Osteosarcoma Arising as a Secondary Malignancy following Treatment for Hematologic Cancer: A Report of 33 Affected Patients from the Cooperative Osteosarcoma Study Group (COSS).

PURPOSE: Osteosarcoma may arise as a secondary cancer following leukemias or lymphomas. We intended to increase the knowledge about such rare events. PATIENTS AND METHODS: We searched the Cooperative Osteosarcoma Study Group's database for individuals who developed their osteosarcoma following a previous hematological malignancy. The presentation and treatment of both malignancies was investigated, and additional neoplasms were noted. Outcomes after osteosarcoma were analyzed and potential prognostic factors were searched for. RESULTS: A total of 33 eligible patients were identified (male: 23, female: 10; median age: 12.9 years at diagnosis of hematological cancer; 20 lymphomas, 13 leukemias). A cancer predisposition syndrome was evident in one patient only. The hematological cancers had been treated by radiotherapy in 28 (1 unknown) and chemotherapy in 26 cases, including bone-marrow transplantation in 9. The secondary bone sarcomas (high-grade central 27, periosteal 2, extra-osseous 2, undifferentiated pleomorphic sarcoma of bone 2) arose after a median lag-time of 9.4 years, when patients were a median of 19.1 years old. Tumors were considered radiation-related in 26 cases (1 unknown). Osteosarcoma-sites were in the extremities (19), trunk (12), or head and neck (2). Metastases at diagnosis affected eight patients. Information on osteosarcoma therapy was available for 31 cases. All of these received chemotherapy. Local therapy involved surgery in 27 patients, with a good response reported for 9/18 eligible patients. Local radiotherapy was given to three patients. The median follow-up was 3.9 (0.3-12.0) years after bone tumor diagnosis. During this period, 21 patients had developed events as defined, and 15 had died, resulting in 5-year event-free and overall survival rates of 40% (standard error: 9%) and 56% (10%), respectively. There were multiple instances of additional neoplasms. Several factors were found to be of prognostic value (p < 0.05) for event-free (osteosarcoma site in the extremities) or overall (achievement of a surgical osteosarcoma-remission, receiving chemotherapy for the hematologic malignancy) survival. CONCLUSIONS: We were able to prove radiation therapy for hematological malignancies to be the predominant risk factor for later osteosarcomas. A resulting overrepresentation of axial and a tendency towards additional neoplasms affects prognosis. Still, selected patients may become long-term survivors with appropriate therapies, which is an argument against therapeutic negligence.

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.

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.

Surgical microscope integrated MHz SS-OCT with live volumetric visualization.

Intraoperative optical coherence tomography is still not overly pervasive in routine ophthalmic surgery, despite evident clinical benefits. That is because today's spectral-domain optical coherence tomography systems lack flexibility, acquisition speed, and imaging depth. We present to the best of our knowledge the most flexible swept-source optical coherence tomography (SS-OCT) engine coupled to an ophthalmic surgical microscope that operates at MHz A-scan rates. We use a MEMS tunable VCSEL to implement application-specific imaging modes, enabling diagnostic and documentary capture scans, live B-scan visualizations, and real-time 4D-OCT renderings. The technical design and implementation of the SS-OCT engine, as well as the reconstruction and rendering platform, are presented. All imaging modes are evaluated in surgical mock maneuvers using ex vivo bovine and porcine eye models. The applicability and limitations of MHz SS-OCT as a visualization tool for ophthalmic surgery are discussed.

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.

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.

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.

Infantile myofibromatosis: Excellent prognosis but also rare fatal progressive disease. Treatment results of five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry.

BACKGROUND: Infantile myofibromatosis (IM) is a rare benign soft tissue tumor and often a self-limiting disease but rarely includes life-threatening complications. Little is known about optimal treatment of primary localized (LD) and multifocal disease (MFD). METHODS: Treatment and outcome of 95 children with IM registered within five Cooperative Weichteilsarkom Studiengruppe (CWS) trials and one registry (1981-2016) were evaluated. RESULTS: LD was diagnosed in 71 patients at a median age of 0.4 years (range 0.0-17.7). MFD was present in 24 patients. The mainstay of treatment was watch-and-wait strategy (w&w) after initial biopsy or resection. Low-dose chemotherapy (CHT) was administered to 16/71 (23%) patients with LD and eight of 24 (33%) patients with MFD, imatinib was added in two. A delayed resection was possible in eight of 71 (11%) and five of 24 (21%) patients with LD and MFD, respectively. Overall, patients were alive in complete remission (n = 77) and partial remission (n = 10) at a median follow-up time of 3.4 years after diagnosis (range 0.01-19.4); no data available (n = 5). Three patients died of progressive disease (PD) despite CHT. Gender, tumor size, and location correlated with a favorable event-free survival (EFS) in patients with LD. The 5-year EFS and overall survival of patients with LD were 73% (±12, confidence interval [CI] 95%) and 95% (±6, CI 95%), respectively; for MFD 51% (±22, CI 95%) and 95% (±10, CI 95%). CONCLUSION: Prognosis is excellent in patients with LD and MFD. Targeted treatment needs to be evaluated for rare fatal PD.

When Your Ankle Becomes a Knee - Long-Term Functional Outcome and Quality of Life with a Rotationplasty after Resection of Malignant Limb Tumors.

BACKGROUND: Increasing numbers of patients surviving malignant bone tumors around the knee joint have led to an increasing importance to investigate long-term results. This study assessed the long-term results of rotationplasty after resection of malignant bone tumors regarding functional outcome and quality of life to allow better comparison with other treatment options in bone cancer treatment. PROCEDURE: 60 participants who underwent rotationplasty due to bone cancer took part in this multicentric questionnaire-based study. The long-term functional outcome was measured by the Musculoskeletal tumor society score (MSTS) and the Tegner activity level scale. The health-related quality of life (HRQL) was assessed by using the Short Form Health Survey (SF-36). RESULTS: Patients treated with rotationplasty (median follow-up of 22 years, range 10-47 years) regained a high level of activity (median MSTS score of 24). Even a return to high level sports was possible (mean Tegner activity level scale of 4). Duration of follow-up did not influence the functional outcome. HRQL scores were comparable to the general German population. Concerns of psychological problems due to the unusual appearance of the rotated foot have not been confirmed. CONCLUSION: Rotationplasty can be a good alternative to endoprosthetic replacement or amputation, either as primary surgery or as a salvage procedure. Especially for growing children and very active patients rotationplasty should be considered.

Children with progressive and relapsed pleuropulmonary blastoma: A European collaborative analysis.

BACKGROUND: Children with progressive (PD) or relapsed disease (RD) of pleuropulmonary blastoma (PPB) type II/III are known to have a very poor outcome. METHODS: A retrospective review of children registered in national and European databases and trials (2000-2018) with diagnosis of PPB type II/III and PD or RD was performed. RESULTS: A total of 35 patients with PPB were analysed: patients with PD (n = 9) and RD (n = 26). Patients experienced PD at the median age of 3.9 years [range, 0.5-17.8] despite surgery, chemotherapy (CHT, n = 9) and radiotherapy (RT, n = 1) with a median time to progression of 0.58 years [range, 0.02-1.27] from diagnosis. All of them died. Patients suffered from RD at the median age of 4.3 years [1.7-15.1], median delay to relapse 1.03 years [range, 0.03-2.95]. RD occurred locally (n = 12), combined (n = 1) and in metastatic sites (n = 13): central nervous system (n = 11) and unspecified site (n = 2). Patients were treated with salvage CHT (n = 20), surgery (n = 10) ± RT (n = 10). After a median follow-up of 4.2 years [range, 2.1-14.6], a second complete remission (CR) was achieved in nine out of 26 patients. Patients were alive in the second CR (n = 6), in the third CR (n = 1), in partial remission (n = 2) and lost of follow-up (n = 1). Five-year event-free survival (EFS) and overall survival (OS) for patients with RD were both 37% (±19, CI 95%). Local therapy (surgery, RT) had a favourable impact on OS (p = 0.03 and 0.02, respectively). CONCLUSIONS: Cure of patients with RD of PPB type II/III with multimodal treatment is possible but rare. Progressive PPB is fatal and patients need new treatment options.

Usefulness of current candidate genetic markers to identify childhood cancer patients at risk for platinum-induced ototoxicity: Results of the European PanCareLIFE cohort study.

BACKGROUND: Irreversible sensorineural hearing loss is a common side effect of platinum treatment with the potential to significantly impair the neurocognitive, social and educational development of childhood cancer survivors. Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The aim of this cross-sectional cohort study was to confirm the genetic associations in a large pan-European population and to evaluate the diagnostic accuracy of the genetic markers. METHODS: Eligibility criteria required patients to be aged less than 19 years at the start of chemotherapy, which had to include cisplatin and/or carboplatin. Patients were assigned to three phenotype categories: no, minor and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1 and ACYP2) were investigated. Multinomial logistic regression was performed to model the relationship between genetic predictors and platinum ototoxicity, adjusting for clinical risk factors. Additionally, measures of the diagnostic accuracy of the genetic markers were determined. RESULTS: 900 patients were included in this study. In the multinomial logistic regression, significant unique contributions were found from SLC22A2 rs316019, the age at the start of platinum treatment, cranial radiation and the interaction term [platinum compound]∗[cumulative dose of cisplatin]. The predictive performance of the genetic markers was poor compared with the clinical risk factors. CONCLUSIONS: PanCareLIFE is the largest study of cisplatin-induced ototoxicity to date and confirmed a role for the polyspecific organic cation transporter SLC22A2. However, the predictive value of the current genetic candidate markers for clinical use is negligible, which puts the value of clinical factors for risk assessment of cisplatin-induced ototoxicity back into the foreground.

Association of candidate pharmacogenetic markers with platinum-induced ototoxicity: PanCareLIFE dataset.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

EURO-B.O.S.S.: A European study on chemotherapy in bone-sarcoma patients aged over 40: Outcome in primary high-grade osteosarcoma.

INTRODUCTION: The EUROpean Bone Over 40 Sarcoma Study (EURO-B.O.S.S.) was the first prospective international study for patients 41-65 years old with high-grade bone sarcoma treated with an intensive chemotherapy regimen derived from protocols for younger patients with high-grade skeletal osteosarcoma. METHODS: Chemotherapy based on doxorubicin, cisplatin, ifosfamide, and methotrexate was suggested, but patients treated with other regimens at the investigators' choice were also eligible for the study. RESULTS: The present report focuses on the subgroup of 218 patients with primary high-grade osteosarcoma. With a median follow-up of 47 months, the 5-year probability of overall survival (OS) was 66% in patients with localized disease and 22% in case of synchronous metastases. The 5-year OS in patients with localized disease was 29% in pelvic tumors, and 70% and 73% for extremity or craniofacial locations, respectively. In primary chemotherapy, tumor necrosis ≥90% was reported in 21% of the patients. There were no toxic deaths; however, hematological toxicity was considerable with 32% of patients experiencing 1 or more episodes of neutropenic fever. The incidence of nephrotoxicity and neurotoxicity (mainly peripheral) was 28% and 24%, respectively. After methotrexate, 23% of patients experienced delayed excretion, in 4 cases with nephrotoxicity. CONCLUSIONS: In patients over 40 years of age with primary high-grade osteosarcoma, an aggressive approach with chemotherapy and surgery can offer the probability of survival similar to that achieved in younger patients. Chemotherapy-related toxicity is significant and generally higher than that reported in younger cohorts of osteosarcoma patients treated with more intensive regimens.