgery. Once diagnosed correctly, some of the affected patients may still be cured if finally treated according to modern osteosarcoma standards.

Osteosarcoma and causes of death: A report of 1520 deceased patients from the Cooperative Osteosarcoma Study Group (COSS).

PURPOSE: Most aspects of osteosarcoma have been addressed in detail, but there is no comprehensive analysis of deceased patients and causes of death. METHODS: The database of the Cooperative Osteosarcoma Study Group COSS (1980-03/31/2021; 4475 registered high-grade central osteosarcoma patients) was searched deaths from any cause. Affected patients were analyzed for demographic and baseline variables and disease-status at the time of demise. Deaths from causes other than osteosarcoma were analyzed in detail. RESULTS: A total of 1520 deceased patients were identified (median age (range) at osteosarcoma diagnosis 16 (2-78) years; 908 (59.7%) male, 612 (40.3%) female; primary tumor: extremities 1263 (83.1%), trunk 208 (13.7%), craniofacial 47 (3.1%) (site unknown 2); metastases at registration: absent 1.051 (69.1%), present 466 (30.7%) (3 no data). The median time from diagnosis to death was 2.22 (0.08-32.02) years. 1286 (84.6%) patients succumbed to osteosarcoma (370 without achieving complete remission, 488 first, 428 more than one recurrences), 146 (9.6%) to other, 88 (5.8%) to unknown causes. Chemotherapy-related infections (40), secondary malignancies (39), and perioperative complications (19) were among the most frequent potentially treatment-related causes, and high-dose methotrexate (19), doxorubicin (17), and ifosfamide (15) were the drugs most commonly held responsible. Patients with unknown causes of death had an unusually long median follow-up. CONCLUSION: The major cause of death of patients after osteosarcoma is this malignancy, mostly from one of its multiple relapses. However, almost 10% of fatalities are due to other documented causes. Some of these deaths may be preventable with the knowledge gained from comprehensive analyses such as this.

Genotype-phenotype associations within the Li-Fraumeni spectrum: a report from the German Registry.

Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome caused by pathogenic TP53 variants. The condition represents one of the most relevant genetic causes of cancer in children and adults due to its frequency and high cancer risk. The term Li-Fraumeni spectrum reflects the evolving phenotypic variability of the condition. Within this spectrum, patients who meet specific LFS criteria are diagnosed with LFS, while patients who do not meet these criteria are diagnosed with attenuated LFS. To explore genotype-phenotype correlations we analyzed 141 individuals from 94 families with pathogenic TP53 variants registered in the German Cancer Predisposition Syndrome Registry. Twenty-one (22%) families had attenuated LFS and 73 (78%) families met the criteria of LFS. NULL variants occurred in 32 (44%) families with LFS and in two (9.5%) families with attenuated LFS (P value < 0.01). Kato partially functional variants were present in 10 out of 53 (19%) families without childhood cancer except adrenocortical carcinoma (ACC) versus 0 out of 41 families with childhood cancer other than ACC alone (P value < 0.01). Our study suggests genotype-phenotype correlations encouraging further analyses.

Fusion transcripts as liquid biopsy markers in alveolar rhabdomyosarcoma and synovial sarcoma: A report of the Cooperative Weichteilsarkom Studiengruppe (CWS).

BACKGROUND: The possible application of gene fusion transcripts as tumor-specific noninvasive liquid biopsy biomarkers was investigated in blood plasma from patients with alveolar rhabdomyosarcoma (ARMS) and synovial sarcoma (SS). METHODS: Patients entered in the CWS Soft-Tissue Sarcoma Registry (SoTiSaR) with tumors positive for fusion genes and available blood/plasma samples were included in our analysis. Cell-free exosomal RNA was extracted and used to detect PAX-FOXO1 or SYT-SSX fusion transcripts by reverse transcription quantitative PCR (RT-qPCR). RESULTS: The analysis included 112 ethylene diamine tetraacetic acid blood samples from 80 patients (65 with ARMS, 15 with SS; 34 with localized, 46 with metastatic disease). For patients with metastatic ARMS, 62% (n = 18) of initial liquid biopsies were positive, and 16 (89%) of them showed initial bone marrow (BM) metastases. For all patients with primary localized ARMS, liquid biopsy was negative at diagnosis. Of the 48 plasma samples collected during therapy and follow-up, five were positive. None of the liquid biopsies from patients with SS were positive. CONCLUSIONS: This liquid biopsy assay based on the detection of fusion transcripts in cell-free RNA from blood exosomes is suitable for analysis of patients with ARMS. Results showed good correlation with the initial tumor status; liquid biopsy was positive in 94% of patients with metastatic ARMS and initial BM involvement, whereas biopsies from all patients with localized tumors were negative. Prospective validation and optimization of the assay, as well as its application for other markers in diagnostics and monitoring of soft-tissue sarcoma, are ongoing.

Secondary malignant neoplasms after bone and soft tissue sarcomas in children, adolescents, and young adults.

BACKGROUND: Increased survival in young sarcoma patients comes along with a higher incidence of second malignant neoplasms (SMNs). The incidence, latency, histiotype, and outcome of these patients were analyzed because this information is essential to design evidence-based long-term follow-up care programs for young sarcoma survivors. METHODS: Patients entered on clinical trials or registered in registries with a primary sarcoma in 1 of the cooperative sarcoma study groups in the framework of the Society for Pediatric Oncology and Hematology (GPOH) were screened for SMNs. Descriptive analysis, the Kaplan-Meier method, the Gray model, the Fine-Gray model, and the Cox regression model were used for the statistical analyses. RESULTS: A total of 159 out of 7079 (2.2%) patients were registered with a SMN. Among them, 104 solid SMNs (65%) and 56 hematologic SMNs (35%) occurred. Median latency from first diagnosis of sarcoma to the diagnosis of SMN was 6.8 years (range, 0-26.7 years). Cumulative incidence of SMN was 8.8% after 30 years. Five-year-survival was 67.1% (95% confidence interval [CI], 66.0-68.2) for the 7079 patients and it was 45.1% (95% CI, 36.2-53.6) after the diagnosis of a SMN (subcohort of n = 159 patients). CONCLUSIONS: There is a remarkable high cumulative incidence of SMNs after bone and soft tissue sarcomas in children, adolescents, and young adults. Therefore, effective transition as well as risk adapted long-term follow-up care programs should be developed and offered to young sarcoma survivors. LAY SUMMARY: Bone sarcomas and soft tissue tumors are rare tumors in children, adolescents, and young adults. The treatment varies, but may comprise chemotherapy, surgery, and/or radiotherapy. Developing a subsequent malignant tumor is a long-term risk for the patients. To better characterize this risk, we analyzed the data of 7079 patients (up to 21 years old) with bone sarcomas or soft tissue tumors. Our findings provide a basis to counsel young sarcoma survivors on their individual risk of subsequent malignant tumors. Moreover, these data can help to establish recommendations for aftercare in young sarcoma survivors.

Current Insights into the Management of Late Chemotherapy Toxicities in Pediatric Osteosarcoma Patients.

With ever increasing long-term, disease free survival rates, long-term toxicities of otherwise successful therapy have gained increasing importance. They can be grouped into potentially life-threatening, especially secondary malignancies and anthracycline cardiomyopathies, potentially disabling, particularly severe hearing loss and renal insufficiency, other, and rare events. Pathophysiology, frequency, and medical treatment approaches are discussed. Finally, fertility issues and quality of life issues are discussed, together with an outlook into the future. The challenge to cure as many patients as possible from osteosarcoma while enabling a life free of late effects will remain.

Recommendations for Age-Appropriate Testing, Timing, and Frequency of Audiologic Monitoring During Childhood Cancer Treatment: An International Society of Paediatric Oncology Supportive Care Consensus Report.

IMPORTANCE: Ototoxicity is an irreversible direct and late effect of certain childhood cancer treatments. Audiologic surveillance during therapy as part of the supportive care pathway enables early detection of hearing loss, decision-making about ongoing cancer treatment, and, when applicable, the timely use of audiologic interventions. Pediatric oncologic clinical practice and treatment trials have tended to be driven by tumor type and tumor-specific working groups. Internationally accepted standardized recommendations for monitoring hearing during treatment have not previously been agreed on. OBJECTIVE: To provide standard recommendations on hearing loss monitoring during childhood cancer therapy for clinical practice. METHODS: An Ototoxicity Task Force was formed under the umbrella of the International Society of Paediatric Oncology, consisting of international audiologists, otolaryngologists, and leaders in the field of relevant pediatric oncology tumor groups. Consensus meetings conducted by experts were organized, aimed at providing standardized recommendations on age-directed testing, timing, and frequency of monitoring during cancer treatment based on literature and consensus. Consensus statements were prepared by the core group, adapted following several videoconferences, and finally agreed on by the expert panel. FINDINGS: The consensus reached was that children who receive ototoxic cancer treatment (platinum agents, cranial irradiation, and/or brain surgery) require a baseline case history, monitoring of their middle ear and inner ear function, and assessment of tinnitus at each audiologic follow-up. As a minimum, age-appropriate testing should be performed before and at the end of treatment. Ideally, audiometry with counseling before each cisplatin cycle should be considered in the context of the individual patient, specific disease, feasibility, and available resources. CONCLUSIONS AND RELEVANCE: This is an international multidisciplinary consensus report providing standardized supportive care recommendations on hearing monitoring in children undergoing potentially ototoxic cancer treatment. The recommendations are intended to improve the care of children with cancer and facilitate comparative research on the timing and development of hearing loss caused by different cancer treatment regimens.

