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Background: Coagulopathy in isolated traumatic brain injury (TBI) is well-known, and studies have found an association between coagulopathy and unfavourable outcomes. This study was conducted to determine the incidence and causes of coagulopathy in patients with TBI undergoing craniotomy and its effect on post-operative outcome. Materials and Methods: The data collected was demographics, computed tomography diagnosis, post-resuscitation Glasgow Coma Scale (GCS) score, pre- and post-operative platelet count, liver function tests, intraoperative blood loss and transfusion, fluids infused and incidence of redo surgery. Point of care (Coaguchek XS) monitor was used to obtain prothrombin time and international normalised ratio (INR) at 24 h and 72 h of injury. Coagulopathy was defined as INR ≥1.3 and thrombocytopenia as platelet count ≤100,000/mcL. Outcome measures assessed were the length of hospital stay, GCS at discharge and in-hospital mortality. Results: In 166 patients, the average pre-operative GCS was 8.8 ± 3.6. The incidence of coagulopathy was 42.8% and increased to 55.6% on the 3rd day, and thrombocytopenia from 3.5% in the first 24 h increased to 14.7% at 72 h. Patients with coagulopathy had lower pre-operative admission GCS (median 7 vs. 9, P = 0.03), greater intraoperative blood loss and received more intravenous fluids. There was no difference in the incidence of post-operative haematomas, length of hospital stay and GCS at discharge or mortality. Conclusion: In patients with TBI, the incidence of coagulopathy increased at the end of 72 h. In this study, there was no difference in outcomes in patients who underwent craniotomy with deranged coagulation.

Fibrinogen is the primary substrate of coagulation. Fibrinogen depletion occurs in acute traumatic coagulopathy and is associated with unfavorable outcomes. Fibrinogen levels also decrease following traumatic brain injury (TBI) due to hypothermia, acidosis, and hypoperfusion leading to hyperfibrinolysis. This study was conducted to identify risk factors and the incidence of hypofibrinogenemia following TBI and also its effect on perioperative complications and postoperative outcome. A total of 51 adult patients with TBI were included in the study, and 33.3% of them had hypofibrinogenemia. Patients with low fibrinogen levels had lower preoperative Glasgow Coma Score (GCS), had associated derangement of international normalized ratio (INR), received more blood transfusions, and had lower discharge GCS compared with those with normal fibrinogen levels. Patients with hypofibrinogenemia had higher incidence of repeat surgery. In conclusion, hypofibrinogenemia occurs commonly after TBI and is associated with poor outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background Glucocorticoids such as prednisolone and dexamethasone are critical drugs used in multi-agent chemotherapy protocols used to treat acute lymphoblastic leukemia (ALL), and response to glucocorticoids is highly predictive of outcome. The NOD/SCID xenograft mouse model of ALL is a clinically relevant model in which the mice develop a systemic leukemia which retains the fundamental biological characteristics of the original disease. Here we report a study evaluating the NOD/SCID xenograft mouse model to investigate glucocorticoid-induced gene expression. Cells from a glucocorticoid-sensitive xenograft derived from a child with B-cell precursor ALL were inoculated into NOD/SCID mice. When highly engrafted the mice were randomized into groups of 4 to receive dexamethasone 15 mg/kg by intraperitoneal injection or vehicle control. Leukemia cells were harvested from mice spleens at 0, 8, 24 or 48 hours thereafter, and gene expression analyzed on Illumina WG-6_V3 chips, comparing all groups to time 0 hours. Results The 8 hour dexamethasone-treated timepoint had the highest number of significantly differentially expressed genes, with fewer observed at the 24 and 48 hour timepoints, and with minimal changes seen across the time-matched controls. When compared to publicly available datasets of glucocorticoid-induced gene expression from an in vitro cell line study and from an in vivo study of patients with ALL, at the level of pathways, expression changes in the 8 hour xenograft samples showed a similar response to patients treated with glucocorticoids. Replicate analysis revealed that at the 8 hour timepoint, a dataset with high signal and differential expression, using data from 3 replicates instead of 4 resulted in excellent recovery scores of > 0.9. However at other timepoints with less signal very poor recovery scores were obtained with 3 replicates. Conclusions The NOD/SCID xenograft mouse model provides a reproducible experimental system in which to investigate clinically-relevant mechanisms of drug-induced gene regulation in ALL; the 8 hour timepoint provides the highest number of significantly differentially expressed genes; time-matched controls are redundant and excellent recovery scores can be obtained with 3 replicates.

Background: Gemcitabine and docetaxel (GD) is a common chemotherapy regimen for metastatic soft tissue sarcoma (STS). The GeDDiS trial compared GD with doxorubicin in the first-line setting, using gemcitabine 675 mg/m 2 over a prolonged rate of 90 min-reporting a 20% response rate and 5.4-month median progression-free survival (PFS). We aimed to examine the real-world efficacy and toxicity of GD in our center, using a standardized dose of gemcitabine 900 mg/m 2 over 30 min on Days 1 and 8 and intravenous docetaxel 75 mg/m 2 over 60 min on Day 8 every 21 days., Methods: A retrospective analysis was conducted of patients with unresectable or metastatic STS receiving GD between July 2018 and October 2022. Data collected included patient and tumor characteristics, dose intensity, toxicity, response, PFS, and overall survival (OS)., Results: Thirty-eight patients were included. Median follow-up was 19 months (range 3-30). Line of treatment (n) was first line (10), second line (13), ≥ third line (15). The median number of cycles was 6. Response rate was 42%, including 5% with a complete response. At the time of data collection, 33 patients had disease progression and 24 patients had died. PFS (median, 6-month rate) was 4.5 months and 44%. OS (median, 12-month rate) was 15 months and 65%. Grade 3/4 toxicity included anemia (21%), neutropenia (5%), thrombocytopenia (5%), and febrile neutropenia (3%)., Conclusion: These data demonstrate the activity of gemcitabine using a standardized dose and rate with docetaxel comparable to other published data and favorable toxicity in a real-life patient population despite altered gemcitabine dosing and a heavily pretreated patient population., (© 2024 John Wiley & Sons Australia, Ltd.)

Background: Tenosynovial giant cell tumour (TGCT) is a locally aggressive neoplasm for which few systemic treatment options exist. This study evaluated the efficacy and safety of vimseltinib, an oral, switch-control, CSF1R inhibitor, in patients with symptomatic TGCT not amenable to surgery., Methods: MOTION is a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial done in 35 specialised hospitals in 13 countries. Eligible patients were adults (aged ≥18 years) with a histologically confirmed diagnosis of TGCT for which surgical resection could potentially worsen functional limitation or cause severe morbidity. Patients were randomly assigned (2:1) with interactive response technology to vimseltinib (30 mg orally twice weekly) or placebo, administrated in 28-day cycles for 24 weeks. Patients and site personnel were masked to treatment assignment until week 25, unless progressive disease was confirmed earlier. The primary endpoint was objective response rate by independent radiological review using Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST) at week 25 in the intention-to-treat population. Safety was assessed in all patients who received the study drug. The trial is registered with ClinicalTrials.gov, NCT05059262, and enrolment is complete., Findings: Between Jan 21, 2022, and Feb 21, 2023, 123 patients were randomly assigned (83 to vimseltinib and 40 to placebo). 73 (59%) patients were female and 50 (41%) were male. Nine (11%) of 83 patients assigned to vimseltinib and five (13%) of 40 patients assigned to placebo discontinued treatment before week 25; one patient in the placebo group did not receive any study drug. Objective response rate per RECIST was 40% (33 of 83 patients) in the vimseltinib group vs 0% (none of 40) in the placebo group (difference 40% [95% CI 29-51]; p<0·0001). Most treatment-emergent adverse events (TEAEs) were grade 1 or 2; the only grade 3 or 4 TEAE that occurred in more than 5% of patients receiving vimseltinib was increased blood creatine phosphokinase (eight [10%] of 83). One patient in the vimseltinib group had a treatment-related serious TEAE of subcutaneous abscess. No evidence of cholestatic hepatotoxicity or drug-induced liver injury was noted., Interpretation: Vimseltinib produced a significant objective response rate and clinically meaningful functional and symptomatic improvement in patients with TGCT, providing an effective treatment option for these patients., Funding: Deciphera Pharmaceuticals., Competing Interests: Declaration of interests VB reports institutional research funding from Deciphera Pharmaceuticals and participation on a medical advisory board for Deciphera Pharmaceuticals. SS reports institutional research funding from Abbiski, Daiichi Sankyo, and Deciphera Pharmaceuticals, and advisory board roles with Daiichi Sankyo and Deciphera Pharmaceuticals. SB reports honoraria from Blueprint Medicine, Boehringer Ingelheim, Pfizer, PharmaMar, Uptodate, and Deciphera Pharmaceuticals; consulting or advisory roles with Adcendo, Bayer, Boehringer Ingelheim, Cogent Biosciences, Daiichi Sankyo, Lilly, IDRx, and Deciphera Pharmaceuticals; institutional research funding from Adcendo, Blueprint Medicine, Incyte, and IDRx; participation on a board for the University of Aachen; unpaid board of directors positions with The Connective Tissue Oncology Society and Deutsche Sarkomstiftung; and a faculty position with the European Society for Medical Oncology. AJW reports consulting or advisory roles and institutional research funding from Daiichi Sankyo and Deciphera Pharmaceuticals. MvdS reports travel partly supported by Deciphera Pharmaceuticals. NMB reports research support from Deciphera Pharmaceuticals. AAR reports consulting or advisory roles with Boehringer Ingelheim and Medison; institutional research funding from 23andMe, Abbisko, AbbVie, Adaptimmune, Amgen, Bayer, Blueprint Medicines, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GSK, Inhibrx, Iterion Therapeutics, Karyopharm Therapeutics, MedImmune, Medison, Merck, Neoleukin Therapeutics, Pfizer, Rain Therapeutics, Roche/Genentech, Symphogen, and Deciphera Pharmaceuticals; and participation on an advisory board for Inhibrx. AI reports consulting or advisory roles for Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Merck, Merck Sharp & Dohme, Novartis, Parthenon, PharmaMar, and Roche; and institutional research funding from Bayer, Bristol Myers Squibb, Chugai Pharmaceutical, Merck, Merck Sharp & Dohme, Novartis, Parthenon, PharmaMar, and Roche. ALC reports honoraria from Bayer, PharmaMar, and Deciphera Pharmaceuticals. GT reports consulting or advisory roles with Daiichi Sankyo and Servier. KB reports honoraria from Incyte, Lilly, Novartis, and Deciphera Pharmaceuticals; expert testimony for Deciphera Pharmaceuticals; and advisory board participation for Bayer, GSK, and NEC OncoImmunity. JM-B reports consulting or advisory roles for Amgen, Asofarma, Boehringer Ingelheim, Bayer, GSK, Lilly, Novartis, PharmaMar, Roche, and Tecnofarma; speakers bureau involvement for PharmaMar; and institutional research funding from Adaptimmune, Amgen, Ayala Pharmaceuticals, Bayer, Blueprint Medicines, Bristol Myers Squibb, Cebiotex, Celgene, Daiichi Sankyo, Eisai, GSK, IMMIX Biopharma, Inhibrx, Karyopharm Therapeutics, Lilly, Lixte, Novartis, Pfizer, PharmaMar, Philogen, PTC Therapeutics, Rain Therapeutics, and Deciphera Pharmaceuticals; expert testimony for Amgen, Bayer, Boehringer Ingelheim, Eisai, Lilly, PharmaMar, and Roche; travel support from Novartis, Pfizer, and PharMar; advisory board participation for Asofarma and Tecnofarma; and a leadership or fiduciary role for Sarcoma Research solutions. EP reports advisory board roles with Daiichi Sankyo, SynOx, and Deciphera Pharmaceuticals. PRe reports honoraria for participation in advisory boards for Bayer, Blueprint Medicines, Boehringer Ingelheim, Clinigen, GSK, MundiBioPharma, Novartis, PharmaMar, Roche, and Deciphera Pharmaceuticals, and a leadership position for the German Sarcoma Foundation. PRu reports honoraria from AstraZeneca, Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Pierre Fabre, and Sanofi; speakers bureaus for Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, and Pierre Fabre; travel support from Orphan Europe and Pierre Fabre; consulting fees from Bristol Myers Squibb, Merck Sharp & Dohme, Novartis, Pfizer, Philogen, and Pierre Fabre; and institutional research funding from Bristol Myers Squibb, Novartis, Pfizer, and Roche. CT, FZ, and BH report employment with and stock or other ownership interests in Deciphera Pharmaceuticals. MGS reports employment with, stock or other ownership interests in, and travel support from Deciphera Pharmaceuticals. RR-S reports employment with, stock or other ownership interests in, and patents, royalties, or other intellectual property from Deciphera Pharmaceuticals (inventor in pending patents at Deciphera Pharmaceuticals for which the rights have been transferred to Deciphera Pharmaceuticals; RR-S has not received and will not receive any royalties). MLS reports employment in a leadership role with, stock or other ownership interests in, travel support from, and patents, royalties, or other intellectual property from Deciphera Pharmaceuticals (inventor in pending patents at Deciphera Pharmaceuticals for which the rights have been transferred to Deciphera Pharmaceuticals; MLS has not received and will not receive any royalties). J-YB reports honoraria from Bayer and Deciphera Pharmaceuticals; consulting or advisory roles with Bayer and Deciphera Pharmaceuticals; institutional research funding from Bayer and Deciphera Pharmaceuticals; academic support from the French National Cancer Institute (INCA) NETSARC, INTERSARC, and EURACAN; and funding for travel, accommodation, or expenses from OSE Pharma. WDT reports advisory board roles for Aadi Biosciences, Abbisko, Amgen, AmMax Bio, Avacta, Bayer, BioAtla, Boehringer Ingelheim, C4 Therapeutics, Cogent Biosciences, Daiichi Sankyo, Foghorn Therapeutics, IMGT, Inhibrx, Ipsen, Lilly, PharmaEssentia, Servier, Sonata, and Deciphera Pharmaceuticals; owns stock or shares in Atropos and Certis Oncology Solutions; reports a patent for Companion Diagnostics for CDK4 inhibitors (14/854,329) and for Enigma and CDH18 (SKI2016–021–03); and reports institutional funding from Deciphera Pharmaceuticals. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Ewing sarcoma (EwS) is a rare and highly malignant bone tumor primarily affecting children, adolescents, and young adults. The pelvis, trunk, and lower extremities are the most common sites, while EwS of the sacrum as a primary site is very rare, and only few studies focusing on this location are published. Due to the anatomical condition, local treatment is challenging in sacral malignancies. We analyzed factors that might influence the outcome of patients suffering from sacral EwS., Methods: We retrospectively analyzed data of the GPOH EURO-E.W.I.N.G 99 trial and the EWING 2008 trial, with a cohort of 124 patients with localized or metastatic sacral EwS. The study endpoints were overall survival (OS) and event-free survival (EFS). OS and EFS were calculated using the Kaplan-Meier method, and univariate comparisons were estimated using the log-rank test. Hazard ratios (HRs) with respective 95% confidence intervals (CIs) were estimated in a multivariable Cox regression model., Results: The presence of metastases (3y-EFS: 0.33 vs. 0.68; P < 0.001; HR = 3.4, 95% CI 1.7 to 6.6; 3y-OS: 0.48 vs. 0.85; P < 0.001; HR = 4.23, 95% CI 1.8 to 9.7), large tumor volume (≥200 ml) (3y-EFS: 0.36 vs. 0.69; P =0.02; HR = 2.1, 95% CI 1.1 to 4.0; 3y-OS: 0.42 vs. 0.73; P =0.04; HR = 2.1, 95% CI 1.03 to 4.5), and age ≥18 years (3y-EFS: 0.41 vs. 0.60; P =0.02; HR = 2.6, 95% CI 1.3 to 5.2; 3y-OS: 0.294 vs. 0.59; P =0.01; HR = 2.92, 95% CI 1.29 to 6.6) were revealed as adverse prognostic factors., Conclusion: Young age seems to positively influence patients` survival, especially in patients with primary metastatic disease. In this context, our results support other studies, stating that older age has a negative impact on survival. Tumor volume, metastases, and the type of local therapy modality have an impact on the outcome of sacral EwS. Level of evidence: Level 2. This trial is registered with NCT00020566 and NCT00987636., Competing Interests: The authors declare that there are no conflicts of interest., (Copyright © 2024 Victor Rechl et al.)

Background: Conventional cytotoxic drugs are not effective in alveolar soft-part sarcoma (ASPS). Immune checkpoint (programmed cell death protein 1/programmed death-ligand 1) inhibitors (ICIs) are promising drugs in ASPS. A worldwide registry explored the efficacy of ICI in ASPS., Materials and Methods: Data from adult patients diagnosed with ASPS and treated with ICI for advanced disease in expert sarcoma centers from Europe, Australia and North America were retrospectively collected, including demographics and data related to treatments and outcome., Results: Seventy-six ASPS patients, with a median age at diagnosis of 25 years (range 3-61 years), were registered. All patients received ICI for metastatic disease. Immunotherapy regimens consisted of monotherapy in 38 patients (50%) and combination in 38 (50%) (23 with a tyrosine kinase inhibitor). Among the 68 assessable patients, there were 3 complete responses and 34 partial responses, translating into an overall response rate of 54.4%. After a median follow-up of 36 months [95% confidence interval (CI) 32-40 months] since the start of immunotherapy, 45 (59%) patients have progressed on ICI, with a median progression-free survival (PFS) of 16.3 months (95% CI 8-25 months). Receiving ICI in first line (P = 0.042) and achieving an objective response (P = 0.043) correlated with a better PFS. Median estimated overall survival (OS) from ICI initiation has not been reached. The 12-month and 24-month OS rates were 94% and 81%, respectively., Conclusions: This registry constitutes the largest available series of ASPS treated with ICI. Our results suggest that the ICI treatment provides long-lasting disease control and prolonged OS in patients with advanced ASPS, an ultra-rare entity with limited active therapeutic options., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Local treatment is a crucial element in the standard of care for Ewing sarcoma (EWS). While systemic treatment is improved in randomised clinical trials, local treatment modalities are discussed controversially. We analysed the association between local therapy and event-free survival (EFS), overall survival (OS), and local recurrence (LR) in prospectively collected data of patients with localised EWS., Patients and Methods: We analysed data from the international Ewing 2008 study registered between 2009 and 2019 in 117 centres. After induction chemotherapy, patients received surgery, radiotherapy, or a combination thereof. We performed Cox regression, conducted propensity score-weighted sensitivity analysis, and performed subgroup analyses. Hazard ratios (HRs) and 95% confidence intervals are reported., Results: We included 863 patients with localised EWS (surgery alone: 331, combination therapy: 358, definitive radiotherapy: 174). In patients treated with combination therapy compared to surgery alone, EFS HR was 0.84 (0.57-1.24; p = 0.38), OS HR was 0.84 (0.57-1.23; p = 0.41), and LR HR was 0.58 (0.26-1.31; p = 0.19). Hazards of any event were increased in patients treated with definitive radiotherapy compared to surgery only, HR 1.53 (1.02-2.31; p = 0.04). Patients with poor responses to chemotherapy benefitted from combination therapy over definitive surgery with an EFS HR 0.49 (0.27-0.89; p = 0.02). Patients with pelvic tumours benefitted from combination therapy over surgery only regarding LR, HR 0.12 (0.02-0.72; p = 0.02)., Conclusion: Patients with poor responses to chemotherapy benefitted from radiotherapy added to surgery. In the whole group, radiotherapy alone as opposed to surgery alone increased the hazards of any event., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Radiation therapy (RT) is an integral part of Ewing sarcoma (EwS) therapy. The Ewing 2008 protocol recommended RT doses ranging from 45 to 54 Gy. However, some patients received other doses of RT. We analyzed the effect of different RT doses on event-free survival (EFS) and overall survival (OS) in patients with EwS., Methods and Materials: The Ewing 2008 database included 528 RT-admitted patients with nonmetastatic EwS. Recommended multimodal therapy consisted of multiagent chemotherapy and local treatment consisting of surgery (S&RT group) and/or RT (RT group). EFS and OS were analyzed with uni- and multivariable Cox regression models including known prognostic factors such as age, sex, tumor volume, surgical margins, and histologic response., Results: S&RT was performed in 332 patients (62.9%), and 145 patients (27.5%) received definitive RT. Standard dose ≤ 53 Gy (d1) was admitted in 57.8%, high dose of 54 to 58 Gy (d2) in 35.5%, and very high dose ≥ 59 Gy (d3) in 6.6% of patients. In the RT group, RT dose was d1 in 11.7%, d2 in 44.1%, and d3 in 44.1% of patients. Three-year EFS in the S&RT group was 76.6% for d1, 73.7% for d2, and 68.2% for d3 ( P  = .42) and in the RT group 52.9%, 62.5%, and 70.3% ( P  = .63), respectively. Multivariable Cox regression revealed age ≥ 15 years (hazard ratio [HR], 2.68; 95% confidence interval [CI], 1.63-4.38) and nonradical margins (HR, 1.76; 95% CI, 1.05-2.93) for the S&RT group (sex, P  = .96; histologic response, P  = .07; tumor volume, P  = .50; dose, P  = .10) and large tumor volume (HR, 2.20; 95% CI, 1.21-4.0) for the RT group as independent factors (dose, P  = .15; age, P  = .08; sex, P  = .40)., Conclusions: In the combined local therapy modality group, treatment with higher RT dose had an effect on EFS, whereas higher dose of radiation when treated with definitive RT was associated with an increased OS. Indications for selection biases for dosage were found. Upcoming trials will assess the value of different RT doses in a randomized manner to control for potential selection bias., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2023 The Authors.)

A Phyllodes Tumour (PT) is an uncommon fibroepithelial lesion, with three histological grades - benign, borderline and malignant. PTs cause significant challenges in diagnosis, management and prognostication. Recent publications have clarified the definitions and prognostication of PTs. Contemporary data currently challenge international guidelines on PT management. We performed an in-depth literature review to develop a best-practice management algorithm for PTs. Diagnostic recommendations are that neither current imaging techniques, nor fine-needle biopsies, can reliably diagnose a PT. Core needle biopsy is the optimal diagnostic technique. Indeterminate or suspicious lesions are recommended to undergo an excisional biopsy due to the inherently heterogeneous nature of PTs. Management guidelines are that benign PTs should be completely excised, although an involved margin is acceptable in select situations. Borderline PTs should have a clear margin on excision due to their higher risk of recurrence, as well as the potential for a recurrence to progress to a malignant PT. In malignant PTs, a margin of 3 mm is acceptable as there is no reduction in recurrence risk if margins are >3 mm. Routine axillary surgery is not indicated in PTs, with axillary surgery only indicated in a histologically-confirmed positive axilla. Adjuvant treatment recommendations are that borderline and malignant PTs should be discussed at MDT, with radiotherapy considered in both. Chemotherapy should be discussed in malignant PT patients. In summary, we have developed an up-to-date simple algorithm to guide the surgeon's management of patients diagnosed with PTs and reduce excessive surgery., Competing Interests: Declaration of competing interest None., (Copyright © 2022 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.)

Purpose: Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS)., Methods: Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method., Results: Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9); P = .035; HR 0.52 (0.28 to 0.97). Patients age < 14 years benefited from TreoMel-HDT with a 3-years EFS of 39.3% (95% CI, 20.4 to 75.8%) versus 9% (95% CI, 2.4 to 34); P = .016; HR 0.40 (0.19 to 0.87). These effects were similar in the per-protocol collective. This observation is supported by comparable results from the nonrandomized trial EE99R3., Conclusion: In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Osteosarcoma is the most common paediatric and adolescent primary bone malignancy and is highly chemosensitive. Gastrointestinal metastases from osteosarcomas are rare. Bowel perforation secondary to chemotherapy is a potential serious complication reported in ovarian, colorectal and haematological malignancies. We report the first documented case of chemotherapy-mediated bowel perforation in an osteosarcoma patient with gastrointestinal metastases. A man in his 20s, with a history of resected osteosarcoma in remission, presented with abdominal pain. A computed tomography (CT) scan demonstrated a large calcified intrabdominal mass (15×13×9 cm) consistent with new peritoneal disease. After one cycle of palliative ifosfamide and etoposide chemotherapy, he developed a large bowel perforation and neutropenic sepsis consequently requiring resection of the perforated mass. Chemotherapy-induced bowel perforation is a rare but serious complication that should be considered in patients with osteosarcoma, and other chemosensitive malignancies, with intra-abdominal metastases. Recommencement of systemic therapies after bowel complications must be assessed cautiously on a case-by-case basis., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Rhabdomyosarcoma is a rare mesenchymal malignancy with four different morphological subtypes: alveolar, embryonal, pleomorphic and spindle cell/sclerosing. It is the most common soft tissue sarcoma of children and adolescents but occurs less commonly in adults. We describe a male patient in his 20s with sclerosing rhabdomyosarcoma of the left cheek who developed an isolated free flap donor site metastasis in the first instance but subsequently progressed with bilateral pulmonary metastases. Multidisciplinary team involvement in a sarcoma specialist centre is essential and collaboration between the pathologist, radiologist, head and neck surgeon, orthopaedic surgeon, radiation oncologist and medical oncologist were integral in providing optimal management in this patient. Furthermore, this case report highlights this phenomenon of implantation metastasis in a patient with rhabdomyosarcoma, and emphasises the importance of surgical barriers between the resection and reconstruction teams in an oncological case., Competing Interests: Competing interests: AH received consultancy fee from Bayer, Provectus and Q Biotics., (© BMJ Publishing Group Limited 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Alveolar soft-part sarcoma (ASPS) is a rare soft-tissue sarcoma that is unresponsive to chemotherapy. Cediranib, a tyrosine-kinase inhibitor, has shown substantial activity in ASPS in non-randomised studies. The Cediranib in Alveolar Soft Part Sarcoma (CASPS) study was designed to discriminate the effect of cediranib from the intrinsically indolent nature of ASPS., Methods: In this double-blind, placebo-controlled, randomised, phase 2 trial, we recruited participants from 12 hospitals in the UK (n=7), Spain (n=3), and Australia (n=2). Patients were eligible if they were aged 16 years or older; metastatic ASPS that had progressed in the previous 6 months; had an ECOG performance status of 0-1; life expectancy of more than 12 weeks; and adequate bone marrow, hepatic, and renal function. Participants had to have no anti-cancer treatment within 4 weeks before trial entry, with exception of palliative radiotherapy. Participants were randomly assigned (2:1), with allocation by use of computer-generated random permuted blocks of six, to either cediranib (30 mg orally, once daily) or matching placebo tablets for 24 weeks. Treatment was supplied in number-coded bottles, masking participants and clinicians to assignment. Participants were unblinded at week 24 or sooner if they had progression defined by Response Evaluation Criteria in Solid Tumors (version 1.1); those on placebo crossed over to cediranib and all participants continued on treatment until progression or death. The primary endpoint was percentage change in sum of target marker lesion diameters between baseline and week 24 or progression if sooner, assessed in the evaluable population (all randomly assigned participants who had a scan at week 24 [or sooner if they progressed] with target marker lesions measured). Safety was assessed in all participants who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01337401; the European Clinical Trials database, number EudraCT2010-021163-33; and the ISRCTN registry, number ISRCTN63733470 recruitment is complete and follow-up is ongoing., Findings: Between July 15, 2011, and July 29, 2016, of 48 participants recruited, all were randomly assigned to cediranib (n=32) or placebo (n=16). 23 (48%) were female and the median age was 31 years (IQR 27-45). Median follow-up was 34·3 months (IQR 23·7-55·6) at the time of data cutoff for these analyses (April 11, 2018). Four participants in the cediranib group were not evaluable for the primary endpoint (one did not start treatment, and three did not have their scan at 24 weeks). Median percentage change in sum of target marker lesion diameters for the evaluable population was -8·3% (IQR -26·5 to 5·9) with cediranib versus 13·4% (IQR 1·1 to 21·3) with placebo (one-sided p=0·0010). The most common grade 3 adverse events on (blinded) cediranib were hypertension (six [19%] of 31) and diarrhoea (two [6%]). 15 serious adverse reactions in 12 patients were reported; 12 of these reactions occurred on open-label cediranib, and the most common symptoms were dehydration (n=2), vomiting (n=2), and proteinuria (n=2). One probable treatment-related death (intracranial haemorrhage) occurred 41 days after starting open-label cediranib in a patient who was assigned to placebo in the masked phase., Interpretation: Given the high incidence of metastatic disease and poor long-term prognosis of ASPS, together with the lack of efficacy of conventional chemotherapy, our finding of significant clinical activity with cediranib in this disease is an important step towards the goal of long-term disease control for these young patients. Future clinical trials in ASPS are also likely to involve immune checkpoint inhibitors., Funding: Cancer Research UK and AstraZeneca., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aim: Fluorescence in situ hybridization (FISH) is an important ancillary tool for the classification of bone/soft tissue (BST) tumors. The aim of this study was to evaluate the contribution of FISH to the final classification of common BST entities in the molecular pathology department of the Royal Prince Alfred Hospital (RPAH), which is one of the most important referral centers for the management of sarcomas in Australia., Methods: All routine diagnostic FISH tests performed on BST formalin-fixed paraffin embedded (FFPE) tissue specimens at the RPAH in a 5-year period (February, 2010-November, 2015) were reviewed. FISH analyses presented in this study include commercial break-apart probes (SS18, FUS, DDIT3, FUS, USP6, PDGFB, TFE3 and ALK) and a single enumeration (MDM2) probe., Results: There were 434 interpretable FISH assays on BST samples including MDM2 (n=180), SS18 (n=97), FUS (n=64), DDIT3 (n=37), USP6 (n=30), PDGFB (n=13), TFE3 (n=8) and ALK (n=5). Discrepancies between the histopathological diagnosis and the FISH results were seen in 12% of the cases. In this subset of discordant cases, FISH contributed to the re-classification of 7% of cases originally diagnosed as synovial sarcoma (SS18) and 6% of adipocytic neoplasms (MDM2) based on the presence or absence of the expected gene alteration., Conclusion: Our study confirms that paraffin FISH is a sensitive and specific ancillary tool in the diagnosis of BST neoplasms when used in the appropriate clinicopathological context. These findings highlight the need for further ancillary molecular tools in the diagnosis and characterization of challenging cases., (© 2018 John Wiley & Sons Australia, Ltd.)

Background: Febrile neutropenia is a common complication in children undergoing chemotherapy for malignancies. A microbial agent is only identified in 15-30% of the fever episodes and corresponds mostly to bacterial findings., Objective: To investigate viral infections as possible etiologic agents in episodes of febrile neutropenia., Study Design: Nasopharyngeal aspirates (NPAs) from patients presenting with neutropenic fever at two pediatric oncology wards in Sweden and Australia were analyzed with a conventional virus-diagnostic approach and RT-PCR. Coupled blood samples were analyzed for the detection of CMV, EBV, adenovirus and erythrovirus. Bacterial blood culture was performed routinely., Results: Conventional virus-diagnostic approach coupled to routinely performed bacterial analyzes revealed an infectious agent in 29% compared to 60% when using PCR. By adding PCR, a viral pathogen was detected in 46% of the NPAs and in 4% of the blood samples collected. In half of the patients with bacteremia, respiratory tract viruses were co-detected., Conclusion: Respiratory viruses were frequently detected in NPAs suggesting a significant role of viral infections in children presenting with neutropenic fever. The meaning of these findings needs to be further evaluated but has the potential to individualize infection treatment and to reduce the extensive use of antibiotics in immunocompromised children with neutropenia.