Outcome in dedifferentiated chondrosarcoma for patients treated with multimodal therapy: Results from the EUROpean Bone Over 40 Sarcoma Study.

INTRODUCTION: The role of chemotherapy for patients with dedifferentiated chondrosarcoma (DDCS) is still under discussion. Here, we present the outcome in patients with DDCS treated with intensive chemotherapy from the EUROpean Bone Over 40 Sarcoma Study. MATERIALS AND METHODS: The chemotherapy regimen included doxorubicin, ifosfamide and cisplatin. Postoperative methotrexate was added in case of poor histological response. Toxicity was graded based on the National Cancer Institute expanded common toxicity criteria, version 2.0, and survival was analysed using Kaplan-Meier curves, log-rank tests and univariate Cox regression models. RESULTS: Fifty-seven patients with DDCS (localised, 34 [60%]; metastatic, 23 [40%]) aged 42-65 years were included. Surgical complete remission (SCR) was achieved in 36 (63%) patients. The median overall survival (OS) was 24 months (95% confidence interval, 22-25), and the 5-year OS was 39%. Patients with extremity localisation had a 5-year OS of 49% compared with 29% in patients with a central tumour (P = 0.08). Patients with localised disease had a 5-year OS of 46%, whereas patients with metastatic disease had a 5-year OS of 29% (P = 0.12). Patients in SCR had a 5-year OS of 49%, whereas patients not in SCR had a 5-year OS of 23% (P = 0.004). Chemotherapy toxicity was considerable but manageable. There was no treatment-related death, and 39 (70%) patients received ≥6 cycles of the planned nine chemotherapy cycles. CONCLUSIONS: Adding intensive chemotherapy to surgery for treatment of DDCS is feasible and shows favourable survival data compared with previous reports. With the limitations of data from a non-controlled trial, we conclude that chemotherapy could be considered in the management of patients aged >40 years.

The role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma.

BACKGROUND: To investigate the role of combined ion-beam radiotherapy (CIBRT) with protons and carbon ions in a multimodal treatment strategy of inoperable osteosarcoma; final analysis of a one-armed, single center phase I/II trial. METHODS: Between August 2011 until September 2018, 20 patients with primary (N = 18), metastatic (N = 3), or recurrent (N = 2) inoperable pelvic (70%) or craniofacial (30%) osteosarcoma were treated with protons up to 54 Gy (RBE) and a carbon ion boost of 18 Gy (RBE) and followed until May 2019. A Fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) was performed before CIBRT in search for a prognostic factor. The primary endpoint was toxicity. Secondary endpoints included treatment response, global, local and distant progression free survival (PFS, LPFS and DPFS) and overall (OS), among others. RESULTS: The median age was 20; all patients finished treatment per protocol. LPFS, DPFS, PFS and OS were 73%, 74%, 60% and 75% after one year and 55%, 65% 65.3%, 45% and 68% after two years, respectively. The median clinical target volume (CTV) was 1042 cc and 415 cc for the primary and boost plan, respectively. Craniofacial localization, lower uptake of FDG in PET/CT and boost plan CTV ≤ median were associated with improved overall survival (p = 0.039, p = 0.016 and p = 0.0043, respectively). No acute toxicities > grade III were observed. We observed one case of secondary acute myeloid leukemia (AML) seven months after CIBRT for recurrent disease and one case of hearing loss. CONCLUSION: CIBRT shows a favorable toxicity profile and promising results particularly for patients with inoperable craniofacial osteosarcoma